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Study of the association of serum procalcitonin with leukocytosis in predicting complicated acute appendicitis

Background: Delay in the diagnosis of complicated appendicitis and its treatment results in an increased rate of postoperative morbidity, mortality and hospital stay. The diagnosis of appendicitis rests on a combination of signs of inflammation such as fever, pain and tenderness; leukocytosis, and elevated C-reactive protein levels, interleukin-6 (IL6) and procalcitonin. Raised level of serum procalcitonin in bacterial infection has been used to further improve the diagnosis of complicated AA.Methods: One-hundred ten patients of appendicitis confirmed by intra-operative findings and final pathologist report, who underwent appendectomy consisting 25 women (22.73%) and 85 men (77.27%) with a mean age of 25 years (age range 15-55 years) were included in this study. Serum procalcitonin value was measured by chemi E411 Cobas method (chemilumiscent immunoassay system) using the B.R.A.H.M.S PCT kit. Serum PCT level >0.5 ng/ml was consider as risk for progression to severe systemic disease.Results: At a 0.5 ng/dl cut-off value of PCT, the sensitivity and specificity of PCT level measurement for acute complicated appendicitis prediction was 90% and 97.14% respectively. Association between WBC count and PCT value shows the sensitivity and specificity in 40 case of acute complicated appendicitis prediction was 86% and 75% respectively.Conclusions: Both the higher PCT values and leukocytosis correlates well with  infectious post-operative complications for acute appendicitis and it can help to carry out timely surgical intervention which is highly recommended in complicated appendicitis(correlates PCT >0.5 ng/dl).


INTRODUCTION
It is estimated that as much as 6% to 7% of the general population will develop appendicitis during their lifetime, with the incidence peaking in the second decade of life. 1 As appendicitis progresses, the blood supply is impaired by bacterial infection in the wall and distention of the lumen; gangrene and perforation occurs at about 24 hours, though the timing is highly variable. Gangrene implies microscopic perforation, bacterial contamination of the peritoneum, and peritonitis. This process may be effectively localized by adhesions from nearby viscera. 2 Appendectomy remains one of the most commonly performed operations worldwide. 3 Following the introduction and widespread use of antibiotics in the 1940s, mortality rates improved further. C-reactive protein, bilirubin, Il-6, and procalcitonin have all been suggested to be helpful in the diagnosis of appendicitis, specifically in predicting perforated appendicitis. 4 Delay in diagnosis and treatment results in an increased rate of perforation, postoperative morbidity, mortality and hospital stay.

Aim
The aim of this study was to assess the value of procalcitonin as a predictor of severity of appendicitis in order to improve the clinical decision making. 5,6 Objectives Primary objective: To assess the value of procalcitonin as a predictor of severity (inflamed, gangrenous, perforated) of appendicitis in order to improve the clinical decision making for timely intervention.
Secondary objective: To establish relation between PCT, leukocytosis histopathological finding of appendix and its correlation with post-operative complications.

METHODS
Study design was hospital based cross sectional study. Study was conducted in between 1 January 2018 to 31 November 2019. Study area was Department of general surgery of SMS hospital, SMS medical college, Jaipur.
Study population was selected as per the inclusion and exclusion criteria.

Inclusion criteria
Those patients who have given written and informed consent, Age group 15-50 years in either sex, all patients without exclusion criteria, who underwent appendectomy, in which peri-operatively complicated appendicitis were found.

Exclusion criteria
Diagnosis other than acute appendicitis confirmed during the operation, Presence of another acute infectious lesion or disease in any other part of the body, immunosuppressive disease like HIV.
Sample size was calculated at 95% confidence level assuming 65% specificity of PCT to detect peritonitis due to appendicitis and prevalence of peritonitis due to appendicitis was 9.5%. At 10% absolute allowable error sample size was found 102 patients of peri-operatively complicated confirmed appendicitis which was further rounded off to 110 such patients.

Methodology
Patients diagnosed with symptomatic appendicitis were selected based on the clinical signs or USG report. The patients were informed about the details of the procedure and written informed consent was obtained. All routine blood tests specifically TLC and serum procalcitonin were assessed. And all the cases divided in two groups on the basis of procalcitonin value. Serum procalcitonin value was measured by chemi E411 Cobas method (chemilumiscent immunoassay system) using the B.R.A.H.M.S PCT kit.
Status of the appendix (peri-operative finding) and histological diagnosis (normal/ inflamed/ gangrenous/ perforated) was recorded. Patients were analyzed whether they have uncomplicated or complicated appendicitis, complicated appendicitis patients were those having gangrenous or perforated appendix with or without appendicular abscess formation. Serum procalcitonin value <0.5 ng/ml was considered normal. Patients with procalcitonin value >0.5 ng/ml (value as a risk for progression to severe systemic disease) were consider positive. Similarly TLC >10,000 was taken significant.
Statistical analysis was performed by MS excel worksheet 2007. Analysis of distribution of data was assessed by the Chi-square test.

