Abstract
Purpose
As one of the most common surgical emergencies, nonoperative management of acute appendicitis becoming more widespread. Failure rate and recurrences are main problems against nonoperative management. The aim of the current study is to evaluate long term recurrence rate of acute appendicitis after nonoperative management.
Methods
This cohort included patients treated between February 2017 and December 2021 with a mean follow up of 64.2 months. The cohort consists of patients with clinically and radiologically approved uncomplicated acute appendicitis. All patients had a course of nonoperative management with antibiotics. Primary outcome of the study is the recurrence rate of acute appendicitis. Secondary outcomes are failure rate of medical treatment and neoplasia rate.
Results
The mean age of the participants was 41.51 ± 18.7 years. The cohort consists of 51.7% male and 48.3% female patients. The success rate of nonoperative management of acute appendicitis was found to be 95.7%. At the end of the study 209 patients included in analysis with a mean follow up of 64.2 months. The recurrence rate was found as 5%.
Conclusion
Nonoperative management of uncomplicated acute appendicitis can be used with high success and low recurrence rate.
Keywords: Acute appendicitis, Surgery, Conservative treatment, Medical treatment
Key Points
Question: What is the long term recurrence rate after nonoperative management of uncomplicated acute appendicitis?
Findings: In this cohort study that included 209 cases with nonoperative management of acute appendicitis with a mean follow of 64.2 months, recurrence rate is found to be 5%.
Meaning: Nonoperative management of uncomplicated acute appendicitis is safe and feasible.
Introduction
As one of the most common surgical emergencies, traditional treatment of acute appendicitis is appendectomy [1–3]. Despite the use of imaging modalities like ultrasonography and computed tomography, the negative appendectomy rate still remains between 5 and 20% [4, 5]. Both to avoid unnecessary surgeries and complications of surgery, nonoperative treatment of acute appendicitis can be an option [6]. Randomized studies have shown that nonoperative management with antibiotics can be successful in patients with noncomplicated appendicitis who wish to avoid surgery and accept the risk of recurrence [7–10]. In complicated appendicitis, such as perforation and peritonitis, surgery remains as the gold standard treatment modality. There are several meta-analysis have concluded that nonoperative treatment of acute appendicitis with antibiotics is a safe choice.
Recurrence and misdiagnosis of appendiceal tumors are the main concerns against nonoperative management. The risk of neoplasia in all appendicitis patients is about 0.7–1.7% [11, 12]. In complicated appendicitis neoplasia rate is also increased [13]. Most of the randomized controlled trials comparing appendectomy vs. nonoperative management of acute uncomplicated appendicitis have a short follow up period for early recurrences as one year. Longer follow up results about the recurrence is unknown. There is only one study with more than three years follow after nonoperative management of acute appendicitis [14].
Another important point in decision-making for nonoperative management of uncomplicated acute appendicitis should be appendicoliths. As concordant with the literature our previous clinical experience show that; presence of appendicolith both decreases the success of treatment and increases recurrence rate.
The aim of this study is to evaluate the efficacy and safety of nonoperative management of acute uncomplicated appendicitis and its long term results.
Materials and methods
This cohort study was conducted at Uşak Training and Research Hospital. Ethical Committee approval was obtained from the institutional Ethical Committee. Patient inclusion was started in February 2017 and terminated in December 2021. The study has been registered to ClinicalTrial.gov (ClinicalTrials.gov ID: NCT04594486). This observational study was reported according to STROBE guidelines for observational studies, where appropriate [15].
Adult patients with radiological and clinically approved diagnosis of acute uncomplicated appendicitis were evaluated for inclusion. Complicated cases with signs of perforation were not included in the study. For eligible patients presence of appendicolith was excluded even by ultrasonography or computed tomography. Cases with appendicolith underwent primary surgery due to high failure and recurrence rate. Other exclusion criteria were immunodeficiency, diagnosis of previous gastrointestinal malignancy, drug allergy to antibiotics established for the study.
Diagnosis of acute appendicitis was made by experienced surgeons according to clinical findings. Moreover all diagnoses were approved by ultrasonography or computed tomography. Primarily, all patients included were examined by ultrasonography both for presence of appendicolith and appendiceal diameter measurement. In case of doubt in diagnosis an abdominal computed tomography was obtained.
