Comparison of Clinical Features Between Patients with Positive and Negative Appendectomy

Objective: The objective of this study was to retrospectively compare clinical features and prognostic values between the patients who were referred to the general surgery clinic of our hospital with the presumed diagnosis of acute appendicitis and underwent positive or negative appendectomy. Methods: Patients were divided into two groups as positive (PA) (n:425) and negative appendectomy (NA) (n:425) and the data obtained were compared between these two groups. Laboratory investigations were performed in all patients, and white blood cell (WBC), mean platelet volume (MPV), neutrophils count (NEU), neutrophils (%) (NEU%), C-reactive protein (CRP) and total bilirubin (TBIL) values were studied. Results: The mean MPV value was found as 7.66 in PA groups and 7.90 in NA group, and the mean MPV value was statistically signi�cantly lower in PA group, compared to NA groups (p=0.034). The mean TBIL value was 0.75 in PA group and 0.90 in NA group, and the mean TBIL value was statistically signi�cantly lower in PA group (p=0.034).There was no statistically signi�cant difference between the two groups in terms of the other studied laboratory parameters (for all p>0.05). Conclusion: The mean MPV and TBIL values can be used as speci�c biomarkers in predicting positive acute appendicitis. We believe that these results will contribute to the literature and will be guiding for future studies.


Introduction
Appendicitis is the most common emergency surgery, with a lifetime risk for appendicitis estimated as 8.6% in men and 6.7% in women (1).In Europe, 112/100000 persons present to emergency departments each year due to acute appendicitis (2).The rate of morbidity from acute appendicitis has been reported between 7%-16% in the general population (3).Appendicitis usually presents with anorexia and tenderness in the right lower abdominal quadrant (4).However, pain in the right lower quadrant can be associated with numerous pathologies.Because of the wide spectrum of differential diagnosis and lack of speci c markers for appendicitis, preoperative diagnosis of this disease is quite challenging (5).
Today, the incidence of appendicitis is increasing in developing countries (6).Since serious complications may occur in the case of delayed diagnosis, prompt action is necessary.The management of appendicitis focuses on the prevention with a timely intervention before an uncomplicated appendicitis progresses to a complicated one.Appendectomy, which is sometimes performed on a normal appendicitis is known as "negative appendectomy" (NA) (7).
Complications of acute appendicitis include perforation, peritonitis and sepsis (8).This can increase the rate of negative appendectomy operations.Negative appendectomy rate (NLR) is de ned as the incidence of removing appendices that are pathologically normal (9).Negative appendectomy leads to prolonged hospitalization, morbidity and increased costs.In addition, negative appendectomy may be associated with severe postoperative complications.Therefore, an accurate preoperative diagnosis is essential in the cases of suspected acute appendicitis.In the United States of America (USA) over 250000 appendectomy operations are performed yearly, and the rate of negative is approximately 15% in these operations (10).However, owing to better imaging modalities, a constant decrease is seen in the rate of NAs (11).Gynecological pathologies in female patients in child bearing period mimic acute appendicitis, which can cause an increase in the rate of negative NAs (12).
According to the current guidelines, the diagnosis of acute appendicitis is established according to clinical examination and con rmed with imaging investigations and some biomarkers including WBC count and CRP (13).Computed tomography (CT) and ultrasonography are used as imaging modalities in order to set a more accurate diagnosis.
The objective of this study was to retrospectively compare clinical features and prognostic values between the patients who were referred to the general surgery clinic of our hospital with the presumed diagnosis of acute appendicitis and underwent positive or negative appendectomy.

Material & Methods
Data of a total of 2368 patients who were referred to our general surgery clinic with the presumed diagnosis of appendicitis and underwent appendectomy between .... and ...... were retrospectively evaluated.Among these patients, 1518 were excluded from the study because of missing data, and those who underwent interval appendectomy, and incidental appendectomy, and the patients for whom appendectomy operation was delayed due to conservative treatment.Finally, data of 850 patients were obtained and evaluated.Patients aged between 1-90 years.Patients were divided into two groups as positive (PA) (n:425) and negative appendectomy (NA) (n:425) and the data obtained were compared between these two groups.
Patients' demographic data such as age and gender, date and type of operations, investigations, clinical presentation, macroscopic and microscopic ndings, imaging and pathological ndings were recorded and analyzed.In addition, laboratory investigations were performed in all patients, and white blood cell (WBC), mean platelet volume (MPV), neutrophils count (NEU), neutrophils (%) (NEU%), C-reactive protein (CRP) and total bilirubin (TBIL) values were studied.
Inclusion criteria included all patients operated during..... years.Considering clinical conditions of the patients and in the cases of uncertain diagnosis or where the clinical picture did not meet physical ndings (age, pregnancy, having gynecological examination, comorbidities etc.) abdominopelvic computed tomography and ultrasonography examinations were performed in some patients.The diagnosis of appendicitis was established based on macroscopic ndings.Histological diagnosis of appendicitis was set according to the in ltration of muscularis propria with neutrophils granulocytes.
Appendectomy operations were performed by conventional or laparoscopic methods.
Lack of the appendicitis in the pathology reports was considered negative appendectomy.In order to identify appendectomy cases with negative samples, pathology reports were interpreted by an author blinded to whether preoperative imaging was performed.Negative appendectomy was de ned as a normal appendix following the resection due to suspected appendicitis or medically unnecessary appendectomy.Medically unnecessary appendectomy was de ned as an appendectomy operation performed in the case of typically contraindicated surgery.

