A Novel Diagnostic Scoring System for Pediatric Appendicitis Based on Age and Sex-Adjusted Hematological Parameters

doi:10.21203/rs.3.rs-1990698/v1

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A Novel Diagnostic Scoring System for Pediatric Appendicitis Based on Age and Sex-Adjusted Hematological Parameters

https://doi.org/10.21203/rs.3.rs-1990698/v1

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Objective

Our aim is to establish the importance of age and sex-adjusted NLR, PLR, and other hematological parameters in the prediction of acute appendicitis and describe a novel scoring system.

Methods

The consecutive medical records of 946 pediatric patients (between 5–18) hospitalized with a diagnosis of acute appendicitis at our high-volume university hospital between January 2018 and December 2021 were retrospectively collected for analysis. The patients were divided based on perioperative findings into the negative exploration group (Group I) and the acute appendicitis group (Group II). This study developed a new scoring system based on “age and sex-adjusted” NLR, PLR, LMR, and CRP parameters.

Results

The mean age of Group I and II were 12.20 ± 2,31, and 11,56 ± 3,11, respectively. The white blood cell count (WBC) (p < .001), neutrophil percentage (p < .001), NLR (p < .001), PLR (p = .001), LMR (P < 0,001), and CRP (p < 0,001) were higher in the Group II compared with the Group I. The score was calculated between 0–8 points. 4.5 and above was determined as the best cut-off value for acute appendicitis with higher AUC (0,96), sensitivity (94%), specificity (86%), PPV (97,5%), NPV (65%), Accuracy (92,6%), and Misclassification Rate (7,4%).

Conclusion

Present scoring system calculated pertaining to patients' age and gender can be used to avoid unnecessary surgery.

Pediatric appendicitis

Adjusted NLR

Novel scoring system

Appendicitis is inflammation of the appendix vermiformis and is the most common cause of surgical abdominal pain requiring surgery both in children and adults [1]. Although the reported data indicate that appendicitis is seen at young ages, it is mentioned that there is a lifetime risk of around 7–8% [1, 2]. It is very difficult to say that excluding the diagnosis of acute appendicitis is an easy decision, even since many studies have been conducted on the subject of appendicitis for decades and tens of thousands of operations have been performed on this subject in practical surgery [3]. However, despite the advances in diagnostic tools, physical examination still maintains its importance [3]. Of course, we also know that some surgeons predict which patient needs appendectomy, relying solely on their own experience and physical examination. It is also a fact that hematological examinations such as Neutrophil to Lymphocyte Ratio (NLR), Platelet to Lymphocyte Ratio (PLR), Lymphocyte to Monocyte Ratio (LMR), and similar diagnostic tools that examine the rates of these hematological parameters have been added to these experiences recently, and it has become popular in the literature in recent years [4, 5]. However, it is a fact that our knowledge is just the tip of the iceberg. This report aims to establish the importance of the age and sex-adjusted NLR, PLR, and other hematological parameters in the prediction of acute appendicitis and to propose a novel scoring system for the diagnosis of acute appendicitis based on hematological parameters.

2.1 Patients

The consecutive medical records of 946 pediatric patients (between 5–18) hospitalized with a diagnosis of acute appendicitis at our high volume university hospital between January 2018 and December 2021 were retrospectively collected for analysis. The patients were divided based on perioperative findings into the negative exploration group (Group I) and the acute appendicitis group (Group II).

2.2 Exclusion Criteria

We, therefore, excluded patients with other causes of abdominal pain such as gastroenteritis, constipation, mesenteric lymphadenitis, ureter stone, ovarian torsion, perforated appendicitis or other causes of acute abdomen. Patients who developed peritonitis diarrhea secondary to perforated appendicitis due to late admission to the hospital were excluded. At the time of admission, covid-19 positive, patients with upper respiratory tract infection, symptoms duration > 48 hours, using antibiotics and/or painkillers, patients younger than 5 years old, having other concomitant diseases, history of abdominal surgery, and patients followed by non-operative management were excluded from the study.