Included cases were hospitalized intravenous fluid replacement with saline and ciprofloxacine 500 mg twice daily and metronidazole 500 mg every 8 h were administered. All patients were followed by daily physical examination, white blood cell count and C reactive Protein (CRP) levels. After 24 h progression of clinical findings accepted as treatment failure and those patients were treated surgically. Moreover, if there was no resolution of symptoms after 3 days of hospitalization it was also accepted as treatment failure. Discharge criteria were resolution of symptoms and clinical examination findings, toleration of low fiber diet and pain control with oral medications. Patients with successful nonoperative management discharged from hospital with continuation of oral ciprofloxacine 500 mg twice a day and 500 mg metronidazole three times a day. All patients were called for follow up at 7th and 14th day after discharge. Recurrence of symptoms in 30 days was accepted as treatment failure and those cases underwent appendectomy. After one year all cases were followed by phone calls for any recurrences of symptoms or need for surgery.
Patient demographic data, imaging results, WBC count, CRP levels, failure of medical treatment and recurrences were recorded electronically. IBM SPSS 20 version was used for statistical analysis. Continuous data were expressed as mean and standard deviation; categorical data were expressed as percentages. For comparison of means Student T test and for comparison of proportions chi-square tests were used. For non-parametric data Mann-Whitney U and Fischer’s exact test were used. Level of significance was accepted as 0.05.
Results
Three hundred and eleven patients with a diagnosis of acute appendicitis were evaluated for eligibility in the cohort. After exclusions, 211 cases were included in the cohort, and two patients were lost to follow up. Finally 209 cases were included in final analysis (Fig. 1).
Fig. 1.
Flow diagram
The mean age of the participants was 41.51 ± 18.7 years. The cohort consists of 51.7% male and 48.3% female patients. All diagnoses were confirmed by imaging modalities; 72.2% of cases were approved by ultrasonography and in 27.7% of cases a computed tomography scan was needed for approval. Demographical data of the patients and initial laboratory and imaging results are presented in Table 1.
Table 1.
Demographics of patients, initial laboratory and imaging finding
| Age (Mean ± SD) | 41.51 ± 18.7 | |
|---|---|---|
| Gender n(%) | Male | 108 (51.7%) |
| Female | 101 (48.3%) | |
| Diagnosis approved by n(%) | USG | 151 (72.2%) |
| CT | 58 (27.7%) | |
| Appendix vermiformis diameter at diagnosis (Mean ± SD) | 9.24 ± 1.7 mm | |
| Initial WBC count (Mean ± SD) | 11.6 ± 3.8 × 103/µL | |
| Initial CRP (Mean ± SD) | 78.3 ± 56.2 mg/L | |
USG ultrasonography, CT computed tomography, WBC white blood cell, CRP C reactive protein
There were nine cases that primary nonoperative management failed and those patients underwent appendectomy. Failure rate of nonoperative management of acute appendicitis was found to be 4.3%. At univariate analysis age, gender, diameter of appendix vermiformis, initial WBC count and CRP levels showed no difference in terms of treatment failure. Only CRP levels at the end of primary treatment showed significant difference; which was 25.8 ± 30.6 mg/L in success group and 168 ± 96.1 mg/L in failure cases. Differences of success and failure groups are shown in Table 2. In comparative analysis there were significant decrease in WBC counts and CRP levels in successfully treated cases (Table 3). In treatment failure group drop in WBC count was similar; however CRP levels showed significant increase. In treatment failure group mean initial CRP level was 87.7 ± 38.8 mg/L and mean post-treatment CRP level was 168.1 ± 96.1 mg/L (p: 0.049). Table 4 shows the multivariate analysis of treatment failure. Low post-treatment WBC level is related to treatment success; however, high post-treatment CRP level is found to be related with treatment failure.
Table 2.