Ethics Considerations
Before the beginning of the study, necessary ethics approval was received from the local ethics committee of our hospital.Since the study had a retrospective design, receiving informed consent from the patients was waived.The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Statistical Analysis
Data obtained in the study were analyzed utilizing SPSS version 23.0 (Statistical Package for Social Sciences, SPSS, IBM Incusing Chicago, IL, USA) statistical package software.Normality of the variables was analyzed with the Kolmogorov-Smirnov test.In the comparison of the variables between the groups, Independent Student t test among was used for the normally distributed variables, and Mann-Whitney U test for non-normally distributed variables.Continuous variables were expressed with mean ± standard deviation, while categorical variables were given as frequency and percentage.p < 0.05 values were considered statistically signi cant.

Results
A total 0f 850 patients were included in the study with 425 (50%) being in PA group and 425 (50%) in NA group.Of all patients included in the study, 480 (56.5%) were male and 370 (43.5%) were female.A total of 249 (58.6%) patients were male and 176 (41.4%) were female in PA group.Whereas, 231 (50.1%) were male and 212 (49.9%) were female in the NA group.No statistically signi cant difference was seen between both groups in terms of gender (p > 0.05).
The mean age of all patients was 30.1 ± 16.9 years, and the mean age was found as 28.2 ± 16.65 years in PA group and 31.9 ± 17.4 years in NA group.There was no statistically signi cant difference between PA and NA groups in terms of age (p > 0.05).
Appendectomy operations were performed with laparoscopic method in 199 (46.8%) of the patients in PA group and in 207 (48.7%) of the patients in NA group.The remaining patients underwent open surgery.
When status of having gynecological examination was examined among the female patients; 136 (77.3%) female patients in PA group and 177 (83.5%) female patients in NA group underwent gynecological examination.
Laboratory outcomes were examined and compared between the two groups.Accordingly, the mean WBC value was found as 9.77 in PA group and 9.70 in NA group, and there was no statistically signi cant difference between both groups (p = 0.756).The mean MPV value was found as 7.66 in PA groups and 7.90 in NA group, and the mean MPV value was statistically signi cantly lower in PA group, compared to NA groups (p = 0.034).NEU (%) value was found as 73.95 in PA group and 74.74 in NA group.No statistically signi cant difference was observed between the two groups in terms of the mean NEU (%) value (p = 0.388).The mean neutrophil count was found as 7.04 in the PA group and 7.29 in NA group, and no statistically signi cant difference was found between the two groups (p = 0.269).The mean CRP value was found as 58.86 in PA group and 49.62 in NA group.There was no statistically signi cant difference between both groups in terms of the mean CRP value (p = 0.097).When total bilirubin values were examined; the mean TBIL value was 0.75 in PA group and 0.90 in NA group, and the mean TBIL value was statistically signi cantly lower in PA group (p = 0.034).
In our study, the examined laboratory parameters were also compared between genders.Accordingly, the mean MPV value was statistically signi cantly lower in male patients compared to female patients in PA group (p = 0.013).NEU (%) value was statistically signi cant between genders both in PA and NA groups.Accordingly NEU (%) value was statistically signi cantly lower in male patients compared to female patients in both PA and NA groups (p = 0.005, p < 0.001; respectively).Neutrophil count was statistically signi cantly lower in male patients in NA group (p = 0.036).Finally, TBIL value was statistically signi cantly lower in female patients compared to male patients in NA group (p = 0.022).
When diameters of appendicitis were evaluated; the mean appendicitis diameter was found as 1.33 cm in PA group and 1.12 cm in NA group, and the mean appendicitis diameter was statistically signi cantly higher in PA group compared to NA group (p < 0.001) (Table 1).

