Acute Appendicitis in Childhood and Adulthood.

Acute appendicitis is the most common cause of the acute abdomen, with an incidence of 1 per 1000 persons per year. It is one of the main differential diagnoses of unclear abdominal conditions.

This review is based on pertinent publications that were retrieved by a selective search in the PubMed and Cochrane Library databases.

In addition to the medical history, physical examination and laboratory tests, abdominal ultrasonography should be performed to establish the diagnosis (and sometimes computed tomography [CT] or magnetic resonance imaging [MRI], if ultrasonography is insufficient). Before any treatment is provided, appendicitis is classified as either uncomplicated or complicated. In both types of appendicitis, the decision to treat surgically or conservatively must be based on the overall clinical picture and the patient�s risk factors. Appendectomy is the treatment of choice for acute appendicitis in all age groups. In Germany, appendectomy is mainly performed laparoscopically in patients with low morbidity. Uncomplicated appendicitis can, alternatively, be treated conservatively under certain circumstances. A meta-analysis of five randomized, controlled trials has revealed that ca. 37% of adult patients treated conservatively undergo appendectomy within one year. Complicated appendicitis is a serious disease; it can also potentially be treated conservatively (with antibiotics, with or without placement of a drain) as an alternative to surgical treatment.

Conservative treatment is being performed more frequently, but the current state of the evidence does not justify a change of the standard therapy from surgery to conservative treatment. Appendectomy is among the more commonly performed operations in Germany, with more than 108 000 procedures per year (1). Acute appendicitis has an incidence of 100 new cases per 100 000 persons per year and is the most common cause of the acute abdomen (2, 3). The lifetime risk of acute appendicitis is slightly higher in men than in women (8.6% versus 6.7%), but women have a higher lifetime risk of undergoing appendectomy (23.1% versus 12.0%) (4). Adolescent girls (age 12�16) are the group at greatest risk for appendectomy (5). In Germany, laparoscopic appendectomy is universally available and has become the usual treatment, replacing conventional appendectomy. Approximately 25% of appendectomies in children are performed by open surgery, there being as yet no unequivocal evidence for the superiority of the laparoscopic approach (3, 5). Appendectomy is associated with very low surgical risk; the morbidity and mortality of patients who have undergone appendectomy is largely determined by the severity of the appendicitis itself and its comorbidities (3, 6). The vermiform appendix plays a physiological role as a reservoir for the intestinal flora (intestinal microbiome), e.g., after antibiotic treatment, as well as the site of origin of mesenchymal stem cells in the colon (7, 8, 9). Three guidelines on appendicitis have been published to date internationally (10, 11, 12), but none yet in Germany.

A selective literature search was carried out in the PubMed and Cochrane Library databases, with the search terms �acute appendicitis,� �acute appendicitis diagnostics,� �acute appendicitis therapy,� �appendectomy,� �uncomplicated appendicitis,� �complicated appendicitis,� �appendicitis in children,� and �appendicitis in adults.� Learning objectives This article should enable the reader to: - distinguish uncomplicated and complicated appendicitis - know the diagnostic and therapeutic options in acute appendicitis in children and adults. Classification Appendicitis is defined as an inflammation of the vermiform appendix. The European Association of Endoscopic Surgery (EAES) classifies acute appendicitis as either �uncomplicated� or �complicated� (12). Uncomplicated appendicitis is defined as inflammation in the absence of phlegmon, gangrene, free purulent fluid, or an abscess. Complicated appendicitis is accompanied by a periappendiceal phlegmon with or without perforation, gangrene, or a perityphlitic abscess (Table 1). Diagnostic evaluation Cases of acute appendicitis vary widely in their clinical presentation, and the diagnosis is made more difficult by a multiplicity of differential diagnoses. Acute appendicitis has been called the chameleon of surgery (13). Up to half of all cases in children present with nonspecific symptoms. There is a wide range of differential diagnoses depending on age; the incidence peak is during the primary-school years and adolescence (Table 2) (4, 14, 15). In our view, appendicitis should already be classified before treatment as either uncomplicated or complicated, in order to enable