Abstract
Purpose
Differentiating abdominal pain due to coronavirus disease (COVID-19)-associated multisystem inflammatory syndrome (MIS-C) in children with acute appendicitis (AA) can cause diagnostic dilemmas. This study aimed to evaluate the efficacy of a previously described scoring system and improve its diagnostic ability in differentiating between these diseases.
Methods
This study was conducted between March 2020 and January 2022. Patients who had MIS-C with gastrointestinal system (GIS) involvement and patients who underwent surgery for appendicitis were included. First, all patients were evaluated using the new scoring system (NSS). The groups were compared by adding new MISC-specific parameters to NSS. The scoring system was evaluated using propensity score matching (PSM).
Results
A total of 35 patients with abdominal pain due to GIS involvement in MIS-C (group A) and 37 patients with AA who had ALT, PRC, and D-dimer results at their first admission (group B) were included in the study. The mean age of patients in group A was lower than that of patients in group B (p < 0.001). False NSS positivity was found in 45.7% of the patients with MIS-C. Lymphocyte (p = 0.021) and platelet counts (p = 0.036) were significantly lower in the blood count and serum D-dimer (p = 0.034), C-reactive protein (CRP) (p < 0.001), and procalcitonin (p < 0.001) were significantly higher in the MIS-C group. We created a scoring system called the Appendicitis–MISC Score (AMS) using the NSS and new parameters. The sensitivity and specificity of AMS diagnostic scores were 91.9% and 80%, respectively.
Conclusion
MIS-C with GIS involvement may present as acute abdomen. It is difficult to differentiate this condition from acute appendicitis. AMS has been shown to be useful for this differentiation.
Keywords: COVID-19, MIS-C, Acute appendicitis, Children
Introduction
The outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2/COVID-19) began in December 2019 in Wuhan, China [1]. After its rapid spread worldwide, a large percentage of children infected with COVID-19 have become asymptomatic or mildly symptomatic [2, 3]. In April 2020, a life-threatening hyperinflammatory condition called multisystem inflammatory syndrome in children (MIS-C) was first recognized [4]. The involvement of two or more organs (cardiovascular, gastrointestinal, renal, hematological, dermatological, and neurological) should be included in the MIS-C criteria [5]. Gastrointestinal symptoms, such as vomiting, diarrhea, and abdominal pain, have been reported in 50–90% of children with MIS-C [6].
Differentiating abdominal pain from MIS-C in children with acute appendicitis can lead to diagnostic dilemmas. In the recent literature, several case reports have described MIS-C mimicking acute appendicitis [7–9]. In 2018, Dokumcu et al. described a new scoring system for appendicitis, which contained radiography and ultrasonography (US) results, in addition to symptoms and signs on physical examination. This “new scoring system (NSS)” has the highest rate of sensitivity (94.6%) and a high rate of specificity (87.9%) [10] in the literature.
The aim of this study is to evaluate the effectiveness of NSS and to develop a stronger scoring system, including NSS in distinguishing between MIS-C and AA.
Materials and methods
Data collection and study group
This study was conducted over 2 years (March 2020–January 2022) at a large urban tertiary center. After obtaining approval from the institutional review board (IRB#2022/02-47), the medical records of the patients (1–18 years old) with MIS-C and acute appendicitis were retrospectively reviewed. For comparison, two groups as MIS-C (Group A) and acute appendicitis (Group B) were constituted. Group A included children diagnosed with MIS-C with gastrointestinal involvement. Patients with incomplete medical records, those without complaints of abdominal pain, and who underwent appendectomy before admission were excluded from Group A. Group B included children who underwent surgery for appendicitis. The existence of polymorphonuclear leukocytes and lymphocytes in the appendiceal specimen was considered positive for AA. Patients who diagnosed as uncomplicated and complicated acute appendicitis were included. Patients who had negative appendectomy (defined as the absence of inflammatory cells in the appendiceal sample) and those with missing data (whose preoperative assessment did not include the parameters used to distinguish MIS-C in this study) were excluded from Group B.
