Current Treatments for Appendicitis

Abstract

One out of every 1000 persons is diagnosed with acute appendicitis (AA) each year. Men are slightly more likely to have AA than women (8.6% vs. 6.7%). A simple or uncomplicated appendicitis is one that is characterized by inflammation and fluid around the appendix. It is recommended that patients with AA undergo a history and physical examination, with attention paid to temperature and rebound tenderness, followed by laboratory tests and radiology studies. A number of indices have been investigated in order to improve the accuracy of diagnosis. CT’s diagnostic sensitivity and specificity are not significantly different whether contrast-enhanced or nonenhanced CT is utilized to diagnose the patient. Numerous studies have proved the safety and effectiveness of laparoscopic appendectomy (LA) for adults. There is mounting evidence that noninvasive therapies, such as those that focus on pain management and draining collection, maybe just as effective as surgery for uncomplicated appendicitis.

1. Introduction

Approximately one out of every 1000 persons are diagnosed with acute appendicitis (AA) each year [1]. While men are slightly more likely to have AA than women (8.6% vs. 6.7%), women are more likely to undergo an appendectomy (23.1% vs. 12.0%) [2]. According to its severity, AA is either classified as “uncomplicated” or “complicated” by the European Association of Endoscopic Surgery (EAES) [3]. A simple or uncomplicated appendicitis is one that is characterized by inflammation and a small amount of fluid or an abscess around the appendix. An abscess collection, phlegmon mass, gangrene, perforation, or peritonitis are present in cases of complex appendicitis (CA). Phlegmons are inflammatory benign mass or tumors composed of appendices, their adjoining viscera, and the omentum (Table 1) [1, 4].

	Uncomplicated	Complicated
Criteria
Inflammation	+	+
Gangrene	−	+
Phlegmon	−	+
Perityphlitic abscess	−	+
Free fluid	−	+
Perforation	−	+

Table 1.

Criteria for distinguishing between uncomplicated vs. complicated appendicitis, based on the European Association of Endoscopic Surgery (EAES), 2016.

It is recommended that patients with AA undergo a history and physical examination, with attention paid to temperature and rebound tenderness, followed by laboratory tests and radiology studies. The results of a pregnancy test should be obtained by all women of childbearing age. It is important to note that the clinical presentation of AA varies even within the same age group. For instance, among children younger than 5 years of age, the presentation is more complicated due to rapid progression and perforation. A comparative study of 142 children found that children less than 5years of age have a 44% chance of developing perforated appendicitis with abscess, while children between 5 and 10 years of age have a 13% chance, p = 0.001 [5].

2. Challenges in the diagnosis

It is a dilemma if appendicitis is not diagnosed in a timely manner, as it can result in perforation of adverse consequences. A perforation can be sealed with phlegmon or abscesses, or it may be free with septicemia and peritonitis. Additionally, it is possible to operate on a negative appendectomy due to an incorrect diagnosis.

A number of indices have been investigated in order to improve the accuracy of diagnosis. The mean platelet volume (MPV), plateletcrit, and platelet distribution width are some of the recent indices. The diagnosis may be bolstered by elevated levels of leukocytes, inflammatory markers, plateletcrit, [6] and low MPV according to one systematic review [7].

To support their clinical judgment, most clinicians use certain scores in addition to radiology scans. The modified Alvarado Score and the Appendicitis Inflammatory Response Score (AIRS) are the most commonly utilized scores in clinical settings (Table 2) [1, 8, 9].

Criterion		Alvarado score	AIR score
Symptoms
Vomiting		—	1
Nausea or vomiting		1	—
Anorexia		1	—
RLQ pain		2	1
Migratory RLQ pain		1	—
Signs
RLQ rebound pain or guarding		1	—
	mild	—	1
	moderate	—	2
	severe	—	3
Body temperature	>37.5 °C	1	—
	>38.5°C	—	1
Laboratory parameters
Leukocyte count	>10,000/L	2	—
	10,000–14,900/L	—	1
	>15,000/L	—	2
Leukocyte shift		1	—
PMN granulocytes	70–84%	—	1
	≥ 85%	—	2
CRP value	10–49 mg/L	—	1
	≥ 50 mg/L	—	2
Sum		10	12
Alvarado score		<5	low probability
		5–6	unclear
		7–8	likely
		>8	high probability
AIR score		<5	low probability
		5–8	intermediate probability
		>8	high probability

Table 2.