2.3 Analytical procedures

For each patient, the age; sex; presenting symptoms; age, and sex-adjusted laboratory values of WBC, neutrophil percentage, thrombocyte count, NLR, PLR, LMR, CRP (mg/dL), Bilirubins; abdominal US (appendiceal diameter); pathological findings, and surgical methods were investigated. In this study, we calculated the hematological ratios and other parameters mentioned below separately for each patient according to age and gender, calculated how much they deviated from the normal value and gave points to these values. Then, we calculated these points for each patient again. As a result of these calculations, we expressed the cut-off values. The complete blood count (CBC) was measured at admission with an automated hematology analyzer (LH 780 analyzer; Beckman Coulter, Inc, Brea, CA, USA).

2.4 Clinical Evaluation and Process

The anamnesis and physical examination of the patients who applied to the pediatric emergency service with the complaints of abdominal pain, anorexia, and/or nausea-vomit were performed by the Pediatrician. Laboratory tests (all samples were measured and analyzed within 45 minutes of specimen collection), abdominal X-ray, and abdominal USG were studied in patients who were thought to have surgical acute abdomen according to the initial evaluations. Afterward, patients deemed necessary were consulted with the pediatric surgery team. Although this is a retrospective study, during the study period, all patients suspected for appendicitis were evaluated by our pediatric surgery team. Regardless of the appendix diameter in ultrasonography, the patient's complaints and physical examination were taken as the basis for the surgical decision. Nonoperative management was performed in patients with a negative physical examination. Surgical intervention was planned for patients whose physical examination was positive despite a single dose of antibiotics and hydration, and then patients underwent appendectomy as soon as possible.

2.5 Statistical Analysis

Statistical analysis of quantitative and qualitative data, including descriptive statistics and frequency, was performed for all items. Continuous data are expressed as mean ± SD. The continuous variables were investigated using Shapiro–Wilk test to determine whether the data had a normal distribution. Continuous, normally distributed variables were compared using Student’s T-test. Non-parametric tests were chosen when the data did not fit the normal distribution. The categorical variables were assessed by the chi-square test or Fisher exact test, as needed. The receiver operating characteristic curve (ROC) was utilized to characterize and compare the accuracy of the variables. The area under the curve (AUC) represented the accuracy of the marker in distinguishing between negative appendectomies and AA. The cut-off value was calculated for the data that could be evaluated. Sensitivity and specificity with 95% confidence intervals and the likelihood ratio (LR) were also calculated. Analyses were performed using SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA). All p-values were two-sided and p ≤ 0.05 was considered statistically significant.

2.6 Ethics

This study was approved by the Clinical Research Ethics Committee of Dicle University Medical School. No: 09062022 / 162.

The data of consecutive 946 patients were analyzed. The mean age of the negative exploration group (Group I) and acute appendicitis group (Group II) were 12.20 ± 2,31, and 11,56 ± 3,11, respectively. The male to female ratio was 2,2:1. There were 116 patients in group 1 and 830 patients in group 2. In terms of mean ages, there was no discernible difference between groups 1 and 2 (p > 0,05). The negative exploration rate was higher in girls (p < 0,05). Although all patients had complaints of abdominal pain, 83% of the patients had anorexia and 72% had both complaints. The following table summarizes the data's baseline characteristics (Table.1).

The table below lists the laboratory results of patients who had surgery due to a preliminary diagnosis of acute appendicitis. There was no difference between the bilirubin levels of the patients who underwent negative exploration and the group diagnosed with acute appendicitis (perioperative definitive diagnosis, and confirmed histopathologically) within the parameters we investigated, although there was a significant difference in the remaining parameters (Table.2).

