VALUE OF ULTRASOUND IN DIAGNOSTIC OF PEDIATRIC APPENDICITIS

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

MEDICAL ACADEMY

Faculty of Medicine,

Radiology Department

VALUE OF ULTRASOUND IN DIAGNOSTIC OF PEDIATRIC

APPENDICITIS

Final Master Thesis

Author: Anna Victoria Sanchez Supervisor: Dr. Kristina Žvinienė Kaunas,

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1. SUMMARY

Anna Victoria Sanchez

Value of Ultrasound in diagnostic of pediatric appendicitis

Aim:

This study aims to analyze the value of ultrasound diagnostics of appendicitis in children and compare its efficacy and advantages with other imaging methods.

Objectives:

The objectives of this literature review are the following:

1) To establish the main and most effective diagnostic criteria of US for the assessment of

pediatric appendicitis. 2) To determine rates of diagnostic accuracy of US in the diagnosis of pediatric appendicitis.3) Investigate the advantages and disadvantages of US investigation of pediatric appendicitis. 4) To compare US with other radiological methods as computed tomography (CT) and magnetic resonance tomography (MRI) in the world.

Methodology:

This study is a literature review based on different major scientific databases: PubMed, Google Scholar, and Ovid. The following Keywords and terms were used and combined during the search of articles: “Ultrasound”, “US” “Sonography” Diagnostic” “Accuracy” “Effectiveness” “Appendicitis” “Children” “Pediatrics” “Computed Tomography” “CT” “Magnetic Resonance” “MRI” “PAS” “Diagnostic criteria” “Secondary signs”. A total of 45 articles were used in this review and 15 studies were selected and analyzed according to the inclusion and exclusion criteria, being less than 10 years old.

Results:

Diagnostic criteria on ultrasound showed that cutoff value of MOD ³ 7 mm and wall thickness of ³ 1.7mm had higher diagnostic accuracy. However, SS signs had lower sensitivity on their own but improved accuracy when US is inaccurate. Ultrasound (US) sensitivity ranged from 56% to 95%, specificity: 68% to 98%, positive and negative predictive ranged from 77% to 96% and 46% to 97% respectively. US accuracy ranged from 72%-92%. Pediatrics radiologist and non-obese patients showed a statistical significance (p<0.05) increased in diagnostic accuracy. Nevertheless, CT showed sensitivity ranging from 96% -98%, specificity of 95%-100%, and MRI 97%-100% and 89%- 97% respectively. Low dose CT showed a decrease of 64% less radiation compared to standard CT.

Conclusion

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Sonography has a great diagnostic accuracy; however, it can widely range due to its operator-dependent technique and obese patients have a high risk of inaccurate US. CT and MRI have higher diagnostic accuracy, but their use should be restricted due to radiation exposure and high cost. Their use should be only after and IE US.

Recommendations

US should be the first-line radiological modality in patients with suspected appendicitis.

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2. ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to my supervisor, Dr. Kristina Žvinienė for her guidance throughout the realization of this literature review.

Special thanks to my family and dear friends: Dr. Sergio Bosy, Helena Castell, Tonet Llinàs, and Mohamed Benomar for their support and help during all this journey. Without them, these 6 years and thesis wouldn’t have been possible.

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3. CONFLICTS OF INTEREST

The author reports no conflicts of interest.

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5. ABBREVIATIONS LIST

AA -Acute appendicitis

ACR – American college of radiology ACS- American college of surgeons

AIR- Pediatric inflammatory response score AUC- Area under the curve

BMIP- Body-Mass-Index-for-Age-percentile CDC- Center for Disease control prevention CRP- C-Reactive Protein

CT- Computed tomography ED- Emergency Department IE- Inaccurate/Equivocal IV- Intravenous

LR- Likelihood ratio

MRI- Magnetic Resonance Imaging NPV- Negative predictive value PAS- Pediatric Appendicitis Score PCT- Procalcitonin

PID- Pelvic Inflammatory Disease PPV- Positive predictive value RLQ- Right Lower Quadrant US – Ultrasound

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6. TERMS

Area under the curve: Allows to compare different test. The greater the value (maximum 1.0) the more accurate is the test (higher sensitivity and specificity).

Coefficient interval: Used to express the variability of an experimental result. Usually reported as the upper and lower bound of variability for your mean value, with x% certainly.

Dose length product: This a measure of CT tube radiation exposure/output, measured in mGy*cm False-negative: Imaging test is negative, and the patient has the disease.

False-positive: Imaging test is positive, and the patient doesn’t have the disease. Fecalith: Stone made of feces.

Negative appendectomy rate: Portion of normal appendix confirmed by pathology which was removed surgically in patients suspected of having acute appendicitis.

Negative predictive value: Portion of patients with a negative result being truly free from the disease. NPV = true negatives / (True negative + False negative).

Positive predictive value: Portion of patients with positive results having truly the disease. PPV = True positives / (True positives + False positives).

Respiratory triggering: Imaging acquisition is synchronized with the patient’s breathing and it’s used to minimize motion artifact in radiology.

Sensitivity: The ability of the test to identify true positive cases of the disease among all those with the condition; Sensitivity = True positives / (True positives + False negative).

Specificity = true negatives detected by test / (True negative + False positive).

Specificity: Is the ability of a test to be true negative in persons without the disease in question. True negative: Imaging test is negative, and the patient doesn’t have the disease.

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7. INTRODUCTION

Ultrasound (US) is an imaging technology that uses high-frequency sound waves to characterize tissue. The use of US it’s been increasing during the past years and it’s widely used to evaluate most body parts of pediatric patients due to the multiple advantages that offer.[1]

Acute appendicitis (AA) is a common disease that usually occurs within the ages of 8 - 20 years old and is one of the most common causes of abdominal pain in emergency departments (ED). It’s considered an emergent condition, requiring immediate attention because the appendix can rupture and lead to a life-threatening condition. [2]

For this reason, is extremely important to have a good clinical diagnosis including a history of the patient, physical examination, laboratory investigations and the use of stratification scores, as well as a radiological examination to diagnose more accurately appendicitis preoperatively and avoid the number of unnecessary appendectomies and the rate of complications in children. [2]

Sonography is the first line of radiological examination when there is suspicion of appendicitis, but not always we can visualize the appendix and in cases where the doubt persists, other radiological methods are performed in addition, such as Computer tomography (CT) or Magnetic resonance (MRI) but their usage should be restricted. [3]

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8. AIM AND OBJECTIVES

The study aims to analyze the value of Ultrasound (US) diagnostics of appendicitis in children and compare its efficacy and advantages with other imaging methods.