Modified Alvarado and AIR scores.

AIR: Appendicitis Inflammatory Response; RLQ: right lower abdominal quadrant; PMN: polymorphonuclear; and CRP: C-reactive protein.

In cases when the likelihood is unsure or intermediate, the score is backed up by several scan modalities. For children and thin patients, ultrasonography (US) is the method of choice, while pregnant women are advised to have a magnetic resonance image (MRI) [10]. When it comes to women of childbearing age, the morbidly obese, and the elderly, computed tomography (CT) is the gold standard for diagnosing appendicitis.

CT’s diagnostic sensitivity and specificity are not significantly different whether contrast-enhanced or nonenhanced CT is utilized to diagnose the patient. One study examined the performance of CT scans with and without contrast on 140 patients, and the accuracy remained between 80 and 87% without statistically significant differences [11]. That finding is vital, particularly when a patient has a renal impairment and is suspected of having AA. The diameter of the appendix that should be considered too small to be indicative of AA varies. Some have proposed a CT scan threshold of 9.25 mm for making the diagnosis [11].

It is not always possible to tell the difference between simple and severe appendicitis using ultrasound, CT, or MR. Even though CT’s sensitivity is low, it has a significant negative predictive value for CA [12].

As opposed to the intraoperative finding, CT scans are not as effective in detecting perforations. In one study, 89 individuals presenting with right lower quadrant discomfort underwent CT imaging and appendectomy.

The pathology results reveal that perforation had occurred in 48% (43/89), 93% (n = 40) of perforations were overlooked by radiography [13].

According to the results of a single systematic review and meta-analysis of CT Features for differentiating complicated and uncomplicated appendicitis. This research identifies 10 useful CT characteristics for distinguishing CA [14]. The overall pooled specificity for the presence of an extra or intraluminal appendicolith, abscess, wall-enhancing defect, extra or intraluminal air, ileus, periappendiceal fluid collection, or ascites was more than 70%. Only stranding of fat around the appendix was very sensitive 94%. in addition to the aforementioned, one of the most sensitive and specific sonographic findings for differentiating complex from uncomplicated appendicitis was the absence of the typically echogenic submucosal layer (sensitivity 100% and specificity 92%) [15].

3. Surgical management and outcome

Numerous studies have proved the safety and effectiveness of laparoscopic appendectomy (LA) for adults. A total of 1251 LA and 898 open appendectomies (OA) were compared in one meta-analysis consisting of 16 researches, 9 of which were randomized controlled trials [16]. Reduced inflammation, quicker recovery and hospital time, earlier bowel function restoration, and shorter operation times are all advantages of laparoscopic over conventional surgery. This is due to the fact that less tissue damage occurs with LA as opposed to open surgery. Although the surgical cost of LA is higher than that of OA, the shorter hospital stay associated with LA makes the total spent for both operations somewhat comparable [17].

Nearly a quarter of surgeons may choose open surgeries on patients less than 18 years old. One review comparing OA with LA in 390 patients (younger than 18 years) found that the minimally invasive technique is linked to less problems and 1 day shorter hospitalization [18].

A debate between surgeons about whether or not it is safe to perform LA on patients with complex conditions. Morbidity, mortality, and duration of hospital stay were significantly reduced in an analysis of 6428 patients with CA, of whom 3174 were treated laparoscopically [19]. This demonstrates not just the safety of LA but also improved recovery and results.