In a study by Moosmann et al., NLR, PLR, and LMR values with 95% CI were calculated and determined according to age and gender in healthy individuals (Table 3) [6]. In our study, we calculated the NLR, PLR, and LMR for each patient. We then divided each patient's value by normal NLR, PLR, and LMR. Thus, these values were calculated as "age and sex-adjusted" for each patient. In Table 3, the values expressed by Moosmann et al. are given according to age and sex (These values belong to the 50th percentile). Based on these values, we calculated the "age and sex-adjusted value" for each patient separately in our study. This value we found was recorded in each patient's file.

Table 1

Baseline Characteristics
Characteristics (Table.1)		N	%
Gender	Male	658	69,60%
	Female	288	30,40%
Symptoms	Anorexia	785	82,90%
	Abdominal Pain	946	100,00%
	Nausea	767	81,07%
Diagnosis	Negatif Exploration	116	12,30%
	Acute Appendicitis	830	87,70%
Surgical Method	Laparoscopy	788	83,30%
	Laparotomy	110	11,62%
Wound Infections		72	7,60%
Intraabdominal Abscess		15	1,58%
LOS	< 24 hour	769	81,20%
	> 24 hour	177	18,80%

Table 2

Laboratory Results
Laboratory Markers	Negative Exploration		Acute Appendicitis
Laboratory Markers	Mean	Std. Dev.	Mean	Std. Dev.	P-value
WBC	9,69	1,93	14,17	3,02	< 0,001
PLT	259,13	63,41	286,17	69,42	< 0,001
LYM	2,38	1,01	1,93	0,63	< 0,001
MONO	0,96	0,33	1,22	0,55	< 0,001
NEU	6,34	1,8	12,01	2,87	< 0,001
NLR	3,4	2,24	6,9	2,83	< 0,001
PLR	127,58	60,23	165	71,95	< 0,001
LMR	2,59	0,96	1,74	0,69	< 0,001
Adjusted NLR	2,41	1,71	5,5	2,23	< 0,001
Adjusted PLR	1,13	0,54	1,52	0,69	< 0,001
Adjusted LMR	0,65	0,24	0,41	0,16	< 0,001
Direct Bilirubin	0,26	0,15	0,27	0,14	> 0,05
Total Bilirubin	0,7	0,44	0,66	0,41	> 0,05
CRP	0,7019	2,01	3,71	5,55	< 0,001

Table 3

NLR, PLR and LMR normal values
	Female			Male
AGE	NLR	PLR	LMR	NLR	PLR	LMR
6	1,08	101,77	5,17	1,13	101,72	4,56
7	1,17	97,28	4,94	1,15	107,74	4,71
8	1,12	105,46	5,05	1,1	105,31	4,56
9	1,17	108,81	4,66	1,18	103,24	4,53
10	1,24	111,53	4,5	1,13	105,15	4,14
11	1,15	108,88	4,16	1,22	112,57	4,27
12	1,19	108,91	4,43	1,21	111,91	4,09
13	1,35	110,32	4,28	1,22	116,85	4,11
14	1,57	109,23	4,12	1,34	109,36	3,95
15	1,56	115,4	3,92	1,22	110,71	3,83
16	1,58	118,11	3,88	1,49	113,63	3,78
17	1,69	122,4	3,86	1,7	112,07	3,55
18	1,76	118,78	3,73	1,76	112,64	3,59

The receiver operating characteristic curve (ROC) analysis was used to predict the cut-off value and other relevant outputs, as shown below. For all three related values (NLR, PLR, LMR), the adjusted variables have a better outcome than the non-adjusted by approximately 3% points for each of them (NLR, PLR, LMR). That’s reported in Table 4.

