Treatment Options for Uncomplicated Acute Appendicitis in adults: A narrative review

Review

Hell J Surg. 2024 Oct-Dec;94(4):194–205
doi: 10.59869/24047

Maria Velikoudi, Athanasios Papatzelos, Nikolaos Voloudakis, Stefanos Atmatzidis, Anestis Basios, Dimitrios Chatzelas, Basilios Papaziogas, Ioannis Koutelidakis

Second Surgical Department, Aristotle University of Thessaloniki, “G. Gennimatas” General Hospital, Thessaloniki, Greece

Correspondence: 

Nikolaos Voloudakis, e-mail: nickvolou@gmail.com, Second Surgical Department, Aristotle University of Thessaloniki, “G. Gennimatas” General Hospital, Thessaloniki, Greece

ABSTRACT

Selecting the optimal management of uncomplicated acute appendicitis in adults presents a contemporary medical challenge. Traditionally, appendectomy has been the cornerstone, but recent literature explores non-operative management (NOM) using antibiotics as a viable alternative. The Antibiotics versus Surgery for Uncomplicated Acute Appendicitis (ASAA) trial, Appendicitis Acuta (APPAC) trial, Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial and the Conservative versus Open Management of Acute uncomplicated Appendicitis (COMMA) trial have contributed conflicting results, fueling the ongoing debate. The decision between antibiotics and surgery hinges on factors like treatment success, recurrence rates, cost, and quality of life. While some studies suggest comparable outcomes between NOM and appendectomy, others highlight the challenges of NOM, including high failure rates and the potential for recurrent appendicitis. Patient perspectives play a crucial role in this dilemma, with shared decision-making emerging as a key consideration. Despite growing evidence favouring antibiotics-first approaches and the 2020 update of the World Society of Emergency Surgery (WSES) guidelines recommending NOM, uncertainties persist. Factors influencing NOM success, such as the presence of appendicolith, need careful consideration. Ultimately, the ideal approach involves a shared decision-making process, integrating patient values and preferences.

Key Words: Acute appendicitis, non-operative management, appendectomy, complicated appendicitis

Submission: 24.02.2025, Acceptance: 15.06.2025

INTRODUCTION

Acute appendicitis is one of the most common causes of acute abdominal pain in adults, especially among patients in the second decade of their life, with a male to female ratio of 1.4: 1 [1]. While precise discrimination may vary across studies, acute appendicitis is traditionally categorized into two groups: uncomplicated and complicated acute appendicitis. Complicated appendicitis is usually defined by the presence of at least one of the following features: perforation, localized abscess or phlegmon formation, peritonitis, presence of fecalith and non-perforated gangrenous appendicitis [2,3]. Recently, there has also been evidence for an immuno-allergic and non-infectious etiology of acute appendicitis; more specifically a type I hypersensitivity reaction [4]. Appendectomy has been for decades the prominent treatment option for acute appendicitis, either complicated or non-complicated [4]. Recent literature has challenged this long-standing belief, revealing that non-operative management (NOM) may stand as a safe alternative to treat uncomplicated cases of appendicitis, avoiding complications associated with surgery [6]. However, conservative treatment over appendectomy has not gained overwhelming support, perhaps due to inconsistent results emerging from relevant studies [7] and conflicting recommendations coming from international guidelines [3]. In light of an increasing number of randomised trials and meta-analyses that may add more confusion to the debate [7–11], we made a modern narrative review of the latest literature in order to primarily discuss the current trends in the management of uncomplicated acute appendicitis in adult patients and secondly assist modern physicians in better patient counselling in real-world settings.

METHODOLOGY

We performed an extensive electronic search of English-language literature from January 2003 up to December 2023, using the electronic medical databases MEDLINE (database provider PubMed) and EMBASE (database provider Ovid). The last search was performed on 02 February 2024. Our search was based on a combination of free text terms and relevant Medical Subject Headings (MeSH). Keywords such as “acute appendicitis”, “conservative treatment”, “antibiotics”, “surgery”, “appendicectomy” και “adults” were used in various combinations. Eligible for inclusion in our review were previous systematic reviews, randomised control trials (RCT) and prospective or retrospective observational studies, like case series, case-control studies or cohort studies, with the following inclusion criteria: 1) included adult patients (age ≥18 years), 2) study sample ≥50 patients and 3) provided sufficient data on clinical outcomes and follow-up. From the review, there were excluded studies on children, as well as experimental studies. Case reports and duplicates were excluded, whereas in case of metachronous publications from the same group, only the latest article or the article with the largest number of patients was included. Additional articles were identified through the references cited in the initially electronically identified studies.