The objectives of this literature review are the following:

1) To establish the main and most effective diagnostic criteria of US for the assessment of pediatric appendicitis.

2) To determine rates of diagnostic accuracy of US in the diagnosis of pediatric appendicitis.

3) Investigate the advantages and disadvantages of US investigation of pediatric appendicitis.

4) To compare US with other radiological methods as Computed tomography (CT) and Magnetic resonance tomography (MRI) in the world.

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9. LITERATURE REVIEW 9.1. Appendicitis definition and its incidence in children.

Appendicitis is an acute inflammation of the vermiform appendix [4]. Acute appendicitis (AA) is considered the most common reason for urgent abdominal surgery in children, in which laparoscopic appendectomy is the therapy of choice. [5] The incidence peak of AA in children ranges between 10 – 18 years old and its slightly higher predominance in males.

The annual incidence in Europe and America, is 100 per 100,000 population, with a lifetime risk of having appendicitis between 5%-10%. [6]

9.2. Anatomy.

The vermiform appendix is a tube, finger-like structure connected to the cecum, usually located in the right lower quadrant (RLQ) of the abdomen. The Appendix length is about 6 to 10 cm.

In the first year of children’s life, appendix is funnel-shaped and its more difficult to become obstructed, by the age of 2 appendix takes the cylindrical adult shape. The tip of the appendix can be variable in location, the most common are: retrocecal 28%-68%, followed by pelvic location in 27-57%. [7 ,8]

9.3. Etiopathogenesis of appendicitis and morphological classification

Etiopathogenesis: The primary cause of AA is luminal obstruction from fecalith, foreign bodies, or 60% of cases due to lymphoid hyperplasia being the most common obstruction for children and young adults [7]. Obstruction in the lumen of the appendix cause an increase of pressure, the appendix continues to secret mucous leading to appendix distention. Obstruction of veins leading to organ ischemia, bacterial overgrowth, gangrene, necrosis and eventual perforation of appendix. [9]

Appendix perforation results in a localized appendicular abscess or diffuse peritonitis. Younger children have more risk to develop diffuse peritonitis due to less developed omentum. [7]

The germs more isolated from cultures of appendix lumen and peritoneal liquid are Escherichia coli, Pseudomonas aeruginosa, Klebsiella and Enterococcus spp .[10]

Morphological classification: Morphological changes of the appendix are evident as the course of inflammation progresses. It can be distinguished 4 morphological forms of acute appendicitis:

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• Phlegmonous or suppurative appendicitis: Is characterized by apparent pathological changes in the wall by the formation of multiple abscesses. The appendix gets swollen, may be increased in diameter and/or dilated, reddened, thickened, compacted and the serosa coating is covered with purple- fibrinous plaque. Inside the appendix may be filled with some pus (empyema of the appendix). In the abdominal cavity, there is clear or cloudy fluid in the cartilage ring.

• Gangrene or necrotic appendicitis: If the course of inflammation progresses further and causes local circulatory dysfunction it will result in infarction. The appendix will become congested dark red with black necrotic areas, in macroscopic appearance; Appendix will be thickened and with a friable wall (being easily perforated), green, purple, or black with micro-perforations. In microscopic examination, we will find extensive mucosal ulceration and transmural inflammation with areas of necrosis. The parietal peritoneum may be altered containing more unpleasant odor fluid, covered by fibrin and edematous.

• Perforated appendicitis: If the pathological process continues, results in perforation of the appendix wall, on the opposite side of the mesentery. In infants and young children, processes are more destructive and cause widespread peritonitis. The parietal peritoneum is thickened, hyperemic and edematous; the abdominal cavity is filled with purulent exudate which gives a fecal odor. [11]

Not complicated appendicitis: There is no evidence of fecalith, necrosis, gangrene or macroscopic perforation, intrabdominal complications and peritonitis; belongs to simple appendicitis.

Complicated appendicitis: There is evidence of phlegmon appendicitis, gangrene, perforation of the appendix, peritonitis and intrabdominal complications. [10]

9.4. Clinical Manifestations in different ranges of age.

Fever, anorexia and acute abdominal pain which is followed by vomiting are the classic symptoms for AA [11]. The most specific symptom is migrating abdominal pain, starting as diffuse periumbilical pain and within 24-48h of onset of symptoms, pain migrates and localizes to the Right Lower Quadrant (LRQ) of the abdomen [12].

Anorexia presents in 80% of patients with AA. However classic symptoms are not always presented in all patients, especially in children less than 5 years old, for this reason, doctors must be aware of the possibility of appendicitis in children presenting with abdominal pain without a previous appendectomy [9,13].

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and internal rotation of the right hip) are also specific for diagnosing AA. [15] Rebound tenderness and guarding might be signs of peritonitis. [9]

- Infants, toddlers and preschool age (1 month -<5 years): AA is not common in this group of age. Abdominal pain, followed by vomiting, fever, anorexia, diarrhea being tricky since doctors might confuse by acute gastroenteritis, RLQ tenderness, crying, irritability, Involuntary guarding and rebound tenderness are typical history and physical findings for AA. In this range of age, there is a high risk for misdiagnosis, appendiceal perforations and more complications due to poor communication which delays the diagnosis of AA in small children and less developed omentum. [7,16]

- Childhood age (5-12 years): Having AA is frequent in this group of age. Symptoms such as abdominal pain, vomiting, pain during movements or coughing, fever, anorexia are common, however, pain migration to RLQ sometimes might not occur. RLQ tenderness is found during a physical examination and signs of rebound tenderness or involuntary guarding can be seen during appendix perforation and peritonitis. [16]

- Adolescence (12-18 years): In this group of age classical findings are seen and similar to adults such as abdominal pain followed by vomiting, RLQ pain migration, fever and anorexia. Signs of appendiceal perforation and peritonitis are involuntary guarding, rebound tenderness and high-grade fever.

