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. 2021 Jul 27;16(7):e0255253. doi: 10.1371/journal.pone.0255253

Usefulness of several factors and clinical scoring models in preoperative diagnosis of complicated appendicitis

Kenji Fujiwara 1,2,*, Atsushi Abe 1, Toshihiro Masatsugu 1, Tatsuya Hirano 1, Kiyohisa Hiraka 3, Masayuki Sada 1
Editor: Robert Jeenchen Chen4
PMCID: PMC8315522  PMID: 34314464

Abstract

Background

The preoperative distinction between uncomplicated and complicated appendicitis is important to determine the appropriate treatments, such as antibiotics, surgery, or interval appendectomy. Computed tomography (CT) plays an important role; however, combining clinical and imaging factors may make preoperative evaluation more reliable. This study evaluated and analyzed cases and the usefulness of several preoperative factors and clinical scoring models to detect complicated appendicitis.

Methods

A total of 203 patients preoperatively diagnosed with acute appendicitis at our facility were included. Complicated appendicitis was defined as appendicitis with gangrene, perforated appendix, and/or abscess formation. Preoperative factors were collected from published clinical scoring models; patient information, symptoms, signs, results of laboratory tests, and findings of CT. Factors were analyzed using a chi-squared test and the Mann-Whitney U test.

Results

The preoperative factors were compared between 151 uncomplicated and 52 complicated appendicitis patients. The significant factors were age ≥40, duration of symptoms >24 hours, body temperature ≥37.3°C, high levels of CRP, findings in CT scan (appendix diameter ≥10 mm, stranding of the adjacent fat, presence of fluid collection, and suspicion of abscess or perforation). We also evaluated the usefulness of clinical scoring models for the detection of complicated appendicitis and found the Appendicitis Inflammatory Response score and two prediction models (Atema score and Imaoka score) showed significance (p < 0.05). High serum CRP level was significantly associated with complicated appendicitis (p < 0.001), and the predicted existence rates of complicated appendicitis were 52.7% for serum CRP level ≥50mg/L, 74.4% for ≥100mg/L, and 82.6% for ≥150mg/L.

Conclusion

The results demonstrated several preoperative factors and clinical scoring models to increase suspicion of complicated appendicitis. Specifically, high serum levels of CRP may be a useful factor in predicting complicated appendicitis prior to surgery when supported by clinical findings and imaging; however, further research is needed.

Introduction

Acute appendicitis is a common affliction; however, the strategy for treating this common inflammatory condition has not been determined [1]. While emergency surgery is often performed for acute appendicitis in order to avoid progression of the condition [2], several studies have reported that antibiotics may treat uncomplicated appendicitis with high success rates of 88–94% [3, 4]. In addition, recent studies demonstrated that complicated appendicitis, defined as having a gangrenous appendix, perforated appendix, or periappendiceal abscess, could also be treated with antibiotics and surgical standby, contrary to the standard thought of complicated appendicitis as a typical candidate for emergency surgery [5, 6]. This method, interval appendectomy, might present fewer complications compared to emergency surgery [7]. Although the debate about whether interval appendectomy after non-operative management is necessary for complicated appendicitis continues, the distinction between uncomplicated and complicated appendicitides is important in deciding the strategy for treatment [8].

The preoperative distinction between uncomplicated and complicated appendicitides is difficult [8]. The diagnosis of acute appendicitis itself is challenging, and studies reported that normal appendixes were found in 5% of patients who had been diagnosed with acute appendicitis using imaging prior to surgery [1, 9]. Salminen et al. reported 1.5% of patients preoperatively diagnosed as having uncomplicated appendicitis, even with confirmation using computed tomography (CT), were then diagnosed as having complicated appendicitis during surgery; it is worth noting that this study excluded many patients (61.6% of all patients) for several factors like the presence of appendicolith, age, evidence of peritonitis, and so forth [3]. While CT plays an important role in detecting complicated appendicitis [1, 8], Atema et al. reported that combining clinical and imaging features were essential for correctly identifying uncomplicated appendicitis as well [10]. From this, it is clear that combining several factors, including imaging and clinical features, is important for the preoperative distinction between uncomplicated and complicated appendicitides.

Several studies have reported on preoperative factors and clinical scoring models used in the diagnosis of acute appendicitis and the prediction of severity of the condition [1, 8, 10–14]. However, each model proposes various factors and different thresholds. We would like to know definitive factors or scoring models to suspect complicated appendicitis preoperatively. Therefore, for this study, we evaluated the usefulness of those factors and scoring models in detecting complicated appendicitis by using our data.

Methods

Patients’ characteristics

We collected the data of patients who had undergone surgery at Sada Hospital, and who had been given a preoperative diagnosis of acute appendicitis, from November 2015 to August 2020. A total of 203 cases with pathological diagnoses and findings of CT scan were included, after excluding 5 cases of patients who underwent standby surgery after being treated with antibiotics. The breakdowns of pathological diagnoses and basic demographic information of the 203 patients are provided in Table 1.

Table 1. The breakdown of the pathological diagnoses of 203 patients.