stage-appropriate treatment. History, physical examination, and laboratory tests The patient should always be asked about the time of onset of symptoms and the site of the pain, as well as the past medical history and current medications (Table 1). A change in the localization of pain from the upper abdomen to the right lower quadrant is often associated with appendicitis (16). In children and adolescents, the history and physical examination should be adapted to the patient�s age and developmental stage. The experience of the examiner is important, particularly when the patient is a small child. Appropriate analgesic medication does not mask the physical findings to any relevant extent (17). In children, the absence of nausea and vomiting, abdominal tenderness, and leukocytosis rules out appendicitis with 98% reliability (18). In pregnant women, the appendix may be cranially displaced by the enlarged uterus, with the result that pain is felt in the upper abdomen, rather than the right lower quadrant; this can make the diagnosis more difficult. Whenever acute appendicitis is suspected, physical examination for the known signs of appendicitis is mandatory (Figure, Table 1) in addition to blood tests (19). Local guarding in the right lower abdominal quadrant indicates irritation of the parietal peritoneum, while diffuse guarding indicates a severe, complicated case of appendicitis. Leukocytosis/neutrophilia and an elevated serum concentration of C-reactive protein (CRP) are considered nonspecific signs of inflammation (20, 21). Procalcitonin plays no role in routine diagnostic testing (22, 23). The body temperature should be measured, and a simple urinalysis with a test strip should be performed, as should a pregnancy test in girls and women of child-bearing age (20). These measures serve to rule out a number of differential diagnoses of right lower quadrant pain, for example, urolithiasis, urinary tract infection, or an ectopic pregnancy. Gynecological consultation should be obtained for stable female patients with unclear clinical presentations in whom the diagnosis remains uncertain. A digital rectal examination is of low diagnostic yield and need not be performed (24). Scoring systems A variety of scoring systems have been developed for the purpose of investigating and objectifying a suspected diagnosis of acute appendicitis independently of the clinical experience of the examiner. The most commonly used ones are the Alvarado score (1986) and the Appendicitis Inflammatory Response (AIR) score (2008) (Table 3) (6). The criterion of an Alvarado score ≥ 5 diagnoses appendicitis with 99% sensitivity, but only 43% specificity; setting the threshold higher (≥ 7) leads to increased specificity (81%), at the cost of lower sensitivity (82%). The Alvarado score, therefore, is most useful for ruling out appendicitis, rather than diagnosing it. In contrast, an AIR score >8 is both highly sensitive and highly specific (99%) for appendicitis (6, 11). In Germany, scoring systems like these are not generally used as an aid to diagnosis in routine clinical practice. Imaging Ultrasonography, CT, and MRI are all used in the evaluation of suspected acute appendicitis. Ultrasonography is the method of first choice, particularly for children (25). It has the disadvantage that its diagnostic benefit depends on the examiner�s experience, and a negative finding may not suffice to rule out appendicitis (sensitivity 71�94%, specificity 81�98%) (12, 26). In children, its sensitivity and specificity are higher: sensitivity 96% [83�99%], specificity 100% [87�100%] (25). CT is superior to ultrasonography (sensitivity 76�100%, specificity 83�100%) (12), yet its role in the evaluation of suspected acute appendicitis is a matter of controversy in Western countries, and it is used to a variable extent depending on location. In the USA, CT is routinely performed in 20�95% of patients, presumably contributing to the less than 5% rate of negative appendectomies (removal of a histopathologically normal appendix) (27, 28, 29). In Europe, on the other hand, the diagnosis is often made on clinical grounds, and there is a higher laparoscopy rate as well as a higher rate of negative appendectomies (up to 32%) (30, 31). The use of low-dose rather than conventional CT does not significantly affect the negative appendectomy rate (difference 0.3%, 95% confidence interval [−3.8; 4.6]); avoiding the administration of oral contrast medium and giving intravenous contrast medium lowers radiation exposure while preserving diagnostic sensitivity (95% versus 92%) (32, 33, 34, 35, 36). Nonetheless, even though CT is both highly sensitive and highly specific, it may not be able to distinguish complicated from uncomplicated appendicitis. In obese persons (BMI >30 