RESULTS
One-hundred ten patients of appendicitis confirmed by intra-operative findings and final pathologist report, who underwent appendectomy consisted of 25 women (22.73%) and 85 men (77.27%) with a mean age of 25 years (age range 15-55 years) were included in this study.
Mean age was 25 years with standard deviation 31.8. Age group 15-24 years and 25-34 years had the most common incidence of appendicitis. Procalcitonin value in 73 patients (26.03% female and 73.97% male patients) was less than 0.5 ng/ml and thence considered negative. In the remaining 37 patients (16.22% female and 83.78%male patients), serum PCT value was more than 0.5 ng/ml and these considered positive (Table 2).    Out of 18 patients with necrotizing appendicitis, 16 (88%) patients had PCT level more than 0.5 ng/ml while only 22 (23%) patients out of 92 were having high levels of PCT in uncomplicated appendicitis group.
Peritonitis due to perforated appendicitis was confirmed in 25 patients intra-operatively. Among 25 patients with peritonitis, 21 patients had a PCT value more than 0.5 ng/ml.
Post-operative complications including surgical site infection (SSI) was detected in 8 patients. In 8 cases of surgical site infection, 7 patient had a PCT value more than 0.5 ng/ml, and one patient had a negative PCT value.
The corresponding sensitivity for detecting peritonitis, necrotizing appendicitis and surgical site infection were 84%, 88.89% and 87.5% and their specificity were 80%, 76.09% and 69.61% respectively. Association between WBC count and PCT value shows the sensitivity and specificity in 40 case of acute complicated appendicitis prediction was 86% and 75% respectively.

DISCUSSION
This study included 110 patients with 25 females and 85 males with a mean age of 25 years.
Based on the intra-operative findings (abscess, gangrenous or perforated appendix), each case was labelled as uncomplicated appendicitis or complicated appendicitis. Peritonitis due to perforated appendicitis was confirmed in 25 patients intra-operatively.
Post-operative complications including surgical site infection (SSI) was detected in 8 patients.
Procalcitonin value in 72 patients was less than 0.5 ng/ml and hence considered negative. In the remaining 38 patients, serum PCT value more than 0.5 ng/ml.
Among 25 patients with peritonitis, 21 patients had a PCT value more than 0.5 ng/ml. In 8 cases of surgical site infection, 7 patient had a PCT value more than 0.5 ng/ml, and one patient had a negative PCT value.
At a 0.5 ng/dl cut-off value of PCT, the sensitivity and specificity of PCT level measurement for acute complicated appendicitis prediction was 90% and 97.14% respectively.
The PPV and NPV of PCT in complicated appendicitis were (94.74%) and (94.44%) respectively The corresponding sensitivity for detecting peritonitis, necrotizing and surgical site infection were 84%, 88.89% and 87.5% and their specificity were 80%, 76.09% and 69.61% respectively.
Chandel et al in their study of 40 patients found sensitivity (95.65%), specificity (100%) and predictive values PPV (100%) and NPV (83.3%) of serum PCT levels as the diagnostic test for the diagnosis of acute appendicitis. 8 Gavela et al study done for diagnosis of peritonitis, a PCT cutoff of 0.18 ng/ml gave a sensitivity of 97%, specificity of 80%, positive predictive value of 72%, and negative predictive value of 89.3%. 9 In Kafetzis et al study, there was a statistically significant indication (p<0.0001) that PCT levels >0.5 ng/ml were observed more frequently in cases of perforated or necrotizing appendicitis than in simple appendicitis. 10 A PCT level of >0.5 ng/ml can indicate perforation or gangrene with 73% sensitivity and 94% specificity.
Sand et al noted that the sensitivity of PCT for the diagnosis of acute appendicitis was 0.14, with a specificity of 1. 12 13 In diagnosing appendicitis and complicated appendicitis the AUC were 0.69 and 0.76 for PCT respectively.
Yamashita et al consider five parameters-plasma procalcitonin level (PCT), body temperature (BT), white blood cell count (WBC), neutrophil/lymphocyte ratio (N/L ratio), and C-reactive protein level (CRP). 14 Univariate analysis of the predictors of abscess and/or perforation revealed that a plasma PCT level ≥0.46 ng/mL had the highest odds ratio (30.3 [95% confidence interval: 6.5-140.5] versus PCT <0.46 ng/ml). These findings indicate that procalcitonin is a useful marker of acute appendicitis with abscess and/or perforation.
Yu et al study ROC curve analysis showed that WBC had high accuracy (area under ROC curve 0.72 per cent C.I. 0·68 to 0·76), followed by procalcitonin (0.65, 0.61 to 0·69). 15 Procalcitonin was found to be more accurate in diagnosing complicated appendicitis, with a pooled sensitivity of 62 (33 to 84) per cent and specificity of 94 (90 to 96) per cent.
In present study WBC count and PCT value shows the sensitivity and specificity in 40 case of acute complicated appendicitis prediction was 86% and 75% respectively.

CONCLUSION
In complicated acute appendicitis leukocytosis suggest further PCT measurement. The PCT values can be used as predictor of complicated appendicitis and infectious complications following surgery for acute appendicitis and it can help to carry out timely surgical intervention which highly is recommended in patients with values more than 0.5 ng/ml and increased PCT values correlates well with leukocytosis and also in this high litigation era both values can guide you to explain the incidence of possible surgical site complication in complicated appendicitis to the patients and its attendants.