Pathological diagnosis Cases (% of total) Age range (median) (years) Sex (male/female) Patients with abscess or perforation (% of total)
Phlegmonous 147 (72.4) 11–84 (37) 84/63 18 (12.3)
Gangrenous 28 (13.8) 14–75 (43.5) 12/16 25 (89.3)
Minimal change 11 (5.4) 16–66 (26) 5/6 1 (9.1)
Chronic appendicitis 6 (3.0) 19–56 (41) 3/3 2 (33.3)
Acute diverticulitis 5 (2.5) 32–53 (39) 5/0 2 (40.0)
Neoplasms* 3 (1.5) 31–82 (63) 0/3 1 (33.3)
Granulomatous appendicitis 2 (1.0) 37–40 (38.5) 1/1 0
Fibrinous serositis 1 (0.5) 44 (44) 1/0 0
Total 203 11–84 (38) 111/92 49 (24.1)
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*Neoplasms include adenocarcinoma, mucinous cystic neoplasm, and microcarcinoid.

Data management

We defined complicated appendicitis, also called complex appendicitis, as appendicitis with gangrene, a perforated appendix, and/or appendicitis with abscess formation in accordance with the article by Bhangu A. et al. [1, 6]. For classifying the cases as either uncomplicated or complicated appendicitis, we utilized the pathological diagnoses provided by pathologists in the case files and referred to the surgical records to determine the existence of abscess and perforation. Any appendicitides fitting the definition of complicated appendicitis were assigned to the complicated group, and all others were assigned to the uncomplicated group.

Several studies were reviewed, and their preoperative factors used in the diagnosis of acute appendicitis and the prediction of severity of the condition were considered [1, 8, 11, 12]. Especially, we mainly collected the factors using for scoring in three clinical risk score models for the diagnosis of acute appendicitis and two scoring models for the prediction of complicated appendicitis: Alvarado score, Appendicitis Inflammatory Response (AIR) score, Adult Appendicitis Score (AAS), the prediction model by Atema et al., and the prediction model by Imaoka et al. [9, 10, 13, 15]. The preoperative factors determined for use in this study were 1) patient information: age, sex, duration of symptoms (from the appearance of symptoms till visiting hospital firstly), 2) symptoms: nausea, vomiting, symptoms of anorexia, 3) signs: body temperature, pain in the right lower quadrant, rebound tenderness or muscular defense, 4) laboratory tests: level of C-reactive protein (CRP), white blood cell (WBC) count, leucocytosis shift, polymorphonuclear leucocytes, 5) findings of CT: appendix diameter, adjacent fat stranding, presence of fluid collection, suspicion of abscess or perforation, and suspicion of appendicolith. The findings of CT were determined by radiologists and surgeons according to Radiopedia (http://radiopedia.org/) or published articles [16, 17]. In our clinical records, some information like symptoms or leukocytosis shift was not recorded or analyzed for some patients, so some tables in this manuscript show different total numbers.

Ethics statement

Sada Hospital has its own Institutional Review Board (IRB) that reviews all studies performed in the hospital. This IRB approved the use of the hospital database for research purposes and waived the requirement for informed consent (IRB approval number: S200911-1). All data were fully anonymized before being assessed.

Statistical analysis

The preoperative factors and the scoring models were analyzed using a chi-squared test. The level of CRP was also studied with the Mann-Whitney U test. Statistical analysis was performed using JMP Pro 15.1.0 (SAS Institute Inc., Cary, NC, USA). A p-value of <0.05 was considered statistically significant.

Results

Usefulness of preoperative factors to predict complicated appendicitis

A total of 203 patients were classified as 151 with uncomplicated appendicitis (74.4%) and 52 with complicated appendicitis (25.6%). The 52 complicated cases contained 28 gangrenous appendicitis cases, 18 phlegmonous appendicitis cases, 2 chronic appendicitis cases, 2 acute diverticulitis cases, 1 minimal change case, and 1 mucinous cystic neoplasm and most of the cases had evidence of abscess/perforation except for 3 gangrenous appendicitis cases. We compared the relevant preoperative factors between the uncomplicated and complicated groups; these results are summarized in Table 2. The factors that showed significantly higher incidence in patients finally diagnosed with complicated appendicitis compared to those finally diagnosed with uncomplicated appendicitis were: aged ≥40 years (66.7% and 41.1%, respectively; p = 0.002), duration of symptoms ≥24 hours (67.3% and 29.8%, respectively; p < 0.001), body temperature ≥37.3°C (71.2% and 36.4%, respectively; p < 0.001), serum CRP level ≥50mg/L (76.5% and 23.2%, respectively; p < 0.001), appendix diameter ≥10 mm (90.4% and 63.6%, respectively; p < 0.001), stranding of the adjacent fat (96.2% and 66.2%, respectively; p < 0.001), presence of fluid collection (69.2% and 11.3%, respectively; p < 0.001), and suspicion of abscess or perforation (40.4% and 1.3%, respectively; p < 0.001).

Table 2. Comparison of preoperative factors between uncomplicated and complicated appendicitis groups.