In teen girls is very important to take gynecological history and if needed an examination to rule out ectopic pregnancies, Ovarian cyst or torsion and PID (Pelvic Inflammatory Diseases). [16]

9.5. Laboratory studies and Risk of stratification scores

Laboratory studies: Together with clinical manifestations and physical examination, laboratory tests are important to help improve the diagnosis of AA. The test usually performed are the following: 1) White blood cell count (WBC) with differential: shows leukocytosis (10,000/microliter) neutrophilia with a shift to the left in 95% of patients, however, itself is not specific since other diseases can cause leukocytosis [14]. 2) C-Reactive protein (CRP): increased >10mg/L, a high value of CRP is seen in gangrenous and perforated appendix, CRP together with WBC increase sensitivity for helping in diagnosing AA. [14,16]. 3) Urinalysis: Is typically normal in AA, used to rule out a urinary tract infection (UTI), however in 7-25 % of patients can be found mild pyuria and hematuria. [7,12,16]. 4) Procalcitonin (PCT): patients with perforated appendix and peritonitis have increased value PCT. 5) Serum or urine Human Chorionic Gonadotropin (ß-hCG) in teenage girls after the first menarche for rule out ectopic pregnancy. [16]

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Tab 1. Risk stratification scores (Matthew J.S et al. 2018, American family physician) [15]

PMN: Polymorphonucleocytes, CRP: C- Reactive protein

In Tab1. Shows the 3 most used scores in children for stratification risk of AA with the points and parameters assessed in each different score. 1)Alvarado score also named MANTRELS is a 10-point scoring system, low risk for AA: 1-4 points which the patient is discharged, moderate: 5-6 points, the patient is admitted for observation and high risk: 7 to 10 points, the patient is sent to surgery. [18] 2)Pediatric appendicitis score (PAS) is based on a maximum of 12 points and is mostly used in children between 1-18 years old. Low risk: 1-3 points, moderate: 4-7 points and high risk: 8-12 points [15,19]. 3) Appendicitis inflammatory response score (AIR) is a recent score and more accurate than Alvarado and PAS score, maximum possible points are 12, being low risk patients with 1-4 points, moderate: 5-8 points and high risk for AA: 9-12 points. [15,20]

9.6. Diagnostic imaging

History of patient, clinical manifestations, laboratory test and the use of risk stratification scores are important for determining AA, however imaging technique is a key factor to establish a good diagnosis of appendicitis and avoid unnecessary appendectomies.

Ultrasound (US), Computed tomography (CT) and MRI (MRI) are the most used modalities for diagnosing acute appendicitis. However, the use of CT and MRI should be limited in children. [15]

9.6.1. Ultrasonography (US):

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in 1986 used to displace air from the bowel loops and have a greater visualization of appendix. Iliac vessels located in the right iliac fossa and psoas muscle are landmarks to help determine if appropriate pressure is being applied. [21] Once the cecum has been identified, appendix should be seen arising from it. Normal appendix presentation should have less than 6mm appendiceal diameter, a thin wall of less than 3mm, no signs of hypervascularization, no fecalith and be compressible. [22] In Fig 1. Shows a normal appendix on US imaging technique of a 10-year-old girl.

Fig. 1. Normal appendix (Quigley AJ, Stafrace S, 2013) [22] Appendicitis diagnostic criteria on US is based on the following presentations:

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All the following images below are features of acute appendicitis on US.

Fig.2 Longitudinal view in an 8yo boy, MOD 10mm. Fig.3 Transverse view, MOD 10mm (Quigley AJ, Stafrace S, 2013) [22] (Quigley AJ, Stafrace S, 2013) [22]

Fig. 4 Target sign, Transverse view in Fig. 5. Hyperemia in thick and edematous appendix a) 15y.o girl, b) 11y.o boy a)8y.o boy b)10y.o girl in Doppler US.

(Quigley AJ, Stafrace S, 2013) [22] (Quigley AJ, Stafrace S, 2013) [22]

Fig.6. Free fluid in appendix region Fig.7.Appendicolith a) 15y.o girl and (white arrow) 10y.o girl with AA b) 10y.o boy small white arrows show

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Using US and/or CT preoperatively increases diagnostic accuracy and decreases negative appendectomy rate. [27] History of the patient with suspected appendicitis, physical examination, laboratory test results and the use of stratification scores like PAS cannot safely rule out AA diagnostic, however, positive US is diagnostic. [28] Graded compression US is a great diagnostic tool that offers multiple advantages, it can be used safely in children and pregnant teenage girls due to lack of radiation, [27] rapid diagnostic imaging, inexpensive compared with CT and MRI, efficient and widely available. [29]

Sonography can reach an accuracy of 87% to 96%, sensitivity values ranging from 75%-90% and specificity of 86%-95% for diagnosing AA [14,30] nevertheless, accuracy of US can change based on several factors: According to the study conducted by [Tantisook T et al. (2021)] children with obesity (BMI of ³95th_{percentile) have a higher risk of presenting IE US [31], sonography is operator dependent,} requiring experience in which pediatric radiologist have more diagnostic sensitivity on US than general radiologist [32,33]. Performing graded compression US can be difficult or impossible in children presenting with intense pain in RLQ region. [30]

According to the American College of Radiology (ACR) and the American College of Surgeons (ACS) recommended not perform CT for diagnostic evaluation in a patient with suspected AA until US has been considered an option. [15]

9.6.2. Computed Tomography (CT)

The optimal imaging approach for suspected AA diagnosis remains controversial between US and CT [34]. However, CT should be used with caution because there is a direct link between ionizing radiation exposure from CT in childhood age and increased risk for cancer especially leukemia and brain tumors. [35,37] For this reason the Academy of Pediatrics, American College of Radiology and the National Cancer Institute recommend the use of US as the initial imaging technique in children with suspected AA. [15]

Nevertheless, CT is a widely available and essential diagnostic imaging tool for diagnosing appendicitis in cases when US is inaccurate or equivocal, [37] this might happen in children presenting with obesity or in young children in which graded compression is impossible due to anxiety or pain.