Discussion
Surgical excision of a normal appendicitis exposes patients to unnecessary anesthesia and surgical complications, and this may be resulted from improper clinical evaluation, and lack of diagnostic methods.Despite the high incidence of acute appendicitis and use of laboratory markers and imaging modalities, the accurate diagnosis remains challenging.Research of the diagnostic process used for acute appendicitis is highly dynamic, within this context information such as novel in ammatory biomarkers is constantly reported in the literature (14).As in our country, high rates of appendicitis cases have been reported in some other countries (15).Therefore, more effort should be made in order to reduce the incidence of NAR and its complications on patients and hospitals (16).Negative appendectomies lead to both postoperative complications, increased morbidity and mortality rates and costs.Thus, investigation of the factors leading to negative appendectomies is of paramount importance.Among these factors, laboratory parameters take an important place.However, to our knowledge there is no consensus in the literature on this subject.In our study, we rst evaluated laboratory values between positive and negative appendectomy cases.
We performed preoperative computed tomography by excluding elderly patients, pediatric patients and those with comorbidities.We observed that the rate of negative appendectomy was lower in patients who underwent CT (24.3%).In a study by Wagner et al., the rate of performing preoperative CT raised to 95% from 32% within 10 years (17).
In our study, 84.6% of female patients were found to have a gynecological examination.In a study by Joshi et al. 57.1% of female patients were reported to have gynecological examination (16).We believe that higher gynecological examination rate in our study resulted from the necessity of transvaginal ultrasound in addition to abdominal ultrasound in cases of suspected gynecological diseases in young women in order to reduce the incidence of negative appendectomy.
Recently, although diagnostic value of laboratory parameters such as MPV, RDW and NLR has been evaluated in patients with suspected appendicitis, results of these studies are highly controversial (18).
MPV is a measurement of thrombocyte size that is obtained as a part of routine complete blood count, and is usually overlooked by clinicians (19).Changes in platelet counts can lead to changes in MPV.The size and activity of platelets can be in uenced by cytokines such as interleukin IL-3 and IL-6.Elevated MPV levels have been reported in several diseases including chronic obstructive pulmonary disease (COPD), myocardial infarction, diabetes mellitus and high altitude (20).Increases in MPV levels are associated with chronic diseases, while decreases are related to acute diseases (21).In our study, the mean MPV value was statistically signi cantly lower in the PA group compared to NA groups (p = 0.034).Although there are a few studies about the role of MPV in acute appendicitis, the results of these studies are variable (20,22).In a study comparing the healthy control group with patients having acute appendicitis, MPV level was found to be signi cantly lower in the acute appendicitis group.In the same study, it was emphasized that MPV level should not be overlooked in suspected acute appendicitis cases (20).In another study, a signi cant reduction was found in MPV level of patients with appendicitis (23).In a study by Uyanik et al., no statistical signi cance was observed in MPV levels of patients with acute appendicitis (22).In another study, higher MPV levels were found in patients with acute appendicitis compared to the control group (18).In a meta-analysis of ve studies including 2101 patients with acute appendicitis, it was reported that MPV can be used as a biomarker for the diagnosis of positive appendicitis and is a rapid and inexpensive indicator (24).Our lower MPV levels in PA groups can be explained by the sequestration of larger platelets in the vascular segments of in amed intestines.Based on our ndings, we believe that MPV values under the lower normal range can be used as a biomarker for positive acute appendicitis cases.
Recent studies have investigated the relationship between hyperbilirubinemia and vermiform of in ammation, and some of these studies have reported that bilirubin can be used as a speci c marker of appendiceal perforation (25,26).In our study, TBIL levels were signi cantly lower in PA group compared to NA group (p = 0.034).However, TBIL levels were within the normal range in both groups.In a study by Akbulut et al., a TBIL cut-off ≥ 0.67 is an independent factor predicting acute appendicitis (27).However, we could not nd any study in the literature investigating the relationship between TBIL and acute appendicitis.Therefore, we could not exactly compare our TBIL nding with the previous studies.
Although there are several studies about the use of various laboratory markers in the diagnosis of acute appendicitis that were mentioned above, there is still no scienti c evidence on the use of blood parameters in predicting acute appendicitis.
In imaging examination, one of the most important ndings for the diagnosis of acute appendicitis is appendicitis diameter.In the present study, appendicitis diameter was statistically signi cantly higher in PA group than in NA group (p < 0.001).Similarly, in a study by Katipoglu et al., the mean appendicitis diameter was signi cantly higher in the positive appendectomy cases (28).

Study Limitations
The main of this study are its retrospective design and being conducted in a single center.However, the number of our patients is relatively higher than the other studies in the literature.In addition, unlike the other studies in the literature lower MPB and TBIL values in the positive appendectomy cases bring a new projection to the literature.Unlike the other studies, WBC and CRP values were not signi cant between PA and NA groups.

Conclusion
According to the results of our study, the mean MPV and TBIL values can be used as speci c biomarkers in predicting positive acute appendicitis.We believe that these results will contribute to the literature and will be guiding for future studies.However, further studies are needed to determine the laboratory parameters that can be used as diagnostic biomarkers. Figures

Table 1
The comparison of MPV and TBIL values that were signi cant between PA and NA groups is seen in Fig.1.