Uncomplicated appendicitis Complicated appendicitis p-value
Patient information
    Age (years) ≥40 62 34 0.002
<40 89 17
    Duration of symptoms (hours) ≥24 45 35 <0.001
<24 106 17
Symptoms
    Nausea/vomiting Yes 57 21 0.736
No 94 31
    Anorexia Yes 58 25 0.235
No 92 27
Signs
    Body temperature (°C) ≥37.3 55 37 <0.001
<37.3 96 15
    Pain in right lower quadrant Yes 142 50 0.314
No 8 1
    Rebound tenderness Yes 44 16 0.370
No 74 19
Laboratory tests
    Level of CRP (mg/L) ≥50 35 39 <0.001
<50 116 12
    Count of WBCs (K/uL) ≥15.0 47 15 0.912
10.0–14.9 79 29
<10.0 25 8
Findings of CT
    Appendix diameter ≥10 mm 96 47 <0.001
<10 mm 55 5
    Stranding of the adjacent fat Yes 100 50 <0.001
No 51 2
    Presence of fluid collection Yes 17 36 <0.001
No 134 16
    Suspicion of abscess/perforation Yes 2 21 <0.001
No 149 31
Presence of appendicolith Yes 48 19 0.530
No 103 33
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CRP, C-reactive protein; WBC, white blood cell/leukocyte.

Findings of CT imaging with complicated appendicitis

As mentioned, CT is frequently used for the diagnosis of acute appendicitis and for evaluating the severity of appendicitis [8]. In our data, the CT finding of a suspicious abscess (such as fluid collection with rim enhancement) or perforation (e.g., the existence of free air outside of the gut) was not highly found in complicated appendicitis (21 of 52 cases or 38.9%, Table 2). During surgery, 28 cases of complicated appendicitis revealed infected fluid collected around the appendix or perforation of appendicitis; these patients did not demonstrate findings to cause suspicion of an abscess or perforation (Fig 1). Most of the complicated appendicitis patients showed appendix diameter 10 mm or larger (90.4%) and stranding of the adjacent fat (96.2%); these findings were also frequent for uncomplicated appendicitis (63.6% and 66.2%, respectively). The presence of fluid collection during CT might well indicate complicated appendicitis (36 of 52 cases; sensitivity 69.2%); 17 cases of uncomplicated appendicitis show fluid collection (17 of 151 cases; false positive was 11.3%). From these results, CT finding is useful but not perfect to distinguish preoperatively between uncomplicated and complicated appendicitides. We may combine other factors to increase the accuracy of preoperative distinction [10].

Fig 1. A case of complicated appendicitis.

Fig 1

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(A, B) Computed tomography images (A, transverse plane; B, coronal plane). A swollen appendix, stranding of the adjacent fat, and fluid collection are found; no obvious abscess is detected. (C) View during abdominal laparoscopy. Collection of infected fluid is found on the right side of abdomen. (D) Macroscopic image of the resected appendix. The appendix did not have signs of necrosis or perforation and was diagnosed as phlegmonous appendicitis.

Comparison between clinical scoring models regarding preoperative prediction of complicated appendicitis

We hypothesized that the clinical risk score models used for the accurate diagnosis of acute appendicitis might also be beneficial for the prediction of complicated appendicitis. Three clinical risk score models of acute appendicitis were chosen: Alvarado score, Appendicitis Inflammatory Response (AIR) score, and Adult Appendicitis Score (AAS) [8–10, 12, 13, 15]. The numbers of patients between uncomplicated and complicated appendicitis groups were contrasted by determining the risk scores of each patient using each model and then comparing the results (Table 3). Only AIR scores showed significance between the score and the existence of complicated appendicitis (p = 0.026). In addition, two scoring models for the prediction of complicated appendicitis were also tested. Atema score and Imaoka score both showed significance between the score and the existence of complicated appendicitis (p < 0.001).

Table 3. Comparison between clinical scoring models for preoperative severity between uncomplicated and complicated appendicitis.

Score Uncomplicated appendicitis (% of total) Complicated appendicitis (% of total) p-value
Clinical risk scoring models for suspected acute appendicitis
    Alvarado score 0–4 (Low risk of acute appendicitis) 12 (13.8) 1 (4.5) 0.274
5–6 (Intermediate risk) 23 (26.4) 4 (18.2)
7–10 (High risk) 52 (59.8) 17 (77.3)
    AIR score 0–4 (Low risk) 23 (21.5) 1 (3.8) 0.026
5–8 (Intermediate risk) 79 (73.8) 21 (80.8)
9–12 (High risk) 5 (4.7) 4 (15.4)
    AAS 0–10 (Low risk) 12 (12.0) 1 (4.5) 0.248
11–15 (Intermediate risk) 63 (63.0) 12 (54.5)
16+ (High risk) 25 (25.0) 9 (40.9)
Scoring models to predict complicated appendicitis
    Atema score 0–6 (Low probability of complicated appendicitis) 124 (82.7) 5 (9.8) <0.001
7+ (High probability) 26 (17.3) 46 (90.2)
    Imaoka score 0 (Low probability) 72 (47.7) 1 (2.0) <0.001
1–3 (High probability) 79 (52.3) 49 (98.0) 　
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AIR, Appendicitis Inflammatory Response; AAS, Adult Appendicitis Score.