kg/m2), the ultrasonographic signs of appendicitis are hard to evaluate; CT is performed more often in this patient group (12). The same holds for persons over age 65, because their symptoms are usually atypical, and because increasing age is associated with higher comorbidity and thus also with a broader differential diagnosis. MRI, compared to CT, has comparable sensitivity (97 versus 76�100%) and specificity (95 versus 83�100%) for the diagnosis of acute appendicitis (12), but it is not universally available in an emergency. MRI is a safe alternative to CT for children and pregnant women, as it does not involve ionizing radiation, and is thus preferable to CT, in our view, if the ultrasonographic findings are equivocal (37). Children under age 5 often require sedation or general anesthesia for MRI to be performed. Treatment Guidelines and literature According to the World Society of Emergency Surgery (WSES), the Society of Gastrointestinal and Endoscopic Surgeons (SAGES), and the European Association for Endoscopic Surgery (EAES), appendectomy is the treatment of choice for uncomplicated acute appendicitis in all age groups (10, 11, 12). Harrison, in 1953, was the first to propose conservative treatment for acute appendicitis (38). A few authors reported spontaneous cures (39). Now that many publications have documented the successful conservative treatment of uncomplicated appendicitis with antibiotics in childhood and adulthood, this approach is attracting increased attention (12, 40, e1, e2, e3). In a recent meta-analysis, children and adolescents with uncomplicated appendicitis who were treated conservatively became free of symptoms in 92% ([88; 96]) of cases, although 16% (10�22%) went on to undergo appendectomy because of a recurrence (follow-up: 8 weeks to 4.5 years) (e3). Another meta-analysis, in 2016, showed no difference with regard to complications or length of hospital stay (e4). In a comparative analysis, Kessler et al. found that conservative management in childhood led to a higher hospital readmission rate (relative risk [RR] 6.98; [2.07; 23.6]) and a lower rate of becoming free of symptoms (RR 0.77; [0.71; 0.84]) (e5). Because the studies analyzed in these publications were not randomized and recruited fewer patients than would have been desirable, it can practically be assumed that the children were more likely to be treated conservatively if they were less clinically ill. The follow-up was inadequate as well, as shown by 5-year follow-up studies both in children (appendectomy rate five years after primary conservative treatment of uncomplicated appendicitis: 46%) (e6) and in adults (APPAC trial appendectomy rates of 27% and 39% at one and five years, respectively) (e7, e8). Moreover, in the APPAC trial, the non-inferiority criterion for antibiotic treatment was not met at one year. In all three of the analyses mentioned above, the state of the evidence is insufficient to justify a change of clinical strategy, although conservative treatment can be regarded as safe (e3, e4, e5). In a meta-analysis of five randomized and controlled trials published in 2019, appendectomy was found to be the more effective method for the definitive treatment of uncomplicated appendicitis in adulthood (37.4% appendectomy rate within one year after conservative treatment; treatment effectiveness [i.e., lack of recurence or appendectomy] with at least one year of follow-up, 62.6% versus 96.3% in the surgical group, RR 0.65 [0.55; 0.76]) (e9). Current evidence is insufficient to enable the detection of any advantage for conservative treatment, and surgery thus remains the treatment of choice for acute uncomplicated appendicitis in both children and adults (e3). The potential long-term adverse effects of conservative treatment (drug side effects, antibiotic resistance) have not been adequately described to date and will be studied in upcoming trials (APPAC-III, MAPPAC) (e10, e11). For all these reasons, the rest of this article will deal mainly with the surgical treatment of acute uncomplicated and complicated appendicitis in children and adults. Laparoscopy In Germany, appendectomy is now performed laparoscopically as a standard. The reasons for this are the shorter hospital stay, lower wound infection rate, and lower morbidity (1.5% versus 11.9% for wound-healing disturbances) and mortality (0.1 versus 1.2%) compared to open surgery, although the negative selection of seriously ill patients must be taken into account (3). Laparoscopy enables abdominal exploration to rule out various differential diagnoses, e.g., adnexitis and Meckel�s diverticulitis. It remains controversial whether a macroscopically normal appendix should be removed if no alternative diagnosis can be made, just as conservative treatment remains