Distribution of gender, age, initial and post treatment WBC count and CRP levels among successful treatment and treatment failure groups
| Treatment success | Treatment failure | p | ||||
|---|---|---|---|---|---|---|
| n | % | n | % | |||
| Gender | Male | 105 | 97.2 | 3 | 2.7 | 0.260 |
| Female | 95 | 94.1 | 6 | 5.9 | ||
| Mean | Std. Deviation | Mean | Std. Deviation | |||
| Age | 41.76 | 18.78 | 35.89 | 17.23 | 0.359 | |
| Initial WBC count (x103/µL) | 11.61 | 3.85 | 11.52 | 2.61 | 0.944 | |
| Initial CRP level (mg/L) | 77.97 | 56.96 | 87.72 | 38.87 | 0.613 | |
| Post-treatment WBC count (x103/µL) | 7.51 | 2.11 | 7.45 | 1.80 | 0.936 | |
| Post-treatment CRP level (mg/L) | 25.86 | 30.69 | 168.15 | 96.13 | < 0.001 | |
| Diameter of Appendix vermiformis (mm) | 9.21 | 1.67 | 9.87 | 3.41 | 0.271 | |
WBC white blood cell, CRP C reactive protein
Table 3.
Mean differences before and after the management in successfully treated patients and treatment failures
| Treatment success | Treatment failure | |||||
| mean ± SD | Mean difference | p | mean ± SD | Mean difference | p | |
| Initial WBC count (x103/µL) | 11.61 ± 3.85 | −4.10 | < 0.001 | 11.52 ± 2.61 | −4.06 | 0.003 |
| Post-treatment WBC count (x103/µL) | 7.5 ± 2.1 | 7.4 ± 1.8 | ||||
| Initial CRP level mg/L | 77.9 ± 56.9 | −51.11 | < 0.001 | 87.7 ± 38.8 | 80.4 | 0.049 |
| Post-treatment CRP level mg/L | 25.8 ± 30.6 | 168.1 ± 96.1 | ||||
WBC white blood cell, CRP C reactive protein
Table 4.
Univariate and multivariate analysis of factors that May affect treatment failure
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| OR | 95% CI | Sig. | OR | 95% CI | Sig. | |
| Diameter of Appendix vermiformis (mm) | 1,204 | 0,865-1,675 | 0,270 | 1,697 | 0,857-3,359 | 0,129 |
| Age | 0,981 | 0,941-1,02 | 0,362 | 0,91 | 0,819-1,01 | 0,078 |
| Gender (male) | 2,211 | 0,538-9,085 | 0,271 | 0,425 | 0,31 − 5,75 | 0,519 |
| Initial WBC count (x103/µL) | 0,994 | 0,832-1,187 | 0,944 | 1,001 | 0,681-1,47 | 0,997 |
| Initial CRP level mg/L | 1,003 | 0,992-1,014 | 0,611 | 0,979 | 0,951-1,007 | 0,137 |
| Post-treatment WBC count (x103/µL) | 0,987 | 0,713-1,365 | 0,935 | 0492 | 0,249-0,974 | 0,042 |
| Post-treatment CRP level mg/L | 1,042 | 1,023 − 1,062 | 0,001 | 1,075 | 1,026 − 1,125 | 0,002 |
WBC white blood cell, CRP C reactive protein
Mean hospitalization time was 2 ± 1.4 days in success group and 2.29 ± 0.9 days in treatment failure group. There was no significant difference in terms of length of hospital stay between groups (p: 0.598).
The mean follow up time of the cohort was 64.2 ± 17.4 months. Minimum follow up time was 26.6 months and maximum follow up time was 96.9 months. During follow up period recurrence was detected in 10 (5%) patients. Three of those cases accepted second time nonoperative management and two of them had wish for surgery and appendectomy was performed. Nonoperatively managed recurrent cases were not included in the cohort. The median time for recurrence was 11.8 (3.7–42.2) months. In 50% of the cases recurrence was seen after first year; in two cases recurrence was seen after three years of follow. In univariate analysis only age showed significant difference in terms of recurrence (Table 5).
Table 5.