Most patients are subjectively given a diagnosis of CA after surgery; however, there is no consensus on particular intraoperative diagnostic criteria, which may lead to erroneous classification [20]. In one review, including 1066 appendectomies, 239 of them were complicated. Histopathological CA may be predicted by a number of factors, including but not limited to age, elevated heart rate, pain duration, appendix size, and appendicolith presence [20]. Forty percent of patients were misclassified as a result of the surgeon’s evaluation. Where there is room for advancement and a better-measured system [20].

Concerns were raised regarding the expense and time commitment involved in sending regular appendix specimens for histopathology. The importance of routine histological testing was the subject of a meta-analysis that comprised 25 studies and 57,357 patients [21].

In 10.6% of cases, the appendix seemed normal, in 88.6% of cases inflammation was present, and in 2.52% of cases abnormalities were discovered (2718 patients). The most common abnormalities were parasitic infections (0.54%), endometriosis (0.03%), granulomatous illness (0.26%), and neoplasms (0.71%). Most neoplasms were neuroendocrine tumors, then adenocarcinoma, and finally lymphoma. The ability of the surgeon in the detection of aberrant appendix at a macroscopic level that necessitates subsequent treatment makes the selective histopathology assessment a potential method. There is currently no agreement on a protocol regarding the use of selective histopathology, which necessitates a precise intraoperative evaluation by the surgeon. To aid surgeons in the detection of aberrant pathology and the minimization of needless histopathology investigation, the FANCY trial is now conducting a cost-benefit analysis of selective histological examination after appendicectomy and cholecystectomy [22].

Surgeons argued for a long time regarding the postoperative abscess after LA. After pooling the results of ten meta-analyses to investigate the post-LA surgical site infection (SSI) and abdominal collection. They discovered that the risk of SSI was about 60% lower in LA than in open surgery, but the rate of the abdominal abscess was twice as high [23]. Contrary to earlier reviews, some did not find any significant difference in the incidence of abdominal abscess with 6.1% in LA group versus 4.6% in OA group, p = 0.91 [19].

This forces many surgeons to go outside the box by resorting to techniques like single-port LA or prophylactic peritoneal lavage in order to minimize postoperative abscess. Lavage does not appear to be more effective than suction in preventing postoperative infections, according to a meta-analysis of eight separate investigations [24].

Moreover, there was no statistically significant difference in the incidence of SSI between the 2749 patients treated with a single port and the 2735 patients treated with traditional LA (p = 0.98) [25].

Having a complicated appendectomy might add days to patient hospital stay. Reviewing data from 450 patients, researchers found that longer pain duration (HR = 2.37, 95% C.I = 1.09–5.16, P = .029), longer operative time (HR = 2.09, 95% C.I = 1.04–4.21, P = .038), and CA (HR = 6.61, 95% C.I = 2.67–14.21, P = .001) were all significantly associated with longer hospital stays [26]. When compared to less problematic appendicitis, those that are more complicated are associated with significantly higher rates of morbidity, readmission, and up to a 6-fold increase in hospitalization [26]. The approach may modify the required hospitalization time, LA had a shorter duration of stay than OA did for CA (6.4 days against 8.9 days, p = 0.02) [19].

4. Nonoperative management (NOM)

In 1930, Bailey et al. documented rest and fasting as part of the conservative therapy of appendicitis before moving on to a delayed elective appendectomy [27]. Also, in 1956, Coldrey et al. reported that antibiotic treatment was used to successfully treat 471 cases of AA, with a very low death rate (0.2%). Furthermore, only 14.4% of patients had a recurrence [28].

Surgical intervention for CA is not without risks, but there is mounting evidence that noninvasive therapies, such as those that focus on pain management and draining collection, may be just as effective. Téoule P et al. [1], in particular when technical variables, such as the presence of phlegmon or suspicion of malignancy, lead to improper ileocecal resection or right-sided hemicolectomy, as was the case in around 3.4% (17/493) of patients in one study [4, 29].