Definition of scoring systems
Both groups were evaluated using NSS parameters [10]. These parameters were;
sex
type (continuous or intermittent), duration and migration of abdominal pain
anorexia, bilious vomiting, pyrexia (body temperature ≥ 38.0 °C [11])
presence of localized right lower quadrant abdominal tenderness, guarding, gurgling, a positive heel drop test, and rebound tenderness in physical examination
leukocytosis (> 10.600/mm3), neutrophilia (> 75%), elevated C-reactive protein (CRP) levels (> 5 mg/L) in blood examination
scoliosis on the right side, localized air-fluid level, gas deposition in the right lower quadrant on standing abdominal radiography
appendix diameter (> 7 mm), presence of a thickened wall, and surrounding loculated fluid collection on US
Consistent with the previous study, an NSS score ≥ 12 was accepted as the cutoff level for the diagnosis of AA [10].
Both groups were compared by new parameters thought to be MISC-specific (fatigue (feeling extra tired [12]), headache, maximum body temperature, and total fever [11] days in the history, serum lymphocyte and platelet counts, serum procalcitonin (PRC), alanine transferase (ALT), CRP, and D-dimer value). Statistically significant parameters were included in the scoring. A scoring system named the Appendicitis–MISC Score (AMS) was created using eight new parameters including the NSS score.
Statistical analysis
For discrete and continuous variables, descriptive statistics (mean, standard deviation, median, minimum, and maximum values) were calculated. In addition, the homogeneity of variances, which is one of the prerequisites of parametric tests, was checked using Levene’s test. The assumption of normality was tested using the Shapiro–Wilk test. To compare the differences between the two groups, an independent sample t-test was used when the parametric test prerequisites were fulfilled, and the Mann–Whitney U test was used when such prerequisites were not fulfilled. The chi-squared test was used to determine the relationships between the two discrete variables. When the expected sources were less than 20%, values were determined using the Monte Carlo simulation method to include these sources in the analysis. Age was determined as covariates (to be excluded), and the groups were compared using covariance analysis.
The cutoff points for the parameters were evaluated using receiver operating characteristic (ROC) curve analysis. Area under curve (AUC) of the ROC curve was calculated. We identified the value for each that maximized the Youden index (J), a summary statistic based on receiver operating characteristic curves that equally weights sensitivity and specificity (sensitivity + specificity − 1). The scores were estimated by constructing a multivariable logistic regression model considering the following covariates: NSS score, age, absence of fatigue, CRP, d-dimer, procalcitonin values, lymphocyte, and platelet counts. Due to the study design, we expected potential imbalances between groups. Propensity score matching was used to reduce potential selection bias between appendicitis group and MIS-C group. Data were evaluated using SPPS, version 25 (IBM Statistics, New York, USA). Statistical significance was set at p < 0.05 and p < 0.01.
Results
A flowchart of the study population is shown in Fig. 1. A total of 77 patients were diagnosed with MIS-C during the study period, and 35 patients (12 girls and 23 boys) of these were included in the study. In the same period, 852 patients underwent surgery for suspected AA, and 37 (15 girls and 22 boys) of these were included.
Fig. 1.
Flowchart of study population. MIS-C Multisystem inflammatory syndrome, GIS gastrointestinal system, AA acute appendicitis, PRC procalcitonin, ALT alanine transferase
The mean age of Group A (7.9 ± 4.3) was significantly lower than that of Group B (12.1 ± 2.2) (p < 0.001; independent samples t-test). There was no difference in sex between the groups (p = 0.761; Yates continuity correction). In terms of NSS parameters, the type (continuous/intermittent) and migration of pain, anorexia, bilious vomiting, gurgling, positive Hell drop test, neutrophilia on blood tests, and abdominal radiographic findings were not statistically different between the groups. Localized abdominal tenderness, guarding, and rebound tenderness on physical examination, and leukocytosis on blood tests were significantly higher in Group B. Pyrexia and CRP positivity were significantly higher in Group A. NSS scores of 12 and above were found in 45.7% of the patients in Group A. In the terms of distinguishing acute appendicitis from MIS-C, NSS had a true negative rate of 26.4%, a false negative rate of 4.2%, a true positive rate of 47.2%, and a false positive rate of 22.2%. In group B, NSS positivity was observed in 91.9% of patients. The sensitivity of the NSS was calculated to be 91.9%, but the specificity of the NSS decreased to 54.3% when patients with MIS-C were included. A comparison of the patient characteristics and findings between the groups is summarized in Table 1.
