Keep it Simple,Laboratory Parameters to Predict Complicated Acute Appendicitis in Children Younger Than Five Years

Abstract

Background

The clinical presentation of acute appendicitis in the youngest age lacks specific signs and symptoms, and it is difficult to obtain an accurate clinical diagnosis. Once the diagnosis is made, it is necessary to determine if the appendicitis is simple and able to be managed non-surgically, or complicated, therefore requiring surgery. Together with the clinical picture and imaging, routine laboratory values play a vital role in this decision. The aim of this study is to evaluate routine blood in their ability to differentiate between complicated and uncomplicated acute appendicitis.

Method

A retrospective analysis was conducted from a single pediatric surgery department of all children 5 years of age or younger who underwent surgery for acute appendicitis between the years 2010-2020.

Results

728 children were diagnosed with acute appendicitis, and 42 children were under the age of 5 years. There was a significant difference in the C-reactive protein, white blood cell count, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio in the complicated group versus the uncomplicated group. The value of these together for prediction complicated appendicitis were 84.8% sensitivity, 80.9% specificity, 82.8% positive predictive value, and 72.8% negative predictive value. These values were all higher than both the Alvarado score and the PAS (P < .05).

Conclusions

C-reactive protein, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio are simple laboratory parameters that can help identify complicated versus uncomplicated appendicitis in children 5 years old or younger. These universal parameters may help guide the treatment and decision to operate on a difficult to diagnose population.

Keywords

appendicitis pediatric surgery inflammatory parameters complicated appendicitis

Introduction

Acute appendicitis (AA) in children is a common abdominal pathology, and an appendectomy is 1 of the most common surgical procedures performed in the pediatric population,¹ with a lifetime cumulative incidence of up to 9.0%.² The peak ages of having appendicitis being between 10 - 19 years, and the number of younger children diagnosed with appendicitis (<5 yo) is between 3-6% of the total pediatric cases.^3,4 Despite continual debate there is a higher percentage of pediatric cases when compared to adults, (especially in the younger children), that are managed non-operatively with antibiotics.^5,19 When deciding which patients have the highest probability to be successfully managed without surgery, it is crucial to first determine if the AA is simple or complicated (perforated, necrotic, abscess).

Children less than 5 years have an “unusual” clinical presentation of acute appendicitis, with a high percentage of these children (up to 100% of those less than 2 years) presenting with an already perforated appendix.^4,6 The difficult diagnosis of AA in young children is based on non-specific signs/symptoms, physical exam, blood work, scoring systems, and imaging modalities. Scoring systems that have been validated in helping predict acute appendicitis include the Alvarado score,⁷ the Pediatric Appendicitis Score (PAS), and the Appendicitis Inflammatory Response (AIR) score.

The Alvarado score has been found to be inconsistent in children, especially as the age decreases,⁶ and therefore is seldomly used in the pediatric populations. The PAS and AIR have been found to be more sensitive and specific in younger populations, yet there is still a paucity of data and no one scoring system that has been clearly accepted as a standard of care. Nevertheless, these scoring systems play an important role in combination with clinical features and imaging in assisting with the diagnosis of AA in children.⁸

Once completing the first challenge of correctly diagnosing appendicitis, the next step is to determine if the acutely infected appendix is complicated or simple. The importance of this step is emphasized by the increasing trend of successful nonoperative management for simple appendicitis, especially in the pediatric populations.^6,9,10 This nonoperative approach has not only been found to be beneficial to the patient—better pain control, less sick leave—but also economically beneficial. Nevertheless, there remains a high rate of recurrence⁹ and ultimate appendectomy rate in the first year of over a quarter of the patients.⁵

Combining laboratory results, clinical scores, and imaging theoretically holds the highest sensitivity to diagnosing appendicitis and determining if it is complicated. Despite positive studies showing the value of combining different modalities, there are no clear guidelines, especially in the very young populations,¹¹ and the most accurate combination of clinical signs and symptoms, scoring systems, laboratory results, and imaging remains to be established. With the optimal “bundle” and diagnostic algorithm in this patient population, there can be a decrease in delayed diagnosis, in missed complicated cases, and unnecessary surgeries.¹² Here we focus on the results of routine laboratory test, C-reactive protein (CRP) and complete blood count values (neutrophil to lymphocyte Ratio, (NLR) and platelets lymphocytes ratio (PLR)) to investigate their ability to help detect complicated versus simple AA in children 5 years old and less. We hypothesize that these standard blood test can be of value, regardless of imaging modality used, when making this difficult distinction in a challenging population.