CT is relatively operator-independent, it’s a more expensive imaging test [38] and presents higher rates of accuracy which sensitivity ranges from 94%-100% and specificity from 93% to 100% compared to US. [39]

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Low-dose CT can reduce radiation dose by 30% without losing the quality of diagnostic image [30] and it could be used after an IE US for diminishing radiation exposure in children. [36]

Fig. 8 Acute appendicitis in a child performing contrast enhanced CT scan (arrowhead) shows periappendiceal fat and (arrow) shows thick enhancing wall with enlarged appendix. (Holmes J et al. 2011). [42]

Fig. 9 Perforated appendix with Fig. 10 Acute appendicitis with fecalith (arrow), Periapendicular abscess (arrow) CT scan performed in a children of N/A age. In a 18-year-old woman who ( Khan et al. 2018) [28]

Underwent enhanced CT scan, Coronal view.

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9.6.3. Magnetic Resonance Imaging (MRI)

MRI can be an alternative choice to CT when US is IE in patients with iodine-based contrast allergy or pregnant women since it avoids ionizing radiation exposure [14]. MRI can be used with IV contrast (Gadolinium-based) or without contrast and it’s been shown to have high values for sensitivity and specificity in the diagnosis of AA. [40]

Despite the high diagnostic accuracy and the lack of radiation, MRI is not commonly used compared to US and CT due to some disadvantages, such as increased time duration of the test compared with other radiological imaging techniques, in children suffering from claustrophobia might increase difficulty. Also, MRI is an imaging technique more expensive than CT and US and does not have the same accessibility. [41]

To carry out MRI is recommended to avoid sedation in children and use a breath-hold technique in patients older than 6 years old and respiratory triggering in children less than 6 years of age. [41]

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10. RESEARCH METHODOLOGY AND METHODS

The methodology used in this study, is a literature review based on different major scientific data bases: PubMed, Google scholar and Ovid. Previously published articles that are relevant for this topic were extracted and analyzed. The following Keywords and terms were used and combined during the search of articles: “Ultrasound”, “US” “Sonography”” Diagnostic” “Accuracy” “Effectiveness” “Appendicitis” “Children” “Pediatrics” “Computed Tomography” “CT” “Magnetic Resonance” “MRI” “PAS” “Diagnostic criteria” “Secondary signs”.

The search started in November of 2020 and continued until February of 2021 and its focused on children. All articles included in this study are less than 10 years old without geographical exclusion, being the oldest article from 2011 and the newest from 2021 with a sample size ranging from 2935 -104. Articles selected to conduct this study were based on the following inclusion and exclusion criteria:

Table 2: Inclusion and exclusion criteria followed to conduct this review.

INCLUSION CRITERIA EXCLUSION CRITERIA

-Articles published in English language - Articles published in another language -Articles published in the last 10 years

Being the range years from 2011 to 2021

-Articles older than 10 years

-Full text articles -Abstracts and not full text studies -Studies performed on humans - Studies not performed in humans -Population with age range 1 month – 18 years

old both included. (Infants to teenagers)

-Newborns and adults (0-28 days) and ³19 years old.

-Patients with suspicion of acute appendicitis who underwent Radiological imaging such as: US, CT or MRI.

-Patients who were not suspected with AA or didn’t underwent a diagnostic imaging. Other radiological techniques that are not US, CT or MRI

Prospective study Retrospective study and reviews, Cross-sectional and blinded studies

Systematic reviews

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Data extraction:

• Author, year and country of the study. • Type of study

• Characteristics of participants: (Sample size, Age, Mean age, sex) • Sensitivity, Specificity, PPV and NPV of US, CT and MRI with 95% CI

• PAS, CRP, obesity, MOD and SS together with imagine technique, Sensitivity, Specificity, PPV and NPV.

• P value with statistically significance of p<0.05 • Area under the curve (AUC)

• Accuracy of US, CT and MRI • Likelihood ratio, LR (+), RL (-)

• Hospital cost and Radiation dose of CT

Articles selection:

Applying the Keywords and Terms into the Databases of PubMed, Ovid and Google Scholar a total of 3.876 studies were primarily identified. After screening the titles and abstracts, applying the inclusion and exclusion criteria plus eliminating the duplicates studies, a total of 224 articles were obtained and evaluated the full text due to their relevancy in which 209 studies were excluded according to exclusion criteria, leaving 15 studies which were therefore included in this study.

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11. RESULTS

A total of 15 quantitative studies were used for the result part of this review. Table 3 contains characteristics of the 4 studies reviewed regarding the objective of the most effective and main diagnostic criteria in diagnosing acute appendicitis in children through Ultrasound imaging technique.

Sonographic criteria for diagnosing acute appendicitis in children

Table 3: Summary of the studies reviewed in the assessment of US criteria diagnosing AA [23-26]

Nr Author, year and reference

Country Aim of the study

Study design

Sample size, Age range and Mean age Methods 1. Chicaiza HP et al. (2018) [23] USA To investigate the optimal outer appendiceal diameter for diagnosing AA in children using US technique. Retrospective chart review Sample: 320 Age range: 2-18 years old. Mean age: 10.9

Children with suspected appendicitis. Appendicitis confirmed by pathology. Relevant variables were taken such WBC count and

appendiceal diameter determined by board-certified pediatric radiologist. 2. Goldin AB et al. (2011) [24] USA To describe a new criterion that improves the accuracy of US appendicitis diagnosis, making comparable with sensitivity and specificity of CT. Retrospective review Sample:304 Age range: <18 Mean age: 10.4

MOD (maximal outer

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AA: Acute appendicitis, WBC: White blood count, MOD: Maximal outer diameter.