Extracted data included: study type, publication year, sample size, gender, age, comorbidities, length of stay, follow-up, white blood count (WBC), C-reactive protein (CRP) levels, Alvarado/AIR/PAS score, type of treatment, efficacy recurrence, reintervention, morbidity and mortality. The primary outcomes were efficacy, recurrence and mortality, whereas secondary outcomes served the length of stay and antibiotic- or surgery-related morbidity. The efficacy of conservative treatment was defined as the complete symptom recession, without the need for surgery during follow-up. Moreover, the efficacy of surgery was defined as the complete symptom recession in conjunction with the histological validation of acute appendicitis.

The initial, electronic databases’ search (MEDLINE, EMBASE) identified 5,959 studies potentially eligible for inclusion in the review. After adjusting for duplicates, 4,678 original papers remained. After excluding articles with no relevant titles, or abstracts not meeting the inclusion/exclusion criteria, the full texts of 73 articles were retrieved and assessed for eligibility. Fourteen articles were excluded due to inconsistency to the inclusion criteria, whereas manual screening of the reference list of the retrieved articles added another one article eligible for inclusion. In conclusion, our review included 60 articles published between January 2003 and December 2023: 9 RCT, 39 observational studies and 12 systematic reviews and/or meta-analyses. However, after meticulous review, the 39 observational studies were found to be of low quality overall, due to study design and methodological quality, risk of bias, quality appraisal, relevance to the research question, data reporting and completeness. Therefore, we chose not to include them in the final qualitative analysis. Moreover, of the previous systematic reviews, only the most recent one is further analyzed in text. In conclusion, our narrative review included 9 RCTs that are discussed consequently. Figure 1 depicts the flow chart of our review. Supplementary Table 1 summarizes the methodology and results of the included RCT.

Figure 1. Study low chart.

RESULTS

Non-operative management of uncomplicated acute appendicitis

Parenteral antibiotics versus appendectomy

The first description of successful conservative management of acute appendicitis cases comes from Coldrey in 1956 [12]. Since then, although several studies have questioned the need of an urgent appendectomy after the diagnosis of acute appendicitis [13–15], it was not until the onset of coronavirus 2019 pandemic that a genuine interest towards NOM of acute appendicitis, that can be applicable to the general population, emerged [16].

One of the first trials with an adequate sample and rigorous design was the Appendicitis Acuta (APPAC) clinical trial that did not manage to establish the non-inferiority of antibiotic treatment (intravenous ertapenem for three days followed by seven days of oral levofloxacin and metronidazole), compared to standard open appendectomy for uncomplicated acute appendicitis within the first year of observation [17]. The results of the long-term follow-up of the patients of the APPAC trial initially treated with antibiotics showed that the cumulative incidence of recurrent appendicitis at five years was 39.1%. The majority of the patients (70/100, 70%) who developed recurrent appendicitis, did this within the first year and none of them experienced any complications related to the delay in surgical management [18]. Additionally, cost analysis of the APPAC trial reported significantly lower overall costs of antibiotic therapy compared to appendectomy even at five-year follow-up [19], while long term quality of life was similar after both treatment alternatives [20].

Antibiotics versus Surgery for Uncomplicated Acute Appendicitis in Adults (ASAA) trial was another monocentric, prospective, randomised control study (RCT) that failed to demonstrate non-inferiority of conservative treatment (intravenous ertapenem for three days, followed by oral amoxicillin/clavulanate for five days) versus appendectomy for uncomplicated acute appendicitis diagnosed with the utilisation of appendicitis inflammatory response (AIR) score and abdominal ultrasound findings in selected cases [21]. The researchers focused on the difficulties encountered to preserve equipoise in an emergency care environment unfamiliar with evidence-based methodology, which led to insufficient patient recruitment rate and inconclusive results.

Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial was a landmark study with the largest to date sample of participants that demonstrated the non-inferiority of a ten-day antibiotic course (with intravenous inception of antibiotics administration for at least 24 hours) versus appendectomy when considering the results of a validated health-status questionnaire at 30 days [10]. CODA inclusion criteria were broader than previous trials, as patients with evidence of an appendicolith on imaging were enrolled in the trial and the presence of perforation was not by itself an exclusion criterion. By 90 days, approximately three in ten participants had undergone appendectomy in the antibiotics group, with a higher rate of visits at the emergency department and hospital admissions following the index treatment, compared to the surgery group. The percentage of the patients who had originally received antibiotics and later underwent surgery were 40%, 46%, 49% and 49% at first, second, third and fourth year, indicating a rather high rate of recurrence in the long-term and raising questions on the efficacy of antibiotics in the management of acute appendicitis. In addition, individuals with an appendicolith were at higher risk for appendectomy compared to those without an appendicolith, but this difference decreased over time [22].

Appendectomy versus Conservative Treatment for Uncomplicated Acute Appendicitis (ACTUAA) study was a prospective, non-randomised trial comparing treatment of ultrasound- and/or CT- diagnosed uncomplicated acute appendicitis with parenteral antibiotic regimens to surgical intervention (open or laparoscopic) in two matched study groups of 87 patients, respectively, from a primary sample of 318 patients. Although the lack of randomisation, and the subsequent selection bias, poses as a strong quality deficit of the study, the inability of the trial to establish the superiority of appendectomy over antibiotic treatment for uncomplicated appendicitis according to the study’s predefined criteria is of note. The primary endpoint, defined as complication-free treatment success, was met in 64,4% of patients in the antibiotics group compared to 83,9% in the post-match surgery group (p=0,005). Interestingly, individuals in the surgery group reported significantly higher quality of life as assessed by the Short Form Health Survey (SF-12) scale at the 30-day follow-up, but lower scores of the same measure at the one-year follow-up compared to the antibiotics group. Patients in the antibiotic-first arm of study reported better outcomes concerning pain assessment both at hospital discharge and at 30-day follow-up, compared to the appendectomy group [23].

Conservative versus Open ManageMent of Acute uncomplicated Appendicitis (COMMA) trial was a single-center, well-powered RCT, evaluating the efficacy, quality of life, cost and length of hospitalisation associated with NOM of uncomplicated acute appendicitis. The COMMA trial demonstrated high failure rates of antibiotic-only management of appendicitis, which exceeded the acceptable rate of 15% at one-year follow-up. The health-related quality of life was thoroughly assessed by two validated instruments at several timepoints during the first post-intervention year. Patients randomised to the surgery group, although presenting a negative impact on quality of life shortly during the early postoperative period, had significantly higher scores on quality of life questionnaires at 12 months compared to the antibiotic-only group. There were no significant differences regarding the length of stay between the two groups, while the antibiotics-only approach was associated with significantly lower overall cost [7]. To our knowledge, COMMA was the last in a series of several highly-esteemed trials that tried to take a stand in the debate between those in favour of NOM and those reluctant to abandon upfront surgery as the gold standard in the management of uncomplicated acute appendicitis. Although the COMMA failure rates are in relative accordance with those of CODA and APAAC studies [10,17], the researching group of COMMA, taking into consideration the latter as well as the results of the quality of life assessment, recommended against the use of NOM as “the mainstay of treatment” of appendicitis [7].

Oral antibiotics versus parenteral antibiotics

The APPAC trial was later followed by the APPAC II multicenter RCT, which intended to optimize the NOM of computed tomography (CT) – confirmed uncomplicated acute appendicitis by comparing the treatment efficacy of oral antibiotic monotherapy versus the combined intravenous followed by oral antibiotic regimen [24]. Although the majority of patients in both groups avoided surgery and 207/295 (70.2%) of patients were successfully treated (treatment success was defined as discharge without appendectomy and absence of recurrence during one-year follow-up) with the oral regimen, the APPAC II trial failed to demonstrate noninferiority of the oral monotherapy compared to the combination of intravenous and oral antibiotics [25].

