Complicated appendicitis: value of inflammatory markers based on EAES 2015 guidelines

Patient characteristics and clinical findings

A total of 559 patients were included in the study (Table 1), with a median age of 38 years (IQR: 26–58) and a median BMI of 25.6 kg/m2 (IQR: 22.9–29.2). The cohort consisted of 301 (53.8%) male and 258 (46.2%) female patients. The median BMI was 25.6 (IQR: 22.9–29.2) with the majority of patients (42.8%) having a BMI within the normal range (18.5–24.9 kg/m2), while 34.4% were classified as overweight (25.0–29.9 kg/m2), and 20.8% were obese (≥ 30.0 kg/m2). Diabetes was present in 7.2% of patients. Regarding the American Society of Anesthesiologists (ASA) classification, most patients had an ASA score of I (33.9%) or II (54.1%), with 12.0% classified as ASA ≥ III. Inflammatory markers showed a median leucocyte count of 14.1 Gpt/L (IQR: 11.2–17.2) and a median C-reactive protein (CRP) level of 23.4 mg/L (IQR: 5.2–72.4). Complicated appendicitis according to guidelines of the European Association of Endoscopic Surgery from 2015 (EAES) was observed in 349 patients (62.5%), including phlegmonous (30.8%), gangrenous (10.2%), abscess-forming (6.3%), and perforated (15.0%) appendicitis. Uncomplicated appendicitis was diagnosed in 209 patients (37.5%). Postoperative complications occurred in 60 patients (10.7%), with 6.3% classified as minor complications (Clavien-Dindo < IIIA) and 4.4% as major complications (Clavien–Dindo ≥ IIIA).

Table 1 Patient characteristicsCRP level as biomarker for the severity of acute appendicitis

CRP levels were significantly higher in complicated compared to uncomplicated appendicitis (Median 48.4 vs. 8.8 mg/L, p < 0.001; Fig. 1a). Subgroup analysis showed progressively increasing CRP levels with disease severity, with the highest values observed in abscess-forming and perforated cases (Fig. 1b–c). The diagnostic performance of CRP in distinguishing CAA from UAA was good (AUC 0.76, 95% CI: 0.72–0.80), with an optimal cutoff of 52.65 mg/L (sensitivity 49%, specificity 95%) (Fig. 1d).

Fig. 1figure 1

Preoperative CRP concentrations of patients with uncomplicated (UAA) and complicated (CAA) acute appendicitis. a Comparison of patients with uncomplicated- and complicated acute appendicitis, including cases of phlegmonous appendicitis according to EAES guidelines (p < 0.001). b Subgroup analysis of acute appendicitis revealed a progressive increase in preoperative CRP concentration in correlation with disease severity compared to UAA (Kruskal–Wallis test, p < 0.001). c A forest plot illustrating the effect size of disease severity on CRP concentration. The dots represent the median values, while the horizontal lines indicate the 95% confidence intervals. A value of 0 represents no effect in CRP concentration. d Receiver operating characteristic (ROC) analysis of preoperative CRP concentration demonstrated a good predictive value for distinguishing CAA (AUC: 0.76; CI: 0.72–0.80). The red dashed line represents an AUC of 0.5, indicating no predictive ability

Leucocyte counts and their prognostic value in appendicitis classification

Leukocyte counts were slightly higher in patients with complicated vs. uncomplicated appendicitis (Median 14.5 vs. 13.4 Gpt/L, p = 0.003), but subgroup differences were modest. Diagnostic performance was poor (AUC 0.57, 95% CI: 0.53–0.62), with an optimal cutoff of 16.65 Gpt/L (sensitivity 34%, specificity 80%) (Fig. 2).

Fig. 2figure 2

Preoperative Leucocyte counts of patients with uncomplicated (UAA) and complicated (CAA) acute appendicitis. a Comparison of preoperative Leucocyte counts of patients with acute appendicitis b The subgroup analysis using one-way ANOVA reveals no difference between UAA and phlegmonous appendicitis. However, leucocyte counts were higher in patients with gangrenous- and perforated acute appendicitis compared to UAA. c Forest plot of posthoc analysis utilizing Bonferroni multiple comparison test illustrates that leucocyte counts differ only between phlegmonous- (PHL) and gangrenous appendicitis (GAN), as well as phlegmonous- (PHL) and perforated appendicitis (PER). There was no other significant difference of leucocytes between subgroups of CAA. A d ROC analysis demonstrates only poor diagnostic performance of leucocyte count for the presence of CAA

CRP and leucocyte count and the risk of postoperative complications in acute appendicitis

A total of 558 patients were included in the analysis. 54 of 349 (15.47%) patients had postoperative complications (30d-morbidity) after complicated acute appendicitis (CAA), whereas only 6 of 209 (2.87%) patients suffered complications after surgery for uncomplicated acute appendicitis (UAA) (χ2 = 21.63, p < 0.001, Fig. 3a). Figure 3b illustrates the proportions of postoperative complications across appendicitis subtypes. 19 of 172 (11.0%) patients with phlegmonous appendicitis (PHL) and 3 of 54 (5.28%) patients with gangrenous appendicitis developed postoperative complications. 6 of 35 (17.14%) with abscesses and 26 of 84 (30.95%) patients with perforated appendicitis had postoperative complications.