However, there is currently little data to support the use of conservative therapy for simple cases of appendicitis, making surgery the preferred option for both children and adults [1]. Patients in the 11 trials (5 randomized clinical trials RCTs, 3 retrospective studies, and 3 prospective cohort studies) totaling 2751 were split into two groups: those who received conservative treatment (n = 1463) and those who had surgery (n = 1288) [30]. Conservative treatment resulted in an 83% success rate (95% CI: 77.2–88.2%), a 10.3% incidence of complication (95% CI: 8.5–12.6%), a 5.6% need surgery (95% CI: 3.1–10.2%), and a 0.47 day longer length of stay than the surgical group.

In a meta-analysis, 3618 individuals with uncomplicated appendicitis were assigned to antibiotics (n = 1743) or appendectomy (n = 1875) [31]. There was a failure rate of 8.5% for antibiotic therapy, and a recurrence rate of 19.2% at the 1-year follow-up. The risk of perforation was low, and it was not considerably increased by nonoperative treatment.

While the effectiveness of nonsurgical therapy is quite well, it is somewhat lower than that of appendectomy; nevertheless, the rate of complications is much lower than that of urgent surgery [32, 33].

When it comes to nonsurgical treatments, how long they really work is up for debate. One study found that, among children, 82% of NOM are still effective after 4 years, whereas 14% have seen a recurrence [32]. Another found that the NOM plan using just antibiotics had a 67.1% success rate and was linked to considerably fewer disability days at 1 year compared with urgent surgery [33].

There were 530 participants in the APPAC trial, and they were randomly assigned to get either appendectomy (n = 273) or antibiotic treatment (n = 257). Cumulative incidence of appendicitis relapse was 34, 35, 37, and 39% at 2, 3, 4, and 5 years, respectively. At 5 years, the incidence of complications, such as SSI, incisional hernias, obstruction, and pain, was statistically significantly higher in the surgical group with a rate of 24.4% (95% CI: 19.2–30.3%) (n = 60/246), compared to 6.5% (95% CI: 3.8–10.4%) (n = 16/246) in the antibiotic group, p = 0.001 [34].

Appendectomy is still considered the best option for treating acute uncomplicated appendicitis, according to the European Association for Endoscopic Surgery’s (EAES) recommendation. This is backed up by a recent meta-analysis of 3203 patients (1613 received antibiotics versus 1590 appendicectomy) [35]. Treatment at 1 year was successful for 1016 of 1613 patients (63%), revealing that antibiotics were less effective than appendicectomy, as well as, hospital readmissions increased by a factor of six [35].

However, definitive findings about the management of complex appendicitis remain elusive [3]. Conservative therapy of AA is not recommended by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and they lean toward discussing the safety, effectiveness, and appropriateness of LA [36].

Antibiotic treatment regimens and durations favored in different studies were widely reported. Initially, single-agent parenteral antibiotics of amoxicillin-clavulanate, piperacillin-tazobactam, or a carbapenem were employed, as well as combination therapies with a second- or third-generation cephalosporin and metronidazole. After leaving the hospital, patients began taking a combination of fluoroquinolone or a third-generation cephalosporin and metronidazole by mouth. Ten days is the typical length of therapy [37].

The high rates of Escherichia coli resistance make amoxicillin-clavulanic acid an unwise choice for treating intraabdominal infections, notwithstanding recommendations. In mild-to-moderate community-acquired infections, broad-spectrum regimens are not recommended until antimicrobial resistance is apparent [38, 39]. Persistent pain or discomfort after 48–72 hours of antibiotics may warrant appendectomy [37].

Nonetheless, there are problems that require fixing with conservative therapy such as the benefits of NOM over appendectomy in cases of microperforation, comorbidities, pediatrics, and geriatrics. Long-term risks of recurrence or undetected cancer. The optimal treatment plan, duration, response criteria, and when appendectomy is needed [37].

5. New practice of colonoscopic drainage

Despite advances in treatment, the appendicular abscess is difficult to manage. For stable patients, radiologically guided drainage is the therapy of choice. There was a 25% failure rate for percutaneous drainage in a study of 2209 appendiceal abscesses, which lead to longer hospital stays and higher overall costs [40].