Ceresoli et al. [26] recently reported the results of their non-inferiority, multicenter, retrospective observational trial comparing outpatient to inpatient NOM of imaging-confirmed uncomplicated acute appendicitis. The primary endpoint was the 30-day appendectomy rate, with a non-inferiority limit of 5%. Secondary endpoints were negative appendectomy rate, 30-day unplanned emergency department (ED) visits, and length of stay. Although, a CODA study subgroup analysis had already investigated the safety of outpatient antibiotic management of acute appendicitis [27], the definition of outpatient management between the two studies was different. In the CODA outpatient protocol, patients were treated with a first dose of intravenous antibiotics in the emergency department and were later discharged within 24 hours, whereas patients in the outpatient protocol of Ceresoli et al. [26] they were discharged within 12 hours from emergency department registration and received only oral antibiotics. Inpatient protocol included administration of intravenous antibiotics followed by oral regimens in both studies. Ceresoli et al. demonstrated that outpatient NOM protocol was non-inferior to inpatient NOM protocol, with similar rates of 30-day appendectomy between the two groups, while mean cumulative length of hospitalisation was shorter for patients in the outpatient protocol. A relatively small percentage of outpatient-NOM individuals (17,7%) required unplanned medical evaluation within 30-days and no difference was reported for cases of negative appendectomy between the two groups. In the long-term analysis (24 months) appendectomy rate was 25% in both groups [26]. These results were consistent with the CODA subgroup analysis [27] in terms of efficacy and safety of outpatient NOM compared to inpatient NOM, taking into account the administration of intravenous antibiotics in the CODA outpatient NOM group, as well as the broader inclusion criteria for appendicitis patients in CODA trial [10]. Although conducted under pragmatic conditions, the fact that patients were allocated to treatment groups according to surgeon’s preference introduced a serious selection bias  in the study by Ceresoli et al. [26], which is a major evidence-based methodology limitation, in addition to the study’s observational design. Similarly, CODA subgroup analysis’ results are prone to bias arising from the absence of randomisation [27].

Placebo versus antibiotics

The first RCT that investigated the hypothesis that uncomplicated acute appendicitis can resolve spontaneously without the use of antibiotics came from South Korea in 2017 [28] and noted similar treatment failure rates between those who received a four-day antibiotic therapy and those who received simple supportive care.

The APPAC III trial was designed as a double-blind, placebo-controlled, superiority RCT in patients with CT-confirmed uncomplicated acute appendicitis comparing placebo with the combined (intravenous followed by oral) antibiotic schema on the basis of treatment success (defined as resolution resulting in discharge without surgery within ten days) [29], serving as a research continuum from the two previous Finnish studies [17,25]. This study encountered methodology barriers, especially due to poor patient recruitment and the consequent small sample size, therefore the non-superiority of antibiotics reported in the results can only serve as a marker to guide future larger non-inferiority RCTs.

Patients’ perspective

Given the reasonable doubts and hesitancies over the most reasonable treatment approach for uncomplicated acute appendicitis, latest literature claims that the final decision must be made after taking into account patients’ satisfaction and preferences in the form of a shared-decision strategy [20,30]. In an observational follow-up of the APPAC trial, patients that underwent appendectomy were more satisfied than those in the antibiotic group. However, this difference was attributed to the patients that ultimately required appendectomy, as shown in a subgroup analysis of the same trial [20]. Sallinen et al. in their meta-analysis of 2016 noted that patients averse to surgery are likely to choose an antibiotic first approach, whereas those averse to the possibility of recurrence may opt out for immediate surgery, raising a point over the need of understanding patients’ personal values [30]. A recent analysis of patient reported outcomes derived from CODA trial participants, revealed high levels of satisfaction and low levels of regret for both antibiotics and appendectomy groups at 30 days, with a small proportion of patients reporting negative outcomes, more often by patients undergoing antibiotic treatment. Female gender, presence of appendicolith and larger diameter of appendix were factors associated with higher levels of dissatisfaction and regret among those treated with antibiotics [31]. Kadera et al., in an attempt to assess patients’ understanding of appendicitis, treatment preferences and concerns, conducted an observational study of 129 patients at a Los Angeles County public hospital emergency department. Among those, fewer than half (43%) correctly defined appendicitis and nearly half of them (53%) indicated surgery as appendicitis’ treatment. After giving current evidence for the use of antibiotics in the setting of acute appendicitis and a hypothetical scenario, 57% of patients chose antibiotics over appendectomy, and this rate was raised up to 74%, in cases of patients with previous appendectomy [32]. In another survey of  American adults recruited via Amazon Mechanical Turk, although only 9,1% were aware of the use of antibiotics as an alternate in the management of appendicitis prior to the survey, a vast majority of them (83,1%) were willing to try antibiotic approach and 57,3% of the latter would still try antibiotics regardless of the risk of treatment failure [33].