In (Table 4) Results of Sensitivity, Specificity, PPV and NVP in a 95% CI are presented according to the Outer appendiceal diameter, Wall thickness and secondary signs observed during a diagnostic Sonography.

(Table 5) presented additional diagnostic data which is relevant for this study and the interpretation of results. 3. Mirza W.A. et al. (2018) [25] Pakistan To determine the utility of US and its Secondary signs (SS) in diagnosing AA. Retrospective review Sample: 1115 Age range: 2-16 Mean age: 9.5

Patients with suspected AA who have undergone graded compression RLQ US.

Classified in 3 groups

G1: Normal appendix or no visualized and no SS.

G2: Appendix not clearly seen and ³1SS

G3: Primary signs AA.

Board certificate radiologist performed US during day. Senior resident radiologist during night.

4. Penticuff R et al. (2021) [26]

USA To test the hypothesis that different types of hyperechoic fat are specific sonograph indicators of AA in pediatric patients. Retrospective Sample: 271 Age range: 1-18 Mean age: 9.5 Graded compression

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Table 4: US findings and its sensitivity, specificity, PPV and NPV for diagnosing acute appendicitis in children. [23-26]

Author, year and reference US findings Sensitivity (%) Specificity (%) PPV (%) NPV (%) Chicaiza HP et al. (2018) [23]

Outer appendiceal diameter: -³6mm - ³7mm -³8mm -³9mm 100 94 77 61 43 71 81 91 89 94 95 97 100 71 43 33 Goldin AB et al. (2011) [24] Diameter (mm): -³6 -³6.5 -³7 -³7.5 -Appendiceal diameter >7.5 or 6-7.5 mm with at least a secondary finding

Wall thickness (mm) -³1 -³1.7 Secondary signs -Fecalith -Hyperemia -Excess fluid -Fat stranding 91 91 89.7 76.9 89 100 92.2 33.3 56.4 20.5 70.5 79.8 91.5 95.4 96.9 95 55.1 100 96.1 98.5 99.2 100 N/A N/A

Mirza W.A. et al. (2018)

[24]

In G2 a total of 68 SS were seen in 52 patients.

Secondary signs; AA /Total: -Lymph nodes (18/21) - RLQ Echogenic fat (10/15) -Decrease Peristalsis (7/10)

-Free fluid (Moderate to large) (6/8)

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US: Ultrasound, PPV: Positive Predictive Value, NPV: Negative Predictive Value, G2: Group 2 RLQ: Right Lower Quadrant, MOD: Maximal outer dimeter.

-Collection (5/7) -Cecal thicken/edema (3/3) -Appendicolith (2/2) -Omental thickening (1/2) 6 4 3 1 100 100 100 100 71 100 100 50 91 91 91 91 Penticuff R et al. (2021) [26] MOD 6-8mm -MOD 6-8mm alone

-MOD 6-8 mm with Fat Type 1 -MOD 6-8mm with Fat Type 2 -MOD 6-8 mm with Fat Type 1 or 2 MOD ³6mm

-MOD ³ 6mm alone

-MOD ³6mm with Fat type 1 -MOD ³6mm with Fat type 2 -MOD ³6mm with Fat type 1 or 2 MOD ³8mm

-MOD ³8mm alone

- MOD ³8mm with Fat type 1 -MOD ³8mm with Fat type 2 - MOD ³8mm with Fat type 1 or 2

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Table 5: Additional data and conclusions of the studies reviewed [23-26]

Author, Year and Reference

Additional data relevant in the study Interpretation of results Chicaiza HP

et al. (2018) [23]

138 of patients were female and 182 males.

230/320 patients were positive for AA in US. 239 (75%) of US included an outer appendiceal diameter being the mean diameter 9.3mm for patients with confirmed AA.

The cutoff outer appendiceal diameter of 6mm showed that US have an excellent sensitivity but low specificity, in contrast with a diameter of 7mm sensitivity decreased (94%) and specificity increased (71%). Increasing the outer appendiceal diameter the sensitivity and negative predictive value decreased, and specificity and positive predictive value increased. Therefore, the optimal outer diameter cutoff should be 7mm for an accurate diagnosis of AA in US.

Goldin AB et al. (2011) [24]

Median diameters and wall thickness of appendices were the following: normal – 5mm and 0.9mm, acute-9mm and 2.2mm perforated- 9.8mm and 3.5mm

Highest accuracy regarding appendiceal diameter is >7mm and wall thickness >1.7mm. Fat stranding showed a sensitivity of 70.5% and specificity of 100% being a significant secondary finding.

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US: Ultrasound, AA: Acute appendicitis, MOD: Maximal Outer diameter, SS: Secondary Signs.

Table 6. Presented with the characteristics of 11 studies [27-37] for answering the objectives regarding the diagnostic accuracy of US, advantages, disadvantages and compering with other radiological modalities such CT and MRI.

Mirza W.A. et al.

(2018) [25]

714 patients in the study were males and 401 females. Patients classified in Group 2 were 52/1115.

-1 SS found in 40/52 patients which 28 had AA (70%) -2 SS found in 9/52 which 7 had AA (78%) -3 SS found in 2/52 in which 2 had AA (100%)

-4 SS found in 1/52 in which 1 had AA (100%)

Out of 52 patients in G2, 38 had confirmed AA.

SS itself are not sensitive enough for diagnosing AA, nevertheless, makes the diagnosis of AA more accurate when the appendix is not seen clearly through US.

Enlarged lymph nodes is the most frequent SS found during RLQ US in this study followed by Echogenic fat.

Cecal thickening/edema (3/3) and appendicolith (2/2) had a PPV of 100%.

Mostly patients presented with 1 SS, however, the more SS patient is presenting the higher probability to be diagnosed with AA.

Penticuff R et al.