controversial (12, e12, e13). In our view, incidental appendectomy can be performed if there is no contraindication. In 18�29% of cases, histological study reveals appendicitis or another type of appendiceal pathology, such as endometriosis (0.0�0.9%), neoplasia (0.23�1.2%), or obstruction by an appendicolith (2.7�6.0%) or parasites (1.2�2.5%), despite a macroscopically normal appendix (e14, e15). Complicated appendicitis There is no standard evidence-based approach to the treatment of complicated acute appendicitis. In principle, it can either be treated with urgent surgery or managed conservatively (i.e., with antibiotics alone or with the interventional placement of a drain). Certainly, the clinical condition of the patient and any risk factors that are present should be taken into account in deciding upon the treatment (12). Moreover, if conservative management is adopted, the associated risks must be borne in mind (e16, e17). In Germany, the usual treatment is immediate appendectomy (3). The EAES and WSES have not defined any clear way to proceed in the management of complicated appendicitis (11, 12). They consider initial conservative management a possible option but point out the need for further studies to clarify the role of interval appendectomy, i.e., appendectomy during an inflammation-free interval (12). The WSES recommends primary conservative treatment for an abscess or phlegmon, with the comment that laparoscopy is a feasible alternative (11). Internationally, there is increasing evidence in favor of conservative treatment for complicated appendicitis (mixed meta-analysis: 17 retrospective studies, one prospective study, and three randomized, controlled trials), with low rates of complications (odds ratio [OR] 3.16; [1.73; 5.79], intra-abdominal retentions (OR 3.13; [1.18; 8.3]), and wound infections (OR 3.95; [1.95; 8.00]) compared to surgery. The subgroup analysis of the included randomized, controlled trials did not reveal any significant difference in intra-abdominal retentions (OR 0.46; [0.17; 1.29]) between conservative and laparoscopic treatment. On the other hand, these high-quality randomized and controlled trials did show laparoscopic appendectomy to be associated with a hospital stay that was one day shorter (mean difference [MD] −0.99; [−1.31; �0.67]), without any elevation of the complication rate (e18). Another meta-analysis (three randomized, controlled trials [RCTs] and four controlled clinical studies) favored immediate laparoscopic surgery for appendicitis in the presence of an abscess, rather than conservative management, because of a higher rate of unproblematic recovery (OR 11.91; [4.59; 30.88]), a shorter hospital stay (weighted MD: −2.98; [−5.96; −0.01]), and fewer recurrent abscesses (OR 0.07; [0.3; 0.20]) (e19). Future studies will be needed to determine what treatment is truly best for complicated appendicitis in consideration of the patient�s risk factors and clinical condition. It has been suggested that interval appendectomy might be best reserved for symptomatic patients (e21), in view of the associated higher conversion rate (1.9 versus 0.13%; p <0.001), and higher rates of intraoperative complications (2.8% versus 0.3%; p <0.001) and intra-abdominal retentions (4.7 versus 1.2%, p = 0.003) (e20). The management of a perityphlitic abscess (drainage before surgery) In view of the heterogeneous data that are currently available, there is no uniform, evidence-based way to proceed when a perityphlitic abscess is demonstrated (e16, e17, e18, e19, e22). In this situation, we recommend risk-stratified interdisciplinary management, depending on size. A macroabscess can be treated with the interventional placement of a drain combined with antibiotic treatment and, depending on the further course, an interval appendectomy. A microabscess can be treated with immediate surgery, because puncturing the abscess is generally not technically feasible. The timing of surgery It was once the rule to operate on acute appendicitis as rapidly as possible to avoid perforation and the ensuing complications (12). To date, however, there have been no randomized, controlled trials on this topic. Certain observations�such as a lower risk of perforation with a longer wait before surgery�may well be related to bias in the evidence, because patients who are clinically more severely ill (those with perforation or complicated appendicitis) have tended to be given priority for rapid surgery (e23, e24). In a Swedish multicenter study involving 1675 patients, the perforation rate only rose significantly 12, 18, and 24 hours after admission to the hospital (e23). Accordingly, in a study from the USA, surgery at a delay of more than 12 hours was associated with a longer length of hospital stay (44.6 versus 34.5 hours) and increased costs (e25). In an American study of 857 children in whom the initial CT revealed no evidence of perforation, a weak association was found between triage (i.e., a delay) till the incision was made and the intraoperative finding of a perforation (adjusted odds ratio 1.02 [1.00; 1.04] per hour of delay) (e26). It is also concluded in the up-to-date meta-analysis of Li et al. that a brief (<12-hour) delay is not associated with complicated appendicitis, but that there is nonetheless a progressively strong association between the time since the onset of symptoms, or since hospital admission, and the likelihood of perforated appendicitis�the odds ratio is 1.84 ([1.05; 3.21]) at 24 hours and 7.57 at 48 hours ([6.14; 9.35]) (e27). In adults, delaying appendectomy by 12�24 hours from the time of diagnosis, while giving antibiotics, does not increase the perforation rate (e28, e29, e30). The operation should not be delayed by more than 12 hours for patients with comorbidities or who are age 65 or older. Appendectomy more than 48 hours after diagnosis is associated with a higher surgical infection rate (adjusted OR 2.24; p = 0.039) (e31). In view of the heterogeneous evidence base that is currently available, we recommend a risk-stratified approach. A delay of up to 12 hours in children or 24 hours in adults while antibiotics are given seems not to elevate the morbidity of patients with uncomplicated appendicitis to any relevant extent. Adequate data are lacking concerning the appropriate timing of surgery for complicated appendicitis; the timing of surgery depends on the findings (phlegmon, free fluid, abscess) and on the patient�s clinical condition and comorbidities. In a meta-analysis comparing conservative and surgical treatment of complicated appendicitis with a free perforation in children, based on two randomized, controlled trials and twelve observational studies, the surgical group experienced significantly fewer complications (RR 1.86; [1.20; 2.87]) and hospital readmissions (RR 3.33; [1.49; 7.44]) (e32). We do not know of any comparable study in adults, but one study has shown that the timing of surgery is correlated with survival (e33). Thus, whenever free intraperitoneal air is seen, in a child or adult patient, surgery should be performed urgently. Antibiotics The conservative treatment of acute appendicitis is based on the administration of antibiotics (Cochrane Review: 45 studies, including RCTs and CCTs) (e34). A cephalosporin combined with a nitroimidazole (usually metronidazole) is most commonly used, followed by a penicillin with a beta-lactamase inhibitor and by quinolones. The evidence base is derived from the WSES guideline and a prospective, worldwide multicenter observational study (6, 11). Antibiotics are usually given parenterally for one to three days and then orally for a further 5�7 days (11, e21). The optimal duration of treatment is not clear; the length of treatment generally depends on the clinical course and the normalization of inflammatory parameters (12). Antibiotics should be given perioperatively as part of the treatment of any type of appendicitis (11, e34). A meta-analysis of 12 randomized, controlled trials and one Cochrane Review (47 studies) showed that perioperative antibiotics can lower both the rate of wound infections (Peto OR: 0.33; [0.29; 0.38]) and the abscess incidence (Peto OR: 0.43; [0.25; 0.73]) (e35). Continuing the antibiotics postoperatively is recommended in complicated appendicitis, particularly in case of an abscess, peritonitis, or free perforation (e35). Postoperative and other complications The overall rate of postoperative complications after appendectomy in Germany has been reported as up to 2.1% (e36). Postoperative complications can be categorized as early or late. The former include wound infection, hemorrhage, abdominal wall abscess, and appendiceal stump insufficiency, as well as intra-abdominal retentions (Douglas or loop abscess). The latter include incisional hernias, intra-abdominal adhesions possibly causing bowel obstruction, and stump appendicitis. Whenever a postoperative complication is suspected, the patient should be re-examined by the operating surgeon, and further diagnostic studies should be undertaken including laboratory testing and abdominal ultrasonography. Patient information on the conservative treatment of appendicitis should include the fact that the incidence of bowel cancer is slightly higher than in the normal population (Swedish population cohort study, SIR: 4.1 [3.7; 4.6]) (e37). Nor is there yet any definitive information from RCTs on the possible risk of adhesion formation, or the potentially higher probability of infertility, after conservative treatment. A Swedish study employing