Relationship between the level of CRP and the incidence of complicated appendicitis

Our analysis found serum level of CRP, defined as ≥ 50 mg/L, was significantly associated with complicated appendicitis (p < 0.001, Table 2), and three clinical scoring models that showed significance for predicting complicated appendicitis used level of CRP for their scoring. We compared the serum levels of CRP of the patients between uncomplicated and complicated appendicitis groups. The results showed that CRP level was significantly higher in the complicated appendicitis group compared by uncomplicated appendicitis group (p < 0.001, Fig 2A). We analyzed the sensitivity and specificity of the serum CRP levels by setting each cut-off value (Table 4) and created a receiver operating characteristic curve (Fig 2B). The area under the curve was 0.843, and high serum CRP level was a significant indication factor for complicated appendicitis (p < 0.001). The predicted existence-rates (positive predictive values) of complicated appendicitis were 52.7% for serum CRP level ≥50mg/L, 74.4% for ≥100mg/L, and 82.6% for ≥150mg/L.

Fig 2. The relationship between the level of C-reactive protein (CRP) and the existence of complicated appendicitis.

Fig 2

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(A) Comparison of serum level of CRP between uncomplicated and complicated appendicitis. Bars show median values. (B) Receiver operating characteristic curve of the relationship between the level of CRP and the existence rates of complicated appendicitis. The area under the curve was 0.843.

Table 4. Sensitivities, specificities, and predicted existence rates for cut-off values of serum level of C-reactive protein (CRP).

Cut-off value of serum level of CRP (mg/L) Sensitivity (%) Specificity (%) Predicted existence-rate of complicated appendicitis (%; positive predictive value)
≥10 90.2 39.7 33.6
≥50 76.5 76.8 52.7
≥100 56.9 93.4 74.4
≥150 37.3 97.4 82.6
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Discussion

The diagnosis and evaluation of the severity of acute appendicitis remain challenging, even though surgery has been frequently performed to treat this common condition all over the world [1]. While CT is usually used for definitive evaluation, our data demonstrated that many complicated appendicitis cases (59.6%) did not show the expected images, such as fluid collection with rim enhancement or free air in the abdomen. The stranding of adjacent fat and swelling of the appendix were found in most of the complicated appendicitis cases. However, these findings were also frequently shown in uncomplicated appendicitis (63.6–66.2%), so specificity is not high. The presence of fluid collection seemed a reasonable factor to suspect complicated appendicitis due to the balance of sensitivity (69.2%) and specificity (88.7%). Two scoring models (Atema score and Imaoka score) for the prediction of complicated appendicitis both contained the presence of fluid collection for scoring and also both models recommended combining other factors such as serum level of CRP [10, 14].

CRP may be one useful indicator of complicated appendicitis due to simplicity and objectivity. Comparison among three well-known clinical risk score models showed that only the AIR score demonstrated significance. This might be because the AIR score added a progressively higher score for higher serum levels of CRP. The AAS also used CRP in scoring; however, this scoring model was applied in an inconsistent manner and did not always show the highest score for patients with the highest levels of CRP [13], and the Alvarado score did not use the serum CRP level for its scoring [1]. For the ideal threshold of serum CRP level, Atema score and Imaoka score presented a serum level of 47–50 mg/L. By using our data, both models showed significance for the prediction of complicated appendicitis so we thought the threshold of serum CRP level from the two models is appropriate for the scoring models of the combination of several factors.

This study has the limitation of sample size. Given the significant p-values in our data, we believe that our results remain relevant; however, we acknowledge that further research with larger numbers of cases is required to detect independent factors by multivariate analysis. In addition, the comparison among studies about complicated appendicitis had several limitations. First, many studies used a different definition for complicated appendicitis, such as the presence of an appendicolith, periappendiceal phlegmon, or peritonitis [3, 4, 10, 13, 15]. For comparing the preoperative factors and scoring models with consistent definition, we chose the definition of Bhangu et al. because of its simplicity and objectivity: appendicitis with gangrene, perforated appendix, and/or abscess formation [1, 6]. Due to many definitions of complicated appendicitis, it is important to be careful when comparing studies about complicated appendicitis in order to avoid confusion. Secondly, the availability of imaging like CT is different among facilities although in this study CT was performed for most cases [1]. Atema score also showed the scoring models by using ultrasounds and we can utilize it [10]; however, the reliability of the results by ultrasounds depends on the technique of the operator.

In conclusion, the results showed several preoperative factors and clinical scoring models combining several factors were useful to detect complicated appendicitis. We propose that CRP may be a useful factor in predicting complicated appendicitis when supported by clinical findings and imaging, and look forward to further research of this factor.