DISCUSSION

Growing evidence supports the notion that complicated and non-complicated appendicitis are different entities, with perforation not always being the inevitable consequence of an ongoing appendicitis [29,34]. Interestingly, non-perforating acute appendicitis seems to share clinical and epidemiological similarities with non-perforating acute diverticulitis, suggesting common underlying pathophysiologic processes [35]. However, the question of whether cases of uncomplicated acute appendicitis should be operated or not continues to remain doubtful, in contrast to the cases of uncomplicated acute diverticulitis, where non-operative methods are predominantly the mainstay of treatment [36].

As derived from epidemiological studies, appendix may play a role in immune balance, as its removal has been associated with reduced risk of ulcerative colitis and an increased risk of severe Clostridium difficile colitis requiring surgery and Crohn’s disease. Furthermore, it is hypothesised that the appendix may play a potentially crucial role in the gut microbiome as well, serving as a microbial reservoir of the gastrointestinal tract [37]. These findings come in favour of the conservative management for appendicitis utilizing appendix preserving approaches. In this direction, apart from antibiotics-first strategies, endoscopic retrograde appendicitis therapy (ERAT) is another minimally invasive appendiceal sparing treatment method, developed and performed mainly in China, which involves colonoscopy, irrigation and/or stenting of the appendix. This novel management strategy is associated with high success rates, rapid pain relief and fast recovery, and will challenge both appendectomy and antibiotic therapy in clinical practice, if robust evidence from appropriately designed RCTs emerge [38].

Although the largest to date RCT comparing NOM to appendectomy demonstrated the non-inferiority of a ten-day antibiotic course when considering the results of a validated health-status questionnaire at 30 days [10], the results of the latest RCT that addressed this old dilemma, demonstrated high failure rates of antibiotics, that exceeded the acceptable rate of 15% at one-year follow-up [7]. Regarding the most acclaimed international clinical practice guidelines, the 2020 update of the WSES Jerusalem guidelines strongly recommend in favour of an antibiotic-fist approach as a safe alternative to operation, raising a point in the optimal use of NOM, by selecting the most suitable candidates with uncomplicated acute appendicitis, after an honest discussion with them over the possible risks of misdiagnosis and treatment failure [3]. It is of note that these guidelines have been published just before the publication of the two robust RCTs mentioned previously [7,10], thus adding more confusion to clinical practice.

Given the fact that controversy would persist until further research emerges, focus should shift towards factors related to NOM failure. In a retrospective cohort analysis of 81 patients [39], patients with longer duration of symptoms prior to admission (>25 hours), lower temperature (<37.3°C), lower modified Alvarado score (<4), and lower appendiceal diameter (<13 mm) were more likely to have successful NOM. On the other hand, there is some evidence from a couple of underpowered studies, that male gender [40], diabetes mellitus and higher heart rate on admission [41] are associated with greater recurrence rates of acute appendicitis after NOM. In a cohort study using data from the CODA trial, female sex (odds ratio [OR], 1.53; 95% CI, 1.01-2.31), wider appendiceal diameter (OR per 1-mm increase, 1.09; 95% CI, 1.00-1.18), and presence of appendicolith (OR, 1.99; 95% CI, 1.28-3.10) were associated with increased risk of undergoing appendectomy within 30 days of initiating antibiotics, while patient characteristics that are traditionally associated with adverse outcomes and severity of appendicitis (e.g. older age, obesity, fever) were not independently associated with appendectomy [42]. The presence of appendicolith has already been identified from previous studies as an independent prognostic factor for failure of NOM [15,43], prompting Mallinen et al. to conclude that “the presence of an appendicolith in a patient with acute appendicitis should be classified as complicated appendicitis warranting emergency appendectomy and it is an exclusion criterion for non-operative management of acute appendicitis’’ based on their histopathological findings [44]. Despite maintaining a distance from this unequivocal position, it is crucial that when planning treatment of acute appendicitis, patients should be aware of the worse outcomes of NOM if an appendicolith is present, as well as the exact frequencies of these adverse events according to latest evidence [42].