(2021) [26]

107/271 had acute appendicitis, Fat type 0 observed in 18 patients, Type 1 in 46 and Type 2 in 43 patients. Type 1 had mean MOD 9.5mm and fat type 2 highest mean MOD; 11.2mm.

Fat type 1 or 2 not observed when MOD is below 6mm and all patients with fat type 1 or 2 had AA.

52/271 are known to be equivocal Accuracy of MOD 6-8 mm alone is 66.4%, with fat type 1: 67.5%, fat type 2: 63.1% and MOD with fat time 1 or 2: 70.1%.

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Table 6: Summary of studies reviewed [27-37]

Nr. Author, Year and Ref.

Country Aim of study Study design Sample, age

range and mean age Methodology 1. Pedram et al. (2019) [27]

Iran Assess accuracy of US in pediatric acute appendicitis. Cross-sectional Sample: 230 Age range: 5-15 Mean age: 11.4 +2.90.

Children diagnosed with suspected appendicitis. US was performed before surgery using graded compression technique with a 5MHz linear array transducer. Results were compared with surgical findings and pathological reports. 2. Khan U et al. (2019) [28] UK To determine the accuracy of US in pediatric acute appendicitis keeping histopathology as gold standard. Prospective evaluation and Cross-sectional validation Sample: 223 Age range: 3-14 Mean age: 9.9 Prospective evaluation. US used as first choice imaging modality

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4. Thieme, M.E et al. (2014) [30] Netherlands To compare diagnostic accuracy of MRI and US in children with suspected appendicitis. Fully paired and blinded study design Sample: 104 Age range: 4-18 years Mean age: 12 years

Three imaging modalities used to compare its efficacy for patients with suspected appendicitis: 1) Only US, 2) MRI after inconclusive or negative US, 3) MRI only. US performed by radiologist residents MRI by abdominal radiologist. -P values < 0.05 were considered significant 5. Tantisook T et al. (2021) [31] USA To evaluate if children with higher Body- Mass-Index-for-Age-percentile (BMIP) have higher risk for equivocal or inaccurate (IE) results for diagnosing AA with US imaging technique. Retrospective, observational study. Sample: 1059 Age range: 7-15 Mean age: 11.3

Four years review was performed on children evaluated for appendicitis by US imaging.

CDC (Center for Disease control prevention) BMIP calculator was used. Patients with equivocal or inaccurate US results (IE) were grouped together and compared with patients who presented accurate US results. BIMP was divided in two groups: Obese (≥95%ile) and non-obese <95%ile). 6. Löfvenberg

F et al. (2016) [32]

Sweden To evaluate how gender, age and operator can affect US diagnostic of suspected appendicitis in children together with PAS score

and CRP evaluation. Retrospective study Sample: 438 Age range: 0-15 (except neonates). Mean age: 8.5 Patients underwent abdominal sonography for suspected AA between 2012 -2015 in tertiary pediatric surgery center. Non visualized appendix considered negative. Following parameters were taken age, sex, physical exam, CBC, radiologist experience and PAS score was calculated. A p value <0.05 considered statistically significant. 7. Mangona KLM et al. (2017) [33] USA To investigate the US performance comparing the night shifts covered by radiologist trainees and day

Retrospective study

Sample: 2935 Age range: £18

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shifts covered by attending

radiologist.

Mean age: N/A

night shift was compared with Fisher exact test.

8. Moore MM et al. (2012) [34]

Netherlands To describe the results of a fully implemented clinical program using MRI as a primary modality for diagnose AA.

Retrospective study Sample: 208 Age range: 3-17 Mean age: 11

Four sequence MRI protocol was performed in children with suspicion of AA. No contrast and sedation were used.

9. Yi DY et al. (2017) [35] South Korea To determine the use and accuracy of low dose CT and compare it with abdominal US and standard-dose CT. Retrospective study Sample: 475 Age range: 2-10 years Mean age N/A Patients divided in 3 groups: 1) Low-dose CT 2)US and 3) Standard-dose CT. IV contrast media was applied. P<0.05 statistically significant. 10. Sayed AO et al. (2017) [36]

Egypt To evaluate the diagnostic accuracy of Low-dose CT PAS and US in children with suspicion of AA Retrospective study Sample: 140 Age range: 4-16 Mean age: 11±0.67

Children with suspected AA underwent US, low dose CT and PAS. AA confirmed by pathology. US performed by general radiologist. P<0.05 is statistically significant. 11. van Atta AJ et al. (2014) [37]

USA To describe how to stablish a US protocol among a large group of nonacademic private practice pediatric radiologist while maintaining accuracy in diagnosis and decrease cost. Prospective study Sample: 512 Rage age: <18 Mean age: N/A

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The following Table 7. Shows the results of Sensitivity, Specificity, PPV and NPV of US, CT and MRI. Efficacy of variables which can influence in the diagnosis accuracy such age range, obesity/non-obesity, operator performing US, CRP and PAS are also analyzed.

Table 7: Sensitivity, specificity, NPV and PPV of US, CT and MRI in diagnosis of pediatric AA

Author, year Ref. Radiological modalities Sensitivity (%) Specificity (%) PPV (%) NPV (%) Pedram et al. (2019) [27] -US 58 68 77 46 Khan U et al. (2019) [28] -US -CT 86 N/A 97 N/A 96 N/A N/A N/A Scammell S et al. (2011) [29] -US 83,3 97,4 92,1 94 Thieme, M.E et al. (2014) [30] -US only -MRI after inconclusive or negative US -MRI only 76 100 100 89 80 89 90 87 92 75 100 100 Tantisook T et al. (2021)

[31] -US (Non obese patients)

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Löfvenberg F et al.

(2016)

[32] -US (all patients) Parameters analyzed: Age group: -0-4 -5-9 -10-14 US performer -Pediatric radiologist -Radiologist US, CRP, PAS -Negative US +CRP <15 -Negative US + PAS£5 + CRP <5 82 74 86 81 88 71 92 98 97 96 100 95 98 97 60 41 92 92 100 88 94 90 47 39 93 89 95 92 95 91 95 98 Mangona KLM et al. (2017)

[33] -US Day shift by attending radiologist

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N/A: Not available, PAS: Pediatric Appendicitis Score, CRP: C-reactive protein.