Acknowledgments

We want to thank Dr. Akinori Iwashita for the pathological diagnoses and advice given in these acute appendicitis cases. We would also like to thank all the medical staff of Sada Hospital who contributed to the treatment of acute appendicitis and aided in collecting the data for our research.

Data Availability

Original full data cannot be shared publicly because of containing detailed surgical information like precise surgical date. This information may indicate the patients' information. Data after being anonymized are available from the Sada Hospital Institutional Review Board (contact via e-mail; info@sada.or.jp) for researchers who meet the criteria for access to confidential data.

Funding Statement

The author(s) received no specific funding for this work.

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Usefulness of several factors and clinical scoring models in preoperative diagnosis of complicated appendicitis

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Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an interesting topic to discuss, however, the case number was relatively small, especially the number of complicated appendicitis which was only 14.

Here, I have some concerns:

1. I agree with the idea that preoperative distinction between uncomplicated and complicated appendicitis is important in determining the appropriate treatments, such as antibiotics, surgery, or interval appendectomy. However, if not considering the suitableness of patients’ general condition such as underlying diseases and the severity of infection.

The logic of distinguishing complicated appendicitis from uncomplicated appendicitis is to make the best treatment decision for the patient instead of simply categorizing the “appendicitis.”

2. The laboratory and image criteria in differentiating complicated and uncomplicated appendicitis may not be representative enough.

For example, the abdominal CT scan findings can provide important clues of the inflammation severity, such as the amount of fluid accumulation as well as localization. Additionally, the area of adjacent fat stranding is a key finding of inflammation. The CT image grading for acute pancreatitis can be a model compared to your study by applying grade A-D to show the severities of inflammation. It would be informative if the authors can provide more details.

3. In figure 1B, the author presented an example of complicated appendicitis. However, the swollen appendix was isolated from the cecum and small intestines. It may not be considered as complicated appendicitis for experienced surgeons. In our experience, it won’t be too difficult when applying laparoscopic appendectomy. On the other hand, if the swollen appendix adhered to the adjacent structures or located retro-cecum or retro-ileum, we will be more cautious and consider it as complicated appendicitis.

Reviewer #2: The data are consistent with most of the notion. However, there are still several points need to be addressed in the manuscript. The main topic is not interesting and not sound in scientific research.

**********

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Reviewer #1: Yes: Guo-Shiou Liao

Reviewer #2: No

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PLoS One. 2021 Jul 27;16(7):e0255253. doi: 10.1371/journal.pone.0255253.r002

Author response to Decision Letter 0

12 Jun 2021

Reviewer #1: This is an interesting topic to discuss, however, the case number was relatively small, especially the number of complicated appendicitis which was only 14.

Author Response: Thank you for an excellent opinion. We agreed that the case number seemed small although the data showed significance. We decided to increase the number of cases, and eventually, we collected 203 appendicitides including 52 complicated appendicitis cases. After re-analyzing the data, we revised many tables and figures. The tendencies had not been changed despite drastic changes, so we kept the similar discussion and conclusion. We feel sorry for you for taking your time for the re-review of this drastic updating manuscript, but we strongly believe that our extended collection of the cases increased the reliability of our manuscript.

We summarized our revisions caused subsequently by the increase of total case number.

1. The sample number was changed, so the numbers of patients, percentages, and also p-values were revised. We used the function of the track change in the manuscript so you could find the revised points. All tables (Table 1-4) and Fig 2 were revised.

2. We removed the previous Table 3 (the list of 14 complicated appendicitis cases) because the list would become too huge with the increase of total numbers of complicated appendicitis. We arranged the part of “Findings of CT imaging with complicated appendicitis” in order to make the readers understand without the list of complicated appendicitis cases.

By removing Table 3, previous Table 4 and 5 changed to new Table 3 and 4.

1. I agree with the idea that preoperative distinction between uncomplicated and complicated appendicitis is important in determining the appropriate treatments, such as antibiotics, surgery, or interval appendectomy. However, if not considering the suitableness of patients’ general condition such as underlying diseases and the severity of infection.

The logic of distinguishing complicated appendicitis from uncomplicated appendicitis is to make the best treatment decision for the patient instead of simply categorizing the “appendicitis.”

Author Response: Thank you for a great opinion. We completely agree with your statement that we should select the best treatment for the patients. The distinction between uncomplicated and complicated appendicitis should be for the best selection of the treatment. Actually, we wanted to warn the current tendencies to diagnose mainly with CT scans. Recently, many guidelines have been published for the treatment of appendicitis, and the distinction between uncomplicated and complicated appendicitis has been often used[1][2]. The distinction of uncomplicated or complicated appendicitis is convenient for the selection of treatment, but the definition of “complicated appendicitis” is not the same among the manuscripts[3][4][5][6][7]. Also, CT is frequently used for the diagnosis of complicated appendicitis, but we have often experienced perforation or abscess that was not diagnosed in CT scan. The diagnosis depending on CT scan may incorrectly define some severe cases like “complicated appendicitis” as un-severe cases like “uncomplicated appendicitis.” We would like to warn the problem of the diagnosis depending on mainly CT scan and emphasize the importance of the evaluation with other factors.