Method

A retrospective study was conducted between February 2010 to February 2020 analyzing children who underwent appendectomy in the pediatric surgery department of a single tertiary medical center. Excluded were patients who were older than 5 years old, those with known immunosuppression (leukemia, HIV), on chronic steroid therapy, and when surgery was performed without preoperative imaging. Patient’s demographic, comorbidities, presenting signs and symptoms, laboratory results, preoperative imaging, details of the operation, length of hospitalization, postoperative course, and complications were all analyzed. Postoperative complications were based on the Clavien-Dindo classification.²¹ Alvarado score and PAS were calculated based on the medical records if they were not documented in the patient intake. The blood test used was based on standard, routine blood test taken in our pediatric emergency room for patients presenting with a possible differential diagnosis of acute appendicitis. These blood tests included CBC, CRP, and chemistry. NLR and PLR were calculated from these tests (absolute neutrophil count/absolute lymphocyte count, absolute platelet count/absolute lymphocyte count). AA were classified as simple or complicated (perforated) appendicitis based on preoperative imaging, intraoperative findings, and pathology results. A complicated appendicitis was defined as having necrosis with perforation, perforation, abscess, or generalized purulent peritonitis.²⁰ A simple appendicitis was considered having local inflammation, a phlegmon without perforation, and/or with spotted necrosis without perforation or generalized purulent peritonitis.

Data was analyzed using SPSS version 25.0 software (IBM Corp, Armonk, NY, USA). All P values were two-sided, and the significant level was specified as P < .05. Statistical analysis included descriptive analysis (mean, median, and range), standard deviation for continuous variables, proportions for discrete variables, comparative tests (chi-square for discrete variables and t-test for continuous variables), and multivariate linear regression for correlation. The complicated appendicitis NLR\PNR was established based on independent factors, and the area under the curve (AUC) of ROC was used to quantify the differentiation degree of the prediction model. A P < .05 with 95% confidence interval (95% CI) was considered statistically significant.

Result

A total of 728 patients were diagnosed with AA in this period. Three hundred and forty-two were operated on without preoperative imaging, and 343 children were older than 5 years of age. Forty-two children remained in our cohort, in which 35 children had simple appendicitis (83%) and 7 had complicated appendicitis (17%).

Between the 2 groups there were no differences in age and sex. In the complicated group the mean age was 3.14 +/− .8 years old, with 5 (71.5%) males and 2 (28.5%) females. In the simple appendicitis group the mean age was 3.6 +/− 1.4 years, with 22 (63%) males and 13 (37%) females. In the complicated group a computed tomography scan (CT) was used 57% and ultrasound 43% of the time compared to 6% and 94%, respectively, in the simple AA group (P < .005). Demographic details and preoperative data are summarized in Table 1.

Table 1.

Demographic Data of the Pediatric Study Population.

	Complicated GroupN=7	Simple GroupN=35	P Value
Age (average)	—		.422
Mean (+/− STD)	3.14±.8	3.6±1.4	—
Median	3	4
Range	2-5	1-5
Gender	—		.335
Male	5 (71.5%)	22 (63%)	—
Female	2 (28.5%)	13 (37%)	—
Image modality	—		<.005
CT	4 (57%)	2 (6%)	—
US	3 (43%)	33 (94%)	—
Alvarado score (mean)	9	7	<.005
PAS score (mean)	6	5	.320
Symptoms	—
Abdominal pain	7 (100%)	35 (100%)	.444
Vomiting and nausea	2 (28.5%)	10 (28.5%)	.005
Anorexia	7 (100%)	20 (57%)	.005
Migration	6 (85%)	22 (63%)	—
Signs	—
Tenderness	6 (85%)	24 (68.5%)	<.005
Rebound	5 (71%)	10 (28.5%)	<.005
Fever	38.2 (71%)	37.1 (70%)	n\s

STD = Standard deviation.