In Table 8 additional results of the studies presented previously relevant for the study were included and the results interpretation of the 11 studies.

Table 8: Additional diagnostic results in the study and interpretation of results.[27-37]

Author, year and Ref.

Additional data in the study Interpretation of results

Pedram et al. (2019)

[27]

US results showed 112/230 had AA and 150 reported AA by pathology results.

TP rate was 87 according pathology reports, FP rate 25, TN rate 55 and FN rate 63.

The area under the curve (AUC): 0,853 (CI 95% 0,788-0,917).

In this study US showed a moderate accuracy.

Khan U et al. (2019)

[28]

Appendix visualized in 192/223 patients through US (86%) and not identified in 17 patients (8%) in which, 11patients underwent CT scan and 8patients were positive for AA while 6 were operated based on clinical suspicion. 14 patients presented SS on US. False negative 31 patients (14%), false positive 8 (3.6%) resulting in negative appendectomy rate.

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Accuracy of US with SS was 92% CT is the radiological modality of choice to help diagnosing AA in patients whose appendix are not seen on US.

Scammell S et al.

(2011) [29]

Negative appendectomy rate was 16.5%, positive appendectomy rate 83.5% and perforated

appendectomy rate: 23.7%

US showed a good diagnostic accuracy. Nevertheless, negative appendectomy rate was high in this study.

Thieme, M.E et al. (2014) [30]

58/ 104 patients were diagnosed with AA.

US only was inconclusive in 44 patients and missed 24% of diagnosed appendicitis

MRI after inconclusive US, missed appendicitis is 0%. Patient acceptance: Patients experienced longer duration in MRI technique compared to US (P<0.005), patients experienced US being more painful than MRI (P<0.005), tolerance of MRI compared to US (P<0.005).

Making the comparison between the different radiological modalities US has significant lower sensitivity while comparing with MRI ONLY and MRI after negative or

inconclusive US (76% VS 100% P<0.001) Specificity compared with US, conditional MRI and MRI only has no statistical significance. Tantisook T

et al. (2021) [31]

LR (-) in Non- obese patients is, LR (-) =0,138 and for Obese patients: LR (-) =0,3446.

Likelihood ratio to predict positive appendicitis in Non-obese was LR (+) =21.775 and for Obese LR (+) = 35.458.

Predicting accurately negative appendicitis is decreased in obese patients reflected by increased LR (-), compared with non-obese patients. Higher risk for non-visualize appendix or have equivocal findings in obese population.

LR (+) is increased in non-obese and obese patients meaning that if US is positive for appendicitis is more likelihood to have AA.

Löfvenberg F et al.

(2016) [32]

Appendectomy performed in 118 children with AA Negative appendectomy rate: 10%.

AUC: 0.88 (95% CI 0.83-0.93).

Sensitivity of Pediatric radiologist vs general radiologist (p<0.01)

US had a good diagnostic accuracy. The greatest accuracy was in range age 5-9.

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diagnosing pediatric appendicitis and its statistically significant.

To integrate PAS score and CRP with US showed improved diagnostic accuracy and its useful for prove the diagnosis or rule out AA in equivocal cases.

Mangona KLM et al. (2017) [33]

2161 US performed during the day (73.6%) and 774 during night shift (26.4).

AA prevalence during the day was 25.3% (546/2161) and at night 22.6% (175/774).

Accuracy of US during the day was 93.8 and during night 91.2%.

US has excellent diagnostic accuracy. However, slightly lower sensitivity, specificity and PPV observed when US is performed by a trainee radiologist. US is operator diagnostic dependent.

Moore MM et al. (2012) [34]

208 MRI were performed.

True positives confirmed by pathology were 40, true negatives 162, false positive: 5, false negative: 1

MRI has an excellent diagnostic accuracy and very effective for diagnosing AA in children and avoid the radiation exposure.

Yi DY et al. (2017) [35]

297/475 were diagnosed with AA.

-Low dose CT n=190 (Diagnosis of perforation- 100%)

-Abdominal US n=55 (Diagnosis of perforation 85.7%)

-Standard dose CT n = 230. (Diagnosis of perforation- 100%)

-P-value= <0.027 of 3 imaging groups in diagnosis of perforated appendix.

-P value <0.004 in specificity and p<0.019 in PPV of the 3 imaging groups.

Radiation dose reduced by 64.2% in Lower-dose CT.

Low dose CT and standard-dose CT are effective in diagnosing acute appendicitis and perforated appendix and have very high diagnostic accuracy for AA compared with US which also showed a good accuracy but lower than CT.

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Sayed AO et al.

(2017) [36]

102/140 underwent CT scan as a primary modality imaging and US in 38/140.

Low dose CT accuracy=99.3% and US=71%

Mean dose length product=150mGy/cm and mean effective dose of radiation=3.1mSv (2.2 – 3.4 mSv) PAS performed 140/140. AUC of PAS with 95%CI was 0.951. Accuracy of PAS ³2=49.3%, PAS ³5=89% and PAS ³7=73%.

(P<0.001) of Accuracy of Low-dose CT and PAS. (P<0.02) Poortman’s model and US

Lower dose CT had the highest accuracy in diagnosis of pediatric appendicitis, however there is radiation risk.

US had lower accuracy because its operator dependent and was performed by general radiologist instead of pediatric radiologist. PAS score showed a good accuracy when cutoff is PAS>5 and its very helpful in order to rule out or increase diagnostic accuracy of AA and could be used together with US in order to decrease CT imaging and radiation exposure.

van Atta AJ (2014) [37]

512/512 patients underwent US and in 187/512 CT due to an equivocal US.

2007-2008, US cost was 102 dollars/study and CT 245 dollars/study. In 2012 US became first line imaging. Using US protocol hospital saved 30.182 dollars annually.