Table 1.
Comparison of patient characteristics and findings between groups
| Predictor | Group A (n = 35) | Group B (n = 37) | p |
|---|---|---|---|
| Age | 7.9 ± 4.3 | 12.1 ± 2.2 | < 0.001a |
| Male Gender | 65.7% | 59.5% | 0.761b |
| Continuous abdominal pain | 100% | 91.9% | 0.240c |
| Migration of pain | 17.1% | 37.8% | 0.090b |
| Anorexia | 88.6% | 75.7% | 0.265b |
| Bilious vomiting | 34.3% | 21.6% | 0.349b |
| Pyrexia (≥ 38.0 °C) | 100% | 24.3% | < 0.001b |
| Right lower quadrant tenderness | 71.4% | 100% | < 0.001c |
| Guarding | 20.0% | 54.1% | 0.006b |
| Rebound tenderness | 5.7% | 29.7% | 0.019b |
| Positive heel drop test | 11.4% | 21.6% | 0.399b |
| Gurgling | 17.1% | 13.5% | 0.920b |
| Leukocytosis (> 10.600/mm3) | 45.7% | 86.5% | 0.001b |
| Neutrophilia (> %75) | 77.1% | 86.5% | 0.469b |
| Increased CRP (> 5 mg/L) | 91.1% | 78.4% | 0.028c |
| Scoliosis to the right side | 20.0% | 37.8% | 0.160b |
| Localized air-fluid level | 48.6% | 70.3% | 0.102b |
| Localized gas deposition | 51.4% | 70.3% | 0.162b |
| Appendicolith | 0 | 10.8% | 0.115c |
| Increased appendix diameter (> 7 mm) | 5.7% | 73.0% | < 0.001b |
| Thickened appendix wall | 17.1% | 75.7% | < 0.001b |
| Periappendiceal free fluid | 17.1% | 45.9% | 0.018b |
| NSS Score ≥ 12.0* | 45.7% | 91.9% | < 0.001b |
CRP C-reactive protein, NSS new scoring system
Bold values indicate significant p-values (p < 0.05)
aIndependent samples t-test
bYales Continuity Correction
cFisher's Exact Test
dMann–Whitney U test
*Dokumcu Z, Toker Kurtmen B, Divarci E, et al. Retrospective Multivariate Analysis of Data from Children with Suspected Appendicitis: A New Tool for Diagnosis. Emerg Med Int [Internet]. 2018;2018:1–9. Available from: https://www.hindawi.com/journals/emi/2018/4810730
The groups were compared using new parameters (fatigue, headache, maximum body temperature, total fever days in history, serum lymphocyte and platelet counts, serum procalcitonin (PRC), alanine transferase (ALT), CRP, and D-dimer values). Fatigue, total fever days, maximum body temperature, procalcitonin positivity, procalcitonin level, CRP value, D-dimer positivity, and D-dimer level were significantly higher in group A. Lymphocyte count and platelet count were significantly lower in group A. Comparisons of the new parameters between groups are summarized in Table 2.
Table 2.