From your suggestion, we thought our statement of the manuscript might not be clear, so we newly added the sentence at the end of the paragraph of “Findings of CT imaging with complicated appendicitis” on Page 11, “From these results, CT finding is useful but not perfect to distinguish preoperatively between uncomplicated and complicated appendicitides. We may combine other factors to increase the accuracy of preoperative distinction.”

2. The laboratory and image criteria in differentiating complicated and uncomplicated appendicitis may not be representative enough.

For example, the abdominal CT scan findings can provide important clues of the inflammation severity, such as the amount of fluid accumulation as well as localization. Additionally, the area of adjacent fat stranding is a key finding of inflammation. The CT image grading for acute pancreatitis can be a model compared to your study by applying grade A-D to show the severities of inflammation. It would be informative if the authors can provide more details.

Author Response: Thank you for your great opinion. On page 7, we added the sentence into the Method about how we diagnosed the findings of CT scan, “The findings of CT were determined by radiologists and surgeons according to Radiopedia (http://radiopedia.org/) or published articles.” I think it is a great idea to newly provide CT image grading for appendicitis, but we would like to it for the next project. In this manuscript, we tried to diagnose the findings with the usual and popular sense by referring to Radiopedia or published articles.

3. In figure 1B, the author presented an example of complicated appendicitis. However, the swollen appendix was isolated from the cecum and small intestines. It may not be considered as complicated appendicitis for experienced surgeons. In our experience, it won’t be too difficult when applying laparoscopic appendectomy. On the other hand, if the swollen appendix adhered to the adjacent structures or located retro-cecum or retro-ileum, we will be more cautious and consider it as complicated appendicitis.

Author Response: Thank you for a great question. We agree that some experienced surgeons would not consider this case as complicated appendicitis. And, other surgeons would think this diagnosis is complicated appendicitis. Such confusion about the diagnosis of severity was our motivation to start this research. We think the definition of complicated appendicitis should be objective but many manuscripts used each own definition. We chose Bhangu’s manuscript because they used a relatively objective definition of complicated appendicitis; gangrene, perforation, and/or abscess[2]. And we applied this definition to our experienced cases and compared several factors and risk score models. Actually, we did not find a perfect factor or perfect scoring model. Atema score seemed better than other factors due to the balance of sensitivity and specificity, but the calculation of their scoring model seemed complex[5]. We think that a combination of CT findings and a high serum level of CRP is easy and good to detect severe cases but further research and discussion are necessary. We added the predicted existence rate of complicated appendicitis in Table 4. We wish this table would support surgeons to explain the patients the severity of their appendicitis and support choosing the treatment.

Additional major revisions

1. We found low serum levels of CRP for some complicated appendicitis cases by increasing the total numbers of patients although we described all serum levels of CRP were above 50 mg/L for complicated appendicitis patients before. In the abstract and the end of the discussion, we changed the definition of CRP as “a useful factor” from “a strong factor” even though CRP still showed a high significance for the prediction of complicated appendicitis (p<0.0001).

2. We changed Fig 2A from bar graph to dot-plot graph. We thought the dot-plot style is more appropriate for our data because the serum level of CRP was sparse, and the dot-plot can also show a very high-level value in one figure.

Minor revision.

1. In the Method, we did not describe clearly that we did not include the patients not having CT findings in the previous manuscript. Therefore, we added the sentence “A total of 203 cases with pathological diagnoses and findings of CT scan were included” in order to make it clear. We excluded seven patients diagnosed with only ultrasounds, and we think the rejection of those seven patients did not affect the whole analysis.

2. Some data showed different total numbers due to incomplete records of symptoms or un-enforcement of some laboratory tests. On pages 7-8, we added this sentence at the end of the section of Data management, “In our clinical records, some information like symptoms or leukocytosis shift was not recorded or analyzed for some patients, so some tables in this manuscript show different total numbers.”

3. In the part of “Statistical analysis” of the Method, we removed the sentence “graphic presentations were performed using JMP Pro 15.1.0” because we also used other software in order to remove the gray background of the ROC curve made by JMP Pro.

 

Reviewer #2: The data are consistent with most of the notion. However, there are still several points need to be addressed in the manuscript. The main topic is not interesting and not sound in scientific research.

Author Response: Thank you for a great opinion. We seriously thought about your opinion, and we agreed that our manuscript was not at the level of scientific research and not interesting. We discussed how to improve this manuscript and decided to increase the number of cases to make the manuscript more reliable. Eventually, we collected a total of 203 cases, including 52 complicated appendicitis cases. The tendencies were not changed, and p-values became lower. We believe the increase of case number makes our manuscript more reliable.