All the patients in both groups presented with abdominal pain. The symptoms of anorexia (100 vs 57% in the simple group), and migration of pain (85 vs 63% in the simple group) were present significantly more in the complicated group, along with the signs of rebound (71 vs 28.5%), and tenderness (85 vs 68.5%), respectively. The mean ALVARADO score (9 & 7) and PAS (7 and 5) were significantly higher in patients with complicated appendicitis than that with simple appendicitis. The complicated group had a significantly higher WBC, CRP, NLR, and PLR ratio. The mean WBC was 24.7+-7.9 cell/mm3 in the complicated group compared to the simple group with a mean of 16.2+-5.7 (P = .002). The mean in NLR, PLR, and CRP were 14.9+-3.94, 243.8+-62, and 19.9+-10.6, respectively. The neutrophilia percentage was above 70% in both groups and not statistically significant. Laboratory results including CRP, CBC, NLR, and PLR were calculated and are summarized in Table 2.

Table 2.

Laboratory Data of the Pediatric Study Population.

	Complicated Group N=7	Simple Group N=35	P Value
NLR	—		<.005
Mean (+/− STD)	14.9±3.94	8.3±6	—
Median	14.6	6.9
Range	7.8-19.25	.7-24
PLR	—		<.005
Mean (+/− STD)	243.8±62	199.2±119.1	—
Median	240	180
Range	163-357	43.6-507
CRP	—		<.005
Mean (+/− STD)	19.9±10.6	6.7±7.9	—
Median	20	2.59
Range	4.6-35.6	.1-34
WBC (10*9/L)	—		<.005
Mean (+/− STD)	24.7±7.9	16.2±5.7	—
Median	22	16.5
Range	13-36	3.9-29.8
Neutrophilia	—		n/s
>70%	7 (100%)	35 (100%)	—

Operative details, findings, and postoperative course are summarized in Table 3. The surgical findings of all the patients in the complicated group included generalized peritonitis (hypervascularity and diffused purulence within the peritoneum), abscess, perforation, and necrosis with perforation of the appendix. Of the non-complicated group all the intraoperative findings included localized peritonitis, and 3 had small patches of necrosis without perforation or abscess. There was a significant difference in the operation time and length of hospital stay in the complicated group when compared to the simple appendicitis group. Thirty days postoperatively there were no major or minor complications in either group, nor mortality. There were no misdiagnosis (“white appendix”) with any patient.

Table 3.

Operation Results of the Pediatric Study Groups.

	Complicated GroupN= 7	Simple GroupN=35	P Value
Length of operation (hrs)	01.20± .24	.30± 12	<.005
Length of hospitalization From surgery (days)	—		<.005
Mean	10.3±2.5	2±4.2	—
Median	10	2
Range	7-15	1-6
Intraoperative findings	—		<.001
Generalized peritonitis	7(100%)	0	—
Localized peritonitis	0	35(100%)
Abscess	7(100%)	0
Perforation	7(100%	0
Gangrenous	7(100%)	3(8.5%)
Phlegmonous	0	32(92.5%)

Table 4 show the ROC curve analysis of NLR, PLR, WBC, and CRP as having the ability to predict complicated appendicitis, the AUC was .680 (95% CI: .545-.715, P < .05). When the value of P was .5, the Youden index was the largest (.5). Patients with the P of .5 or greater were more likely to have complicated appendicitis versus simple AA. The values of NLR, PLR, WBC and CRP for predicting complicated appendicitis were 84.8% sensitivity, 80.9% specificity, 82.8% positive predictive value (PPV) and 72.8% negative predictive value (NPV). These values were all higher than both the Alvarado score and the PAS (P < .05). There were no significant differences in AUC between the Alvarado score and PAS (P > .05).