Table 4

Patients NLR, PLR, and LMR values with the cut-off values. (*AUC: Area under curve, LR+: Likelihood Ratio)*
	AUC (95% CI)	P-value	Cut-off	Sensitivity	Specificity	LR+
NLR	0,86 (0,81 − 0,90)	< 0,001	4,16	89	75,8	3,33
Adjusted NLR	0,89 (0,85 − 0,93)	< 0,001	2,57	94	72,5	3,41
PLR	0,68 (0,63 − 0,74)	< 0,001	129,1	68	65,5	1,97
Adjusted PLR	0,71 (0,65 − 0,76)	< 0,001	1,14	71,2	65	2,01
LMR	0,24 (0,18 − 0,29)	< 0,001	1,83	37,7	24	0,49
Adjusted LMR	0,20 (0,15 − 0,25)	< 0,001	0,47	26,5	27,5	0,36
CRP	0,77 (0,73 − 0,82)	< 0,001	0,5	70	75	2,77
TOTAL SCORE	0,96 (0,94 − 0,97)	< 0,001	4,5	94	86	6,3

Table 5

Present Novel Scoring System for Pediatric Appendicitis. (Dicle Pediatric Appendicitis Score, DIPAS).
	Adjusted NLR		Adjusted PLR		Adjusted LMR		CRP
	< 2,57	> 2,57	< 1,14	> 1,14	> 0,42	< 0,42	< 0,5	> 0,5
WBC Negative^#	0	1	0	1	0	1	0	1
WBC Positive^#	1	2	1	2	1	2	1	2
	* Score: between 0–8
	** High score implies a high risk of appendicitis # According to the age and sex

The ROC curve graph is as drawn below (Fig. 1).

We developed a new scoring system based on “age and sex-adjusted” NLR, PLR, LMR, and CRP parameters. For a patient admitted to the emergency department, first of all, as mentioned in the method section, patients should not have exclusion criteria. All patients with right lower quadrant pain + nausea or anorexia with abdominal pain have been included. We then gave points according to the patient's blood values. The details of our scores are summarized in the chart below. The total score is between 0 and 8 points. We found a high risk of appendicitis in high scores.

In this score, which we calculated between 0–8 points, we determined 4.5 and above as the best cut-off value for acute appendicitis.

Although acute appendicitis (AA) is one of the most common surgical emergency in childhood, diagnosis still remains challenging due to its potential atypical clinical presentation [7]. In this way, to accomplish the difficulties in diagnosis of AA and to define a standardized diagnostic tool for the diagnosis of acute appendicitis; dozens of different clinical, laboratory and radiological parameters and scores have been declared [7, 8]. But unfortunately, none of them could be helpful enough to distinguish the differential diagnosis of surgical acute abdominal pathologies from non-surgical pathologies. However, despite all efforts, the number of negative explorations did not decrease as desired yet.

Many years ago, the Alvarado score [9], Air score [10], and PAS (pediatric appendicitis score) [11] were started to be utilized to predict the AA diagnosis and its severity either by the surgeon or pediatric emergency physicians. According to the mentioned scores, ultrasonography had been performed in the practice [8]. Ultrasonography (US) is a rapid and safe modality that requires no intravenous (IV) access, no contrast, and no radiation exposure [8]. A meta-analysis, by Doria et all, including 7448 patients, reported the sensitivity and specificity of US were 88% and 94%, respectively [12]. However, to the best of our knowledge, it is also true that ultrasonography is operator-dependent [12]. Although US reports the diameter of the appendix as 9, there are publications reporting that non-operative management (NOM) can be applied if the physical examination is negative even if complicated appendicitis [13]. A meta-analysis published by Fugazzola et all has reported that the pooled proportion rate of NOM success is around 90% [13]. So, in that way, it is still not clear what kind of treatment modality will be followed in patients whose physical examination is positive and the appendix is not visualized in the ultrasonography report.

The classic WBC elevation with neutrophil dominance, which we have been using for a long time, is of course important in diagnosing acute appendicitis [14]. Recently, rapid, cheap, and easily accessible parameters such as NLR, PLR, and LMR have been added to these parameters [15, 16, 17, 18, 19].