Also, we thought the message of our manuscript was not clear. The motivation of this manuscript was the confusion of the research of appendicitis. Many manuscripts used different definitions of complicated appendicitis [3][4][5][6][7]. The dramatic change of the treatment for appendicitis has been progressed by introducing interval appendectomy[8]. On the other hand, we thought that the precise preoperative diagnoses of complicated appendicitis is difficult, and CT scan is not a perfect tool to detect complicated appendicitis. Therefore, we would like to evaluate the current useful factors to use the preoperative diagnosis of acute appendicitis by using the consistent definition of complicated appendicitis by applying it to our data. We used Bhangu’s criteria because their definition was simple and relatively objective; gangrene, perforation, and/or abscess[2]. In addition, on page 12, we added the sentence of our opinion in order to make our statement clear in the result section, “From these results, CT finding is useful but not perfect to distinguish preoperatively between uncomplicated and complicated appendicitides. We may combine other factors to increase the accuracy of preoperative distinction.” In addition, we resummarize the manuscript by deleting one table and delete some redundant sentences. We tried to make our manuscript more straightforward to tell our statement.

We summarize our revisions.

1. The sample number was changed, so the numbers of patients, percentages, and also p-values were revised. We used the function of Track change in the manuscript so you could find the revised points. All tables (Table 1-4) and Fig 2 were revised.

2. We removed the previous Table 3 (the list of 14 complicated appendicitis cases) because the list would become too huge with the increase of total numbers of complicated appendicitis. We arranged the part of “Findings of CT imaging with complicated appendicitis”in order to make the readers understand without the list of complicated appendicitis cases.

By removing Table 3, previous Table 4 and 5 changed to new Table 3 and 4.

3. We found low serum levels of CRP for some complicated appendicitis cases by increasing the total numbers of patients although we described all serum levels of CRP were above 50 mg/L for complicated appendicitis patients before. In the abstract and the end of discussion, we changed the definition of CRP as “a useful factor” from “a strong factor” even though CRP still showed a high significance for the prediction of complicated appendicitis (p<0.0001).

4. We changed Fig 2A from bar graph to dot-plot graph. We thought the dot-plot style is more appropriate for our data because the serum level of CRP was sparse, and the dot-plot can also show a very high-level value in one figure.

Minor revision.

1. In the Method, we did not describe clearly that we did not include the patients not having CT findings in the previous manuscript. Therefore, we added the sentence “A total of 203 cases with pathological diagnoses and findings of CT scan were included” in order to make it clear. We excluded seven patients diagnosed with only ultrasounds, and we think the rejection of those seven patients did not affect the whole analysis.

2. Some data showed different total numbers due to incomplete records of symptoms or un-enforcement of some laboratory tests. On pages 7-8, we added this sentence at the end of the section of Data management, “In our clinical records, some information like symptoms or leukocytosis shift was not recorded or analyzed for some patients, so some tables in this manuscript show different total numbers.”

3. In the part of “Statistical analysis” of the Method, we removed the sentence “graphic presentations were performed using JMP Pro 15.1.0” because we also used other software in order to remove the gray background of the ROC curve made by JMP Pro.

References

1. Di Saverio S, Podda M, De Simone B, Ceresoli M, Augustin G, Gori A, et al. Diagnosis and treatment of acute appendicitis: 2020 update of the WSES Jerusalem guidelines. World J Emerg Surg. 2020;15: 27.

2. Bhangu A, Søreide K, Di Saverio S, Assarsson JH, Drake FT. Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management. Lancet (London, England). 2015;386: 1278–1287.

3. Salminen P, Paajanen H, Rautio T, Nordström P, Aarnio M, Rantanen T, et al. Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial. JAMA. 2015;313: 2340–2348.

4. Vons C, Barry C, Maitre S, Pautrat K, Leconte M, Costaglioli B, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet (London, England). 2011;377: 1573–1579.

5. Atema JJ, van Rossem CC, Leeuwenburgh MM, Stoker J, Boermeester MA. Scoring system to distinguish uncomplicated from complicated acute appendicitis. Br J Surg. 2015;102: 979–990.

6. Sammalkorpi HE, Mentula P, Savolainen H, Leppäniemi A. The Introduction of Adult Appendicitis Score Reduced Negative Appendectomy Rate. Scand J Surg. 2017;106: 196–201.

7. Gorter RR, Eker HH, Gorter-Stam MAW, Abis GSA, Acharya A, Ankersmit M, et al. Diagnosis and management of acute appendicitis. EAES consensus development conference 2015. Surg Endosc. 2016;30: 4668–4690.

8. Andersson RE, Petzold MG. Nonsurgical treatment of appendiceal abscess or phlegmon: a systematic review and meta-analysis. Ann Surg. 2007;246: 741–748.

Attachment

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Decision Letter 1

Robert Jeenchen Chen

25 Jun 2021

PONE-D-21-12222R1

Usefulness of several factors and clinical scoring models in preoperative diagnosis of complicated appendicitis

PLOS ONE

Dear Dr. Fujiwara,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please revise accordingly.

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We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

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Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: For diagnosing acute appendicitis, both clinical and laboratory findings individually do not suffice, combined with

standard imaging increases the diagnostic power for acute appendicitis. Incorporating imaging features in clinical scoring models may provide better differentiation between uncomplicated and complicated appendicitis. Optimizing patient selection for treatment of appendicitis resulting in better treatment outcomes. Too emphasize the CRP value may misdiagnose with other abdominal diseases.