A recent systematic review and meta-analysis (2022) included 8 RCTs, involving 3,203 participants (1,613 in the antibiotics group vs. 1,590 in the appendicectomy group) and compared antibiotic therapy with appendicectomy in adults with uncomplicated acute appendicitis [45]. Four studies were judged to be at low risk of bias. Two studies were judged to have some concerns due to lack of detail regarding random sequence allocation, whereas two studies were judged to be at a high risk of bias; one due to the exclusion of participants with complicated appendicitis and the other for several other concerns. The meta-analysis showed that antibiotic treatment at one year was successful in 62.9% of the participants. Antibiotics had a reduced treatment efficacy compared to appendicectomy. Moreover, there was no significant benefit of antibiotic treatment on complication rates and there was a six-fold increase in hospital readmissions within one year. Therefore, the authors concluded that the earlier optimism regarding the benefits of antibiotic therapy for uncomplicated acute appendicitis does not persist when large trials have been incorporated, and if antibiotic treatment is to be offered routinely as first-line therapy, then patients should be informed and monitored appropriately.

Another systematic review and meta-analysis that examined the efficacy and safety of non-operative (antibiotics) versus surgical treatment for acute uncomplicated appendicitis in adults incorporated data from eight RCTs conducted between 1995 and 2021. [46] The primary outcome – treatment success as defined by each trial – did not show a statistically significant difference between the two treatment modalities, though there was considerable heterogeneity among the studies. Secondary outcomes revealed a non-significant trend toward fewer major complications with antibiotic treatment and a significantly longer hospital stay associated with nonoperative management. The recurrence rate of appendicitis in patients treated conservatively was approximately 18% at one year. Although non-operative treatment appears safe and potentially effective in selected patients, it requires close clinical monitoring and access to advanced healthcare infrastructure, which may limit its applicability in resource-limited settings.

Bidirectional exchange of information should be the base of a shared decision-making process that will determine the ideal treatment strategy in uncomplicated cases of acute appendicitis, according to patient values and preferences [47]. Apart from being the recommended therapy approach for over a century, appendectomy is a brilliant training operation in abdominal surgery, thus it is hypothesised that surgeons would face an understandable bias against the general adoption of NOM for uncomplicated acute appendicitis. In an online survey of 1728 respondents [48], the vast majority of the participants chose surgery as the preferable treatment for uncomplicated acute appendicitis, while about 10% of them preferred antibiotics. In the same survey, surgeons were less likely to choose antibiotics, especially those aged 60 to 79 years old, which would also be the case in our personal clinical experience. However, this study was conducted approximately 4 years before the outburst of coronavirus 19 pandemic, the publication of the latest WSES Jerusalem guidelines and the results of the CODA trial which shifted the status quo in the treatment of acute appendicitis, favouring the use of NOM in selected cases and challenging the physicians’ hesitation [3,10,16].

Limitations

Since it is a narrative review about the treatment options in acute appendicitis, only a qualitative analysis of the included studies could be performed. However, we believe that the quantitative synthesis of largely heterogenous results of the included studies can sometimes be misleading; therefore, a comprehensive review offers occasionally a better insight into the full extent of the review object. Moreover, our electronic database research included only two databases, only articles published in English, and it didn’t include any grey literature. Furthermore, even though we didn’t perform an individual study bias analysis, as in systematic reviews, the vast majority of the observational studies were found to be of low quality and we decided not to present them in text, but rather focus on the higher quality RCT. Finally, our review included only adult patients with acute appendicitis; therefore, its results are not applicable in the pediatric population.

CONCLUSIONS

Contemporary perspectives on managing uncomplicated acute appendicitis are undergoing a paradigm shift. While appendectomy has long been the standard, recent trials explore alternative approaches. NOM with antibiotic therapy alone presents a feasible and safe alternative to appendectomy. This shift prompts a nuanced evaluation of risks and benefits, emphasizing the need for personalised treatment decisions aligned with patient preferences. This evolving landscape underscores the importance of a holistic approach, where medical and surgical interventions are carefully considered, steering away from a one-size-fits-all mentality.

SUPPLEMENTARY MATERIALS

Supplementary Table 1.

AUTHOR CONTRIBUTIONS

Conceptualisation, A.P., N.V., B.P. and I.K; methodology, M.V., A.P., N.V., I.K.; validation, M.V. D.C., and B.P.; investigation, S.A., A.B., M.V.; resources, A.P., M.V., N.V..; data curation, A.P., D.C.; writing—original draft preparation, M.V., A.P., and N.V.; writing—review and editing, N.V., S.A., D.C., B.P., I.K..; supervision, B.P. and I.K.; project administration, I.K.;. All authors have read and agreed to the published version of the manuscript.

FUNDING

This research received no external funding.

INSTITUTIONAL REVIEW BOARD STATEMENT

Ethical review and approval were waived due to the nature of the review (narrative review).

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

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