Zouari et al studied 102 consecutive children who underwent appendectomy and compared the AA group with the negative exploration group [20]. They reported that a CRP level of ≥ 10 mg/L on admission and leukocytosis of ≥ 16,100/mL were predictive factors for pediatric AA. In their study, Çelik et al. reported the cut-off value and AUC as 10.4, 284, and 0.71, 0.64 for NLR and PLR, respectively, in the comparison of uncomplicated and complicated AA [19]. A meta-analysis from Korea included 19 studies comprising a total of 5,974 pediatric cases and reported AUC (0,86), Sensitivity (82%), and specificity (86%) for NLR [4].

There are a lot of studies that investigate the cut-off value, sensitivity, and specificity of WBC, NEU, CRP, NLR, PLR, and LMR in pediatric appendicitis [20, 21, 22]. These defined values differ, in almost all of them. As the main reason for this, it is argued that cut-off values are also different because of different populations. But, we read, discussed, and analyzed; and we found that almost all articles are reported based on non-adjusted values. We know and believe that normal NLR, PLR, and NLR values vary with the age and gender of the child. We think that different results were obtained because choicing random NLR, PLR, LNR, and other values were calculated regardless of the patient's age and gender. In the present study, were calculated adjusted NLR, PLR, and LMR for the individual patients. So to the best of our knowledge, this is the first study utilizing age and sex-adjusted blood parameters and also this scoring system is the first pediatric appendicitis prediction score created with age and sex-adjusted data.

In a patient admitted to the hospital with abdominal pain + right lower quadrant tenderness, mild WBC increase is considered significant for acute appendicitis, while severe WBC increase is considered significant for perforated appendicitis. Bilici et all have found a higher mean of WBC in the AA group compared to non-AA [23]. Eun et all reported the sensitivity and specificity values of WBC and CRP as 0.79, 0.66, and 0.73, 0.68, respectively [4]. Although WBC is generally high in acute appendicitis, WBC may be low in some cases. In patients with low WBC value, we see a decrease in lymphocytes with an increase in Neutrophils count. This dynamic process indicates the initiation of the inflammatory mechanism cascade [19]. Some studies have further increased the diagnostic value by using WBC, together with ischemia-modified albumin, and pentraxin-3 (24). Of course, it should not be forgotten that these values may increase in cases such as testicular torsion, gastric necrosis, volvulus, intussusception, acute mesenteric ischemia, etc., as well as the neutrophil to lymphocyte ratio (.

To summarize, since patients with low WBC are less likely to be diagnosed with acute appendicitis than patients with high WBC, the patients were divided into two as low WBC and high WBC patients, and then the other data of these patients such as NLR, PLR, LMR, and CRP were scored as mentioned in the results section above after the results are statistically proven.

In our study, in which we calculated scores between 0–8 points, we determined 4.5 and above was determined as the best cut-off value for acute appendicitis with higher AUC (0,96), sensitivity (94%), specificity (86%), PPV (97,5%), NPV (65%), Accuracy (92,6%), and Misclassification Rate (7,4%).

In conclusion, Normal NLR, PLR, and LMR values vary according to age and gender in the childhood period. Especially in this scoring system, the age and gender of the patient should be considered when evaluating the blood results. Further studies are needed to determine the optimal cut-off value and the reliability, and validity of this score.

The limitations of the study

The number of patients. Populations heterogeneity.

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No competing interests reported.

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A Novel Diagnostic Scoring System for Pediatric Appendicitis Based on Age and Sex-Adjusted Hematological Parameters

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Abstract

Objective

Methods

Results

Conclusion

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1. Introduction

2. Material-methods

2.1 Patients

2.2 Exclusion Criteria

2.3 Analytical procedures

2.4 Clinical Evaluation and Process

2.5 Statistical Analysis

2.6 Ethics

3. Results

4. Discussion

References

Additional Declarations

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