Reviewer #3: I have read with interest this submission. The authors have for the most part revised and addressed the recommendations of the very thorough review performed by the 1st round of reviewers. As I read the manuscript, I have only identified a minor issue which I think need to be addressed.

As it is known, CRP is a nonspecific acute phase reactant and may increase for many reasons. It would be a overestimated statement to say that CRP alone is a useful factor in predicting complicated appendicitis. In the discussion, it would be appropriate to edit the statement as "may be useful when supported by clinical findings and imaging".

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #3: No

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PLoS One. 2021 Jul 27;16(7):e0255253. doi: 10.1371/journal.pone.0255253.r004

Author response to Decision Letter 1

29 Jun 2021

PONE-D-21-12222

Usefulness of several factors and clinical scoring models in preoperative diagnosis of complicated appendicitis

PLOS ONE

June 29, 2021

Dear Editors and Reviewers,

We are very pleased to re-submit our manuscript, entitled “Usefulness of several factors and clinical scoring models in preoperative diagnosis of complicated appendicitis” by Fujiwara et al. for your consideration for publication in PLOS ONE.

Thank you for taking the time to review our revised manuscript. We believe our manuscript is now fit for the criteria for the journal. Below, we have listed each comment, along with our subsequent revisions and responses.

Sincerely,

Kenji Fujiwara, M.D., Ph.D.

 

Reviewer #1: For diagnosing acute appendicitis, both clinical and laboratory findings individually do not suffice, combined with standard imaging increases the diagnostic power for acute appendicitis. Incorporating imaging features in clinical scoring models may provide better differentiation between uncomplicated and complicated appendicitis. Optimizing patient selection for treatment of appendicitis resulting in better treatment outcomes. To emphasize the CRP value may misdiagnose with other abdominal diseases.

Author Response: Thank you for the thoughtful suggestion. We agreed that we exaggerated the importance of CRP too much, and this may mislead the readers. We arranged some sentences to indicate that CRP may be useful when supported by clinical findings and imaging.

We summarized the changes below.

1. We added the sentence “when supported by clinical findings and imaging” in the abstract (Page 3): Specifically, high serum levels of CRP may be a useful factor in predicting complicated appendicitis prior to surgery when supported by clinical findings and imaging; however, further research is needed.

2. We deleted the sentences “Great benefit of standard blood draws is easier and less invasive than imaging like CT scan (Page 16; Line 240-241)” because this sentence may mislead readers to think that CRP can substitute the imaging.

3. We added the sentence “when supported by clinical findings and imaging” in conclusion (Page 17): We propose that CRP may be a useful factor in predicting complicated appendicitis when supported by clinical findings and imaging, and look forward to further research of this factor.

 

Reviewer #3: I have read with interest this submission. The authors have for the most part revised and addressed the recommendations of the very thorough review performed by the 1st round of reviewers. As I read the manuscript, I have only identified a minor issue which I think need to be addressed.

As it is known, CRP is a nonspecific acute phase reactant and may increase for many reasons. It would be a overestimated statement to say that CRP alone is a useful factor in predicting complicated appendicitis. In the discussion, it would be appropriate to edit the statement as "may be useful when supported by clinical findings and imaging".

Author Response: Thank you for the thoughtful suggestion. We agreed that we exaggerated the importance of CRP too much, and this may mislead the readers. We arranged some sentences to indicate that CRP may be useful when supported by clinical findings and imaging.

We summarized the changes below.

1. We added the sentence “when supported by clinical findings and imaging” in the abstract (Page 3): Specifically, high serum levels of CRP may be a useful factor in predicting complicated appendicitis prior to surgery when supported by clinical findings and imaging; however, further research is needed.

2. We deleted the sentences “Great benefit of standard blood draws is easier and less invasive than imaging like CT scan (Page 16; Line 240-241)” because this sentence may mislead readers to think that CRP can substitute the imaging.

3. We added the sentence “when supported by clinical findings and imaging” in conclusion (Page 17): We propose that CRP may be a useful factor in predicting complicated appendicitis when supported by clinical findings and imaging, and look forward to further research of this factor.

Attachment

Submitted filename: Response_to_Reviewers_KFujiwara.docx

Click here for additional data file. (41.6KB, docx)

Decision Letter 2

Robert Jeenchen Chen

13 Jul 2021

Usefulness of several factors and clinical scoring models in preoperative diagnosis of complicated appendicitis

PONE-D-21-12222R2

Dear Dr. Fujiwara,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: The authors have made all the corrections addressed by the reviewers. With these contributions, the study has become more valuable and ready for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

Acceptance letter

Robert Jeenchen Chen

19 Jul 2021

PONE-D-21-12222R2

Usefulness of several factors and clinical scoring models in preoperative diagnosis of complicated appendicitis

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

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    Data Availability Statement

    Original full data cannot be shared publicly because of containing detailed surgical information like precise surgical date. This information may indicate the patients' information. Data after being anonymized are available from the Sada Hospital Institutional Review Board (contact via e-mail; info@sada.or.jp) for researchers who meet the criteria for access to confidential data.

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