Lower abscess grade, CT-guided drainage, and a transgluteal route have been linked to a higher incidence of abscess clearance than higher abscess grades, ultrasound-guided drainage, and transabdominal approaches [41].

Some have suggested using colonoscopy and internal drainage of the abscess to promote healing and rule out cancer prior to interval appendectomy, as an alternative to external drainage, which has risks of colocutaneous fistula and a lower chance of success [42].

One of the most cutting-edge techniques is endoscopic retrograde appendicitis treatment (ERAT), which is performed via the patient’s natural orifice (NOTES) [43]. By combining diagnosis and therapy, we may get a precise picture of what is going on, eliminate other possible causes of colonic symptoms, and get rid of fecal stones and abscesses all at once.

Abscess draining into the cecum is performed after cannulating the appendiceal orifice. Despite that, ERAT is not an option for patients who had a ruptured appendix, periappendiceal abscess, or an allergy to the contrast agent. While the average operating time for ERAT was longer (50 minutes) than that of LA (10–15 minutes), the procedure might prevent surgery, lessen pain and need for antibiotics, and accelerate the return to normal activities [44].

6. Unexpected finding

Surgeons might trouble by unexpected findings on histopathology, such as neuroendocrine tumor (NET) or epithelial neoplasm. When such results are obtained, the surgeon must decide whether or not to do a right hemicolectomy (RHC) with the purpose of removing a sufficient number of lymph nodes or achieving negative margins.

Appendiceal cancer categorization proposed by WHO and the International Society for Peritoneal Surface Oncology(PSOGI), which undergoes regular revisions [45, 46].

Nonneoplastic mucinous lesions (as mucocele), invasive adenocarcinomas, low-grade and high-grade appendiceal mucinous neoplasms (LAMN and HAMN), and goblet cell adenocarcinomas are all examples of epithelial neoplasms. On the other hand, well and poorly-differentiated neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) are examples of neuroendocrine neoplasm. A clinical illness known as “pseudomyxoma peritonei (PMP) is defined by the presence of a mucinous appendiceal lesion in addition to widespread mucinous peritoneal involvement.

Although wide debate on post-appendectomy management of adenocarcinoma, The American Society of Colon and Rectal Surgeons 2019 recommends right hemicolectomy for stage I-III disease [47]. Depending on the specifics of each case, further treatments, such as cytotoxic chemotherapy, biological therapy, cytoreductive surgery, and hot intraperitoneal chemotherapy (HIPEC), may be used.

Appendiceal NET has received increasing attention since 1907, when Oberndoder first coined the name carcinoid [48]. North American Neuroendocrine Tumor Society (NANETS) and European Neuroendocrine Tumor Society (ENETS) recommend that only appendiceal NET >20 mm should be treated with a RHC due to the increased risk of nodal positivity in these tumors [49, 50, 51].

However, it may be necessary to focus on tumors that are between 10 and 20 mm in diameter at their base, have a Ki-67 index of more than 3%, and have a lymphovascular invasion.

One study of 261 individuals with appendiceal carcinoid tumors found that basing treatment decisions on tumor location, tumor grade, or mesoappendiceal invasion was not only ineffective but also led to needless hemicolectomy. Lymphovascular invasion may help the surgeon decide what to do next for a patient with a 15 mm tumor [52].

The prognosis of appendiceal NETs is better than those of other midgut NETs. The 5-year relative survival rates for patients with localized, regional, and distant metastatic disease are 94, 84.6, and 33.7%, respectively [48, 52].

Goblet cell adenocarcinoma (GCA, previously named goblet cell carcinoids or adenocarcinoids) is another surprising discovery post appendectomy that exhibits characteristics of both NET and adenocarcinomas. It can be distinguished from NET by its positive staining for periodic acid-Schiff (PAS) antigens. Other markers that distinguish GCA from NET include its greater Ki-67 and expression of carcinoembryonic antigen (CEA) [53].

A poorer prognosis than NETs necessitate treatingv GCA as one would invasive adenocarcinoma [54].