Fig. 3figure 3

The influence of CRP levels and leucocyte counts on the risk of postoperative complications. a The proportion of postoperative complications in complicated acute appendicitis (CAA) (p < 0.001) is higher than in UAA. b Also, the proportion of postoperative complications varies between subgroups of CAA (p < 0.001). c Patients with postoperative complications (Co +) had elevated CRP concentrations preoperatively compared to patients without development of complications (Co-). d However, preoperative leucocyte counts did not differ between patients with complications and patients without complications

The odds ratio (OR) was 6.19 (95% CI: 2.64–13.55), indicating that patients with CAA had 6.2-fold higher odds of experiencing postoperative complications compared to those with UAA (not shown). The logistic regression model demonstrated that the severity of appendicitis according to EAES guidelines influenced postoperative complications (LR χ2(4) = 55.08, p < 0.001, Table 2). Patients with perforated appendicitis had the highest estimated odds for complications (aOR: 8.1, 95% CI: 4.2–15.2, p < 0.001). Abscess-forming appendicitis was also associated with an increased odds for complications (aOR: 5.7, 95% CI: 2.8–11.4, p = 0.001). Gangrenous appendicitis (aOR: 4.5, 95% CI: 2.1–9.5; p = 0.002) and phlegmonous appendicitis (aOR: 2.3, 95% CI: 1.2–4.3, p = 0.015) were linked to a moderate but relevant increase in complications. Also, there was a difference in CRP levels between patients with and without postoperative complications (z = − 5.633, p < 0.001; Fig. 3c), indicating that elevated CRP levels were associated with a higher risk of complications. Patients who developed postoperative complications had a median CRP level of 96.6 mg/L (IQR: 19.8–189.6) compared to 22.14 mg/L (IQR: 4.8–63.2) in those without complications. In contrast, leucocyte counts did not relevantly differ between the groups (z = − 0.596, p = 0.5513) (Fig. 3d).

Table 2 Risk of postoperative complications by appendicitis subtype

All subtypes of complicated acute appendicitis (CAA) showed increased odds for development of postoperative complications compared to uncomplicated acute appendicitis (UAA). Phlegmonous appendicitis (PHL) classified as CAA according to EAES guidelines had a 2.3-fold increase of odds compared to UAA to develop postoperative complications.

Association between CRP and leucocyte count and length of hospital stay

We compared the length of hospital stay between patients with uncomplicated (UAA) and complicated appendicitis (CAA) (Fig. 4a). The analysis revealed a difference between the two groups (Z = − 8.239, p < 0.001). Patients with CAA had a longer median hospital stay (Median = 4 days, IQR = 3–6) compared to those with UAA (Median: 3 days, IQR: 3–4). Figure 4b shows the subgroup analysis with differences of hospital stay between UAA (Median = 3; IQR: 3–4) and phlegmonous- (Median = 4; IQR: 3–5; p = 0.022), gangrenous- (p < 0.001), and perforated appendicitis (Median = 6; IQR: 5–8; p < 0.001), as well as abscesses (Median = 5; IQR: 4–7; p < 0.001), respectively. Post hoc analysis showed longer length of hospital stay for perforated appendicitis compared to other subgroups (all p < 0.001), except for abscesses (p > 0.999). Phlegmonous- and gangrenous appendicitis also did not show a difference in length of stay (p > 0.713).

Fig. 4figure 4

Association between CRP levels, leucocyte count, and length of hospital stay in patients with uncomplicated (UAA) and complicated appendicitis (CAA). a The length of stay in hospital is increased in complicated acute appendicitis (CAA) compared to uncomplicated acute appendicitis (p < 0.001). b Subgroup analysis with the results of Kruskal–Willis test and Dunn’s posthoc analysis with multiple comparisons. c Spearman’s correlation analysis reveals only moderate correlation between CRP concentration and hospitalization. d Preoperative leucocyte counts do not correlate with length of stay (p = 0.332)

To test the association between intraoperative classification of appendicitis according to EAES guidelines on length of hospital stay, we performed a negative binomial regression model (Table 3), which revealed an association between the intraoperative classification of appendicitis and the length of hospital stay (LR χ2(4) = 138.03, p < 0.001). The analysis demonstrated that patients with CAA had longer hospitalizations compared to those with UAA. In this model, patients with perforated appendicitis (PER) had the longest estimated hospital stay (β = 0.64, p < 0.001), corresponding to an incidence rate ratio (IRR) of 1.89 (95% CI: 1.68–2.12), indicating a 89% increase (almost twofold) in hospital length of stay compared to the reference of UAA. Similarly, abscess-forming appendicitis (ABS) was associated with a 64% longer hospital stay (β = 0.49, p < 0.001; IRR = 1.64, 95% CI: 1.39–1.91). Gangrenous appendicitis (GAN) was linked to a 30% increase in hospitalization (β = 0.26, p = 0.001; IRR = 1.30, 95% CI: 1.12–1.47), while phlegmonous appendicitis (PHL) resulted in a 21% longer hospital stay (β = 0.19, p < 0.001; IRR = 1.21, 95% CI: 1.09–1.35).

Table 3 Adjusted incidence rate ratios (IRRs) for length of hospital stay by appendicitis subtype

Next, we investigated the dependency of length of hospital stay on preoperative CRP concentration and leucocyte counts utilizing Spearman’s correlation analysis (Fig. 4c, d). CRP levels moderately correlated with hospital stay (r = 0.36, p < 0.001), whereas leukocyte count showed no relevant association (p = 0.332).

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