Comparison of new parameters between groups
| Predictor | Group A (n = 35) | Group B (n = 37) | p |
|---|---|---|---|
| Fatigue | 48.8% | 5.4% | < 0.001a |
| Headache | 11.4% | 0 | 0.051b |
| Total fever days (Q1–Q3) | 4 (3.7–5.2) | 0 (0.1–0.4) | < 0.001c |
| Maximum body temperature (°C) (Q1–Q3) | 39.0 (39.0–39.5) | 36.7 (36.7–37.3) | < 0.001c |
| Lymphocytopenia | 28.8% | 8.1% | 0.051a |
| Lymphocyte count (cells/µL) (Q1–Q3) | 1100 (874–1486) | 1400 (1257–1835) | 0.021c |
| Thrombocytopenia | 11.4% | 0 | 0.051b |
| Platelet count (cells/µL) | 245,457 ± 113,791 | 294,405 ± 77,544 | 0.036d |
| Pro-calcitonin positivity | 97.1% | 56.8% | < 0.001a |
| Pro-calcitonin value (µg/L) (Q1–Q3) | 1.36 (0–21.8) | 0.12 (0–8.7) | 0.001a |
| Alanine-transferase positivity | 5.7% | 2.7% | 0.609b |
| Alanine-transferase value (Q1–Q3) | 14 (12.9–28.6) | 14 (13.9–19.9) | 0.735c |
| CRP value (mg/L) (Q1–Q3) | 144 (125–189) | 39 (51–113) | < 0.001c |
| D-Dimer positivity | 100% | 78.4% | 0.005b |
| D-Dimer value (µg/L) (Q1–Q3) | 2060 (1965–5364) | 990 (1366–5949) | 0.034c |
Q1 first quartile, Q3 third quartile, CRP C-reactive protein
Bold values indicate significant p-values (p < 0.05)
aYales Continuity Correction
bFisher's exact test
cMann–Whitney U test
dIndependent samples t-test
To test the efficiency of the new parameters and NSS score, specificity and sensitivity were calculated using the data of Groups A and B. The cutoff points for the parameters were evaluated using receiver operating characteristic (ROC) curve analysis and propensity score matching. Using propensity score matching, possible biases were prevented and the biostatistical analysis procedure was concluded correctly. The cutoff values and diagnostic performance characteristics of the parameters in the differential diagnosis of patients are summarized in Table 3.
Table 3.
Cut-off values and diagnostic performance characteristics of parameters in the differential diagnosis of patients with acute appendicitis and MIS-C
| Variable(s) | Cut-off value | Specificity (%) | Sensitivity (%) | AUC (95% CI) | p* |
|---|---|---|---|---|---|
| NSS | ≥ 12 | 54.3 | 91.9 | 0.787 (0.678–0.897) | < 0.001 |
| Age (months) | ≥ 92.5 | 83.8 | 54.3 | 0.774 (0.667–0.881) | < 0.001 |
| Body temperature (Celsius) | ≤ 38.4 | 94.3 | 89.2 | 0.963 (0.921–1.000) | < 0.001 |
| Total fever days | < 3 | 82.9 | 97.3 | 0.990 (0.972–1.000) | < 0.001 |
| Lymphocyte count (cells/µL) | ≥ 795 | 86.5 | 42.9 | 0.658 (0.530–0.785) | 0.022 |
| Platelet count (cells/µL) | ≥ 216,000 | 89.2 | 48.6 | 0.675 (0.546–0.805) | 0.011 |
| CRP (mg/L) | ≤ 42.5 | 96.1 | 51.4 | 0.753 (0.640–0.866) | < 0.001 |
| Pro-calcitonin (µg/L) | ≤ 0.13 | 94.3 | 51.4 | 0.728 (0.606–0.850) | 0.001 |
| D-dimer (µg/L) | ≤ 905 | 82.9 | 45.9 | 0.645 (0.514–0.776) | 0.034 |
AUC area under curve, CI confidence interval, NSS new scoring score, CRP C-reactive protein
*Significance of AUC; p value < 0.05 was considered statistically significant
Statistically significant p values shown in bold
Our scoring system, named the Appendicitis–MISC Score (AMS), was created using eight parameters including the NSS score. AMS parameter scores were assigned as 1 for predictors with an odds ratio (OR) < 3, 2 for predictors with an OR of: 3–6, and 3 for predictors with an OR of > 6. The LR (logistic regression) analysis of the predictors and determination of scores that were valued according to the ORs are summarized in Table 4. A total score of 8 or higher was considered the cutoff level for the diagnosis of AA. For the 72 patients, the sensitivity and specificity of the diagnostic score were 91.9% and 80%, respectively. The interpretations of the diagnostic scores are summarized in Table 5.