a historical cohort for comparison did not reveal any higher frequency of infertility after perforated appendicitis in childhood than after appendectomy of an unperforated, or even healthy, appendix (e38). In 0.5% of children who undergo appendectomy, histopathological study of the surgical specimen reveals a neuroendocrine tumor of the appendix, a so-called appendiceal carcinoid, as an incidental finding (e39). Depending on the size of the tumor, more extensive surgery, such as an ileocecal resection or a hemicolectomy, may be necessary. The further course of treatment should always be decided upon in collaboration with a pediatric oncologist (e40). Risk groups Therapeutic decision-making should also take certain special risk groups into consideration. According to the pertinent literature, conservative treatment has a higher risk of failure, and correspondingly higher morbidity, in patients with a demonstrated appendicolith (e41), obesity (BMI > 30 kg/m2) (e42), age over 65 (e43, e44, e45, e46, e47), or immune suppression or acquired immune deficit (e48), as well as in pregnant women (e49, e50, e51) (12). The demonstration of an appendicolith on an imaging study is highly likely to be followed by the failure of conservative treatment (Mantel-Haenszel estimator RR: 10.43 [1.46; 74.26] (e41). Thus, these patients should be treated with early appendectomy (eCase Illustration with eFigures 1 and 2). In this patient collective, high leukocyte counts and CRP values are correlated with the risk of gangrenous appendicitis (Figures 1a and b). Laparoscopic appendectomy is considered a safe treatment in this situation as well (12, e52). In pregnancy, too, acute appendicitis is the most common cause of the acute abdomen, and spontaneous abortion is its most feared complication (e53). Miscarriage is more common in complicated appendicitis than in uncomplicated appendicitis (20% versus 1.5%) (e54, e55). The threshold for operating should, therefore, be set low; appendectomy can be carried out safely in all three trimesters (e56).

In the diagnosis and treatment of acute appendicitis in childhood and adulthood, there is increasing discussion of the possibility of nonsurgical treatment, of the optimal timing of surgery, and of the appropriate postoperative care (12, 40, e1, e2). Nonetheless, the available evidence base does not suffice to justify a change from primarily surgical treatment, in either children or adults (e3, e5, e9). Moreover, there have not yet been any randomized, placebo-controlled, blinded trials investigating the long-term course with regard to the undesired side effects of conservative treatment; such trials are to begin soon (e10, e11). Thus, appendectomy remains the treatment of choice for uncomplicated acute appendicitis in all age groups (10, 11, 12). In adults with uncomplicated acute appendicitis, delaying appendectomy by 12 to 24 hours from the time of diagnosis, while giving antibiotics, does not lead to an increased rate of perforation (e28, e29, e30). Surgery should not, however, be delayed by more than 12 hours in children and adolescents, patients over age 65, or patients with comorbidities (e23, e24, e25, e26, e27, e31). Complicated acute appendicitis is a severe illness that can be managed conservatively, as an alternative to surgical treatment, under certain circumstances. The state of the evidence regarding the morbidity and efficacy of conservative management is mixed (e18, e19, e32). Future studies will be needed for a definitive determination of the best way to treat complicated appendicitis in consideration of the patient�s risk factors and clinical condition. Conflict of interest statement The authors state that they have no conflict of interest. Manuscript submitted on 5 March 2020, revised version accepted on 29 July 2020. Translated from the original German by Ethan Taub, M.D. Corresponding author Dr. med. Patrick T�oule Chirurgische Klinik, Universit�tsmedizin Mannheim Medizinische Fakult�t Mannheim, Universit�t Heidelberg Theodor-Kutzer-Ufer 1�3, 68167 Mannheim [email protected] Cite this as: T�oule P, de Laffolie J, Rolle U, Rei�felder C: Acute appendicitis in childhood and adulthood�an everyday clinical challenge. Dtsch Arztebl Int 2020; 117: 764�74. DOI: 10.3238/arztebl.2020.0764 ►Supplementary material For eReferences please refer to: www.aerzteblatt-international.de/ref4520 eCase Illustration, eFigures: www.aerzteblatt-international.de/20m0764 Department of General Pediatrics and Neonatology, Pediatric Gastroenterology, University of Giessen, Germany: PD Dr. med. Jan de Laffolie Department of Pediatric Surgery, University Hospital Frankfurt, Goethe-University Frankfurt am Main, Frankfurt, Germany: Prof. Dr. med. 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