The use of CT after an equivocal US showed to have a higher accuracy than US diagnostic imaging alone. By implementing a US protocol as a first line of imaging and only using CT when US is equivocal, decreased a lot the hospital cost annually.

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12. DISCUSSION OF RESULTS

The principal objective of this Master Thesis was to analyze different studies describing the main diagnostic criteria of AA in US, it’s efficacy, advantages /disadvantages and compare US with other radiological modalities such as CT and MRI.

This review has been analyzed values such as sensitivity, specificity, PPV and NPV of the 3 different radiological imaging techniques to assess its efficacy depending on the variables analyzed.

Sonography is a great diagnostic tool for children complaining of pain in RLQ region being suspected with AA, due to cost/benefit ratio, great accessibility worldwide and the lack of radiation exposure makes it the preferred radiological modality used as the first line for the diagnosis of AA.

In order to establish the main and most effective diagnostic criteria of appendicitis in US imaging modality MOD was assessed; according to the study conducted by Chicaiza et al. 2018 [23] and Goldin et al. 2011 [24] both studies showed that a cutoff value of MOD ³ 7mm increases diagnostic accuracy rather than the cutoff currently established of ³6mm, however, presenting with a MOD of 6-7.5mm with at least one secondary sign can improve diagnostic accuracy.

Penticuff et al. 2021 [26] conducted a recent retrospective study which showed a MOD of 6-8 mm with a Fat type 1 or 2 had lower sensitivity than MOD alone but increased specificity. In the study Goldin et al., fat stranding had the highest accuracy of SS followed by hyperemia, however, Mirza at a. 2018 [24] demonstrated that more patients presented with enlarged mesenteric lymph nodes having the highest sensitivity and specificity of SS followed by RLQ Echogenic fat.

To detect appendicitis in children, sonography showed good diagnostic accuracy. Nevertheless, CT and MRI have demonstrated to have a better diagnostic accuracy compared to US imaging technique which can be influenced by several factors.

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Tantistook et al 2021 [31] showed that obese patients whose BMI was ³95% percentile undergoing US examination for suspected appendicitis, LR (-) was increased and lower sensitivity and specificity was found compared with non-obese patients (<95% percentile) showing increased risk of inaccurate or equivocal US.

In this review, sonography reported a wide variety of values regarding sensitivity, specificity, PPV and NPV. Pedram et al. 2019 [27] conducted a cross-sectional study in 230 patients using US preoperatively in children with suspected AA, values were the followings: 58, 68, 77 and 46 respectively with a moderate US accuracy, however, Khan et al. and Scammell et al. reported higher values of sensitivity, specificity, PPV and NPV with both studies having very similar values, US accuracy in the study of Khan et al. showed an excellent diagnostic accuracy nonetheless, the negative appendectomy rate in Kahn et al. reported being 3.6% which is a very successful rate and Scammell et al. reported a higher rate of 16.5%.

Löfvenberg et al. conducted a study in which negative US combined with a CRP <15 or a PAS value of more or equal 5 and CRP<5 have great diagnostic accuracy and can be used for safely rule out AA diagnostic, moreover, Sayed et al. state that a PAS score equal or higher than 5 had high diagnostic accuracy for improving diagnosis in US for AA.

In order to detect AA when US is IE followed by CT has been shown to have excellent diagnostic accuracy according to the studies of Sayed et al and Van Atta et al. Also stated when using CT only in cases where US was inaccurate decreased hospital expenses.

Yi et al. conducted a retrospective study which showed that low-dose CT and Standard dose CT had a superior diagnostic accuracy for diagnosing AA and perforated appendix compared to US, low dose CT in comparison with Standard CT contained 64.2% less radiation. Moreover, Sayed et al. also showed a greater diagnostic accuracy in low dose CT compared to US.

Moore et al. and Thieme et al. showed similar results of MRI diagnostic accuracy. Comparing MRI with CT it is seen there is no difference between the two modalities regarding the accuracy, however its higher diagnostic accuracy than US.

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12.1. Study limitations

This review, however, is subject to several limitations. First of all, only 3 databases (PubMed, Google Scholar and Ovid) were used to conduct this literature review. Second of all, only a few research articles were found regarding the main diagnostic criteria of appendicitis in US only based on children that included sensitivity, specificity, PPV and NPV. Moreover, missing data, p values, and AUC were missing in some of the studies. To end with, there are not many studies regarding appendicitis diagnostic performing MRI. The following study limitations could have affected the results.

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13. CONCLUSIONS

1. MOD ³7mm on US has greater diagnostic accuracy than the established ³6mm cutoff, wall thickness >1.7mm and SS has shown to be effective to improve the accuracy for the

diagnosis of AA when US is IE such fat stranding, enlarged mesenteric lymph nodes, fluid collection, hyperemia and fecalith.

2. US has great diagnostic accuracy and its safe for pediatric patients when diagnosing AA, however, its accuracy can widely range from 72%-92%.

3. US is operator-dependent, and accuracy could be diminished. Pediatric radiologists showed to have higher diagnostic efficacy. Moreover, US accuracy is decreased in obese patients.

4. MRI and CT have higher diagnostic accuracy than US. However, the use of CT should be restricted in only IE US due to radiation exposure.

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14. PRACTICAL RECOMMENDATION

First of all, for infants and younger children showing atypical symptoms, appendicitis should be considered an option.

Second of all, sonography should be the first-line imaging modality when appendicitis is suspected. Patients’ complaints, lab tests such CRP, stratifications score as PAS can significantly improve the diagnosis together with imaging.

Third of all, if US cannot visualize the appendix or results is inaccurate, other radiological methods such as repeat US, CT or MRI should be considered.

Fourth of all, CT should be used with caution due to ionizing radiation exposure and only be used after an IE US. Using low-dose CT is preferred in children since it’ll reduce radiation exposure. However, the use MRI should be evaluated in each specific patient case the ratio of benefit/cost.

Finally, a good history, physical examination, laboratory results, risk stratification scores and especially an imaging diagnostic is essential in order not to miss acute appendicitis which could lead to severe complications.

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