Table 4.

NLR, PLR, WBC, and CRP, ALVARADO score, and PAS Performance at Optimal Cutoff Point Values For Complicated Appendicitis.

	Optimal Cutoff Point	Sensitivity %	Specificity %	PPV%	NPV%
NLR	5	—
PLR	141.15
WBC	11
CRP	5	84.8	80.9	82.8	72.8
ALVARADO score	7	67	79	64	67
PAS	6	62	74	67	64

Discussion

Our study demonstrated that admission values of WBC, CRP, calculated NLR, and PLR are significantly increased in patients younger than 5 years old with complicated appendicitis when compared to patients with uncomplicated appendicitis. The ability to distinguish between complicated and simple appendicitis remains a critical step in the young pediatric age group that is difficult to understand and diagnose. Especially when this may be the difference between recommending surgical versus nonoperative management. Studies have documented that in children up to 28% of acute appendicitis was missed and only diagnosed upon a second presentation to the emergency department, with one of the risk factors of misdiagnosis being younger aged children.¹³ To prevent misdiagnosis, and mismanagement, it is vital to understand what signs, symptoms, imaging, and laboratory tests are the most reliable (and cost efficient) individually and in combining modalities.

Regarding prediction, the WBC, NLR, PLR, and CRP could identify children at high risk for complicated appendicitis, and were found in this study to be more sensitive than the Alvarado and PAS scoring systems. As mentioned earlier, the Alvarado score has its limitations in children, and the PAS is difficult to accurately establish in the very young age group.¹⁴ Therefore, in this challenging population, where also the physical exam is unreliable, clinicians must depend more on laboratory results and imaging.

In regard to imaging, US, computed tomography, and magnetic resonance have similar sensitivities and high diagnostic accuracy.¹⁵ Yet the majority of studies involve pediatric groups up to 18 years of age. Most protocols recommend ultrasound followed by computer tomography if there is still a question about the diagnosis.¹⁶ Yet the use of computer tomography is controversial in the very young and may cause more harm than benefit if there is no absolute indication for its use.¹⁷ There is also the possible need for sedation/anesthesia just for small children to undergo the computer tomography.

Together with strong clinical exam, signs, symptoms, sonography, and laboratory parameters there should be enough objective evidence to determine the diagnosis of appendicitis safely and efficiently, and if it is complicated or not. Hao et al found an increased sensitivity when combining US with PAS, yet this was without inclusion of laboratory values and with an average age above 8 years old.¹⁸ A group from Boston led by Dr Anandalwar found that incorporation of the WBC and PMN differential increased the predictive value of US in diagnosis of appendicitis.¹¹ In this study they were able to decrease the utilization of CT by over a quarter, yet again the average age was 11 years old, and their endpoint was not to differentiate between complicated or uncomplicated appendicitis.

Our study is limited by its retrospective design, small sample size, and coming from a single center. Here we also concentrate solely on laboratory parameters. Further prospective studies need to develop the optimal “bundle” incorporated laboratory parameters, imaging, and physical exam/signs/symptoms for the diagnoses of appendicitis and differentiating between complicated and simple appendicitis. This evidence based “bundle” can lead to further age specific recommendations. If future evidence supports the use of a combination of laboratory parameters, US, scoring systems, and clinical picture, then the guidelines may also be beneficial to lower socioeconomic and rural settings by decreasing the need for surgery, transfers, and missed complicated cases.

Results from this study, along with further studies describing an optimal “bundle,” may change clinical practice and decision making. As mentioned above, the option for safe nonoperative management is increasingly popular and proven within the pediatric population. Some studies have also shown an increasing trend of nonoperative management during the COVID pandemic.²² Therefore results like ours may give the treating surgeon more confidence and evidence that they are making the appropriate decision when recommending nonoperative or operative management.

In conclusion, routine laboratory parameters (WBC, CRP, NLR, PLR) are sensitive for predicting complicated appendicitis in children younger than 5 years of age, and therefore may be a valuable tool in correctly diagnosing and treating this difficult patient population.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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