Table 4.
Results of logistic regression and determination of scores according to odds ratios
| Predictor | Odds ratio | 95% CI | ||
|---|---|---|---|---|
| Lower | Upper | Score | ||
| Lymphocyte count ≥ 795(cells/µL) | 0.500 | 0.077 | 3251 | 1 |
| D-dimer ≤ 905 (µg/L) | 2005 | 0.226 | 17,804 | 1 |
| Age ≥ 92.5 (months) | 2311 | 0.423 | 12,626 | 1 |
| Platelet count ≥ 216,000 (cells/µL) | 4756 | 0.686 | 32,966 | 2 |
| Pro-calcitonin ≤ 0.13 (µg/L) | 5675 | 0.495 | 65,019 | 2 |
| Absence of Fatigue | 7055 | 1000 | 49,794 | 3 |
| NSS ≥ 12 | 16,571 | 1464 | 187,519 | 3 |
| CRP ≤ 42.5 (mg/L) | 23,594 | 0.608 | 915,828 | 3 |
CI confidence interval, NSS new scoring system, CRP C-reactive protein
Data for the score of predictors are shown in bold
Table 5.
Interpretation of diagnostic score
Discussion
Abdominal pain due to gastrointestinal (GI) involvement is one of the most common clinical manifestations of MIS-C in children [13]. According to the literature, it has been shown that patients with MIS-C could present in up to 30% as an acute abdomen [14, 15]. In our series, 82% of MIS-C patients had GI involvement and 60% of them presented as an acute abdomen. Several case reports have described MIS-C mimicking acute appendicitis [7–9]. Some patients undergo surgery for abdominal pain without any surgical reasons [8, 14, 16]. This may delay diagnosis, cause loss of treatment time, and increase the need for intensive care. MIS-C has high morbidity and mortality without prompt diagnosis [15, 17, 18]. Furthermore, it has been reported that postoperative resistant fever and shock can develop after appendectomy in MIS-C patients. In our series, three patients with MIS-C underwent surgery for suspected AA. Overall, the appendix appeared normal and no additional surgical pathology was found. Rouva et al. recently published a systematic review of this topic. They found that in more than half of patients with MIS-C and acute abdomen, laparotomy was proven unnecessary [6].
Various scoring systems have been introduced to distinguish between acute appendicitis and non-surgical abdominal pain in children. Pediatric appendicitis score (PAS) and Alvarado scoring system (ASS) are based on symptoms and signs on physical examination and white blood count, excluding radiological data [19, 20]. A new scoring system (NSS) for appendicitis was described in 2018, which includes symptoms and signs on physical examination, radiography, and US results. They found that NSS had a true negative rate of 53.1%, a false negative rate of 1.3%, a true positive rate of 35.1%, and a false positive rate of 10.4%; they also had the highest rate of sensitivity (94.6%) and a high rate of specificity (87.9%) to distinguish acute appendicitis from PAS and ASS [10]. Although the role of radiography in the diagnosis of AA is controversial [21, 22], Dokumcu et al. showed that it is useful together with US [10]. Therefore, we used NSS to distinguish acute appendicitis from abdominal pain in patients with MIS-C. However, the specificity of the NSS decreased to 54.7% when patients with MIS-C were included.
Symptoms and physical examination findings alone were not effective at differentiating acute abdomen of MIS-C and acute appendicitis [6]. MIS-C were reported to have a high frequency of GI symptoms like abdominal pain, vomiting, and diarrhea [13]. In our series, we did not find significant difference between two groups in terms of symptoms such as abdominal pain, anorexia or bilious vomiting. Children with MIS-C mostly present with persistent fever for more than three days. Fever is a cardinal characteristic of this pathology and is essential for diagnosis [23]. In our study, the maximum body temperature and total number of fever days were significantly higher in the MIS-C group. Several studies have reported that MIS-C can present with various symptoms and signs such as headache (19%) and fatigue (14%) [23, 24]. In our series, half of the patients with MIS-C complained of fatigue, and headache was found in more than ten percent of them. There was no significant difference between two groups in terms of headaches; however, fatigue complaints were significantly more frequent in the MIS-C group.
Changes in the blood count were most apparent in the presence of lymphopenia and thrombocytopenia in patients with MIS-C [25, 26]. There were no significant differences in lymphopenia or thrombocytopenia between groups. However, the lymphocyte and platelet counts were significantly lower in the MIS-C group. Extremely elevated levels of inflammatory markers (CRP and procalcitonin) are common in MIS-C patients [27]. In our study, serum CRP level, CRP positivity, and procalcitonin positivity were significantly higher in patients with MIS-C. Increased D-dimer levels were also characteristic of laboratory findings [6, 18]. D-dimer levels and D-dimer positivity were significantly higher in the present study. Patients with MIS-C have also been reported to have high ALT levels [28]. We did not find any differences between groups in terms of serum ALT levels or positivity. The high morbidity and mortality of MIS-C is mostly secondary to cardiac involvement Therefore all patients with a suspicion of MIS-C are evaluated with echocardiography and cardiac markers. However, about 20% of MIS-C patients do not have cardiac damage and these are the group of patients we wanted to differentiate as they are harder to diagnose [29, 30]. Therefore, we did not include markers as Troponin or NT-proBNP as they will prove cardiac involvement and MIS-C.
Abdominal US has become an essential for distinguish acute appendicitis and other abdominal pathologies from MIS-C and is advocated by the consensus guideline [31]. Hameed et al. reported that that only 1 of 19 MIS-C patients who underwent US for abdominal pain had completely normal US findings. Abnormal US findings were anechoic free fluid, localized inflammatory change within the right iliac fossa, echogenic expanded mesenteric fat, multiple mildly enlarged lymph nodes, and bowel wall thickening in these study [32]. Meshaka et al. reported that 84% of the MIS-C patients’ US findings were abnormal, and the most common abnormality was ascites (64%). Bowel and mesenteric abnormalities were hyperechoic inflammatory mesenteric fat (16%), mesenteric lymphadenopathy (14%), and bowel wall thickening (14%) [33]. In our series 17% of patients had thickened appendix wall, 6% of patients had increased appendix diameter (> 7 mm), and 17% of patients had periappendiceal free fluid in abdominal US.
We created a scoring system called AMS with NSS and new statistically significant parameters. In our study, the cutoff points of the parameters were evaluated using ROC curve analysis and propensity score matching. Biases that might have occurred were prevented using PSM, and the statistical analysis procedure was concluded correctly [34, 35]. Based on these evaluations, AMS had a higher specificity than NSS for distinguishing patients with acute appendicitis from those with MIS-C. In addition, the sensitivity of AMS was determined to be the same as that of NSS in recognizing patients with acute appendicitis.
Conclusion
MIS-C with gastrointestinal system involvement may present as acute abdomen and may be difficult to differentiate from acute appendicitis. Therefore, these patients may require unnecessary surgical procedures. This study showed that Appendicitis–MISC Score system can be useful for differentiating acute abdomen in MIS-C with GI involvement from acute appendicitis. Multi-institutional studies with large series are needed to prospectively validate it.
Acknowledgements
No funding was received for this manuscript. No pharmaceutical and industry support was received for this manuscript.
Author contributions
BTK conceived the original manuscript. BTK and YEK contributed to the design and implementation of the research, and MAG analyzed the results. GK and DYC supervised the project.
Data availability
The datasets generated and/or analysed during the current study are not publicly available due to individual privacy, but are some general information is available from the corresponding author on reasonable request.
Declarations
Conflict of Interest
None declared.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analysed during the current study are not publicly available due to individual privacy, but are some general information is available from the corresponding author on reasonable request.