Distribution of gender, age, initial and post treatment WBC count and CRP levels and appendix diameter among healthy and recurrent cases
| No recurrence | recurrence | p | ||||
|---|---|---|---|---|---|---|
| n | % | n | % | |||
| Gender | Male | 100 | 92.6 | 8 | 7.4 | 0.066 |
| Female | 99 | 98.1 | 2 | 1.9 | ||
| Mean | Std. Deviation | Mean | Std. Deviation | |||
| Age | 42.2 | 18.8 | 26.2 | 6.3 | 0.008 | |
| Initial WBC count (x103/µL) | 11.5 | 1.7 | 12.08 | 1.4 | 0.692 | |
| Initial CRP level (mg/L) | 78.4 | 58.1 | 69.1 | 27.5 | 0.615 | |
| Post-treatment WBC count (x103/µL) | 7.4 | 2.01 | 7.9 | 3.5 | 0.545 | |
| Post-treatment CRP level (mg/L) | 26.4 | 31.3 | 15.6 | 8.21 | 0.282 | |
| Diameter of Appendix vermiformis (mm) | 9.2 | 1.7 | 8.4 | 1.4 | 0.125 | |
WBC white blood cell, CRP C reactive protein
During the follow up neoplasia was only seen in one case with treatment failure group. The case was 71 years old male patient; operated on 20th day after nonoperative management of 18 mm appendicitis and histopathological examination revealed adenocarcinoma of appendix vermiformis. The patient is still disease free at 5th years of follow.
Discussion
As role of nonoperative management of acute appendicitis becoming more widespread, there are some questions to be answered. One of the main concerns is recurrence rate after nonoperative management. While surgery decreases recurrence rate to almost 0% there is risk of recurrent appendicitis after nonoperative management. Recent cohort showed successful treatment of acute appendicitis nonoperatively with low failure and recurrence rate. Moreover, the risk of malignancy was found to be 0.47% in uncomplicated acute appendicitis.
Several randomized studies and meta-analysis were evaluated nonoperative management of acute appendicitis. Nonoperative management is reported as non-inferior to surgical management [16]. However they reported the rate of need for surgery in cases with appendicolith as 41%. Our previous clinical experience showed the same increased failure and complication rates in presence of appendicolith; therefore, cases with approved appendicolith in imaging studies were not included in nonoperative management cohort. CODA study showed 25% operation rate in patients without appendicolith. Our results showed 4.3% of operation ate. The main reason of the difference is their failure rate consists of 90 days’ operation rate; while in recent cohort 30 days’ operation need was accepted as treatment failure. The analysis of recurrence times in the recent cohort showed the earliest recurrence time was 3.73 months. The failure rate was found to be low compared to other studies; however, all the cases had clinical and imaging approved acute appendicitis.
In a recent meta-analysis Scheijmans et al. reported that; at 1 year 48.7% of patients with appendicolith needed surgery, while 30.6% of patients without appendicolith needed surgery [17]. Moreover they reported increased complication rate in patients with appendicolith. Similar to CODA study they found decreased complication rates with nonoperative management compared to surgery; however, in case of presence of appendicolith complication rates are found to be higher than surgery groups. All those findings support the exclusion of cases with appendicolith from nonoperative management cohorts. Similarly recent cohort did not include cases with appendicolith and our results show lower failure rates compared to literature.
A multicenter cohort study comparing results of nonoperative management with appendectomy 90days’ failure rate of nonoperative management was found to be 20% [18]. That cohort consisted of a pooled data from COVİD 19 pandemic era. The patients were not randomized to groups and only 65% of patients in nonoperative management group had imaging approved diagnosis of acute appendicitis. In the recent cohort all patients had imaging approved acute appendicitis and no appendicoliths. Therefore the success rate of nonoperative management is found to be higher.
In literature there is limited data about recurrence rate of acute appendicitis after nonoperative management after one year. CODA study reported long term results; however, only 5% of cases could complete more than 4 years of follow [14]. The high rate of recurrence could be the result of dropping healthy individuals from follow up. The recent cohort has more than 5 years follow up and showed 5% recurrence rate, which makes nonoperative management feasible.
Another question should be answered is the rate of neoplasia in patients with acute appendicitis. Recent cohort had only one case with appendiceal neoplasia. Concerning all patients with acute appendicitis risk of neoplasia is about 0.7–17% [11, 12]. This risk is increased in patients with complicated appendicitis [19]. A recent cohort evaluated neoplasia rate in nonoperatively managed cases with complicated acute appendicitis and reported 16% risk of neoplasia [20].
Main limitation of the current study is lack of a control group. There is no surgery group to compare the results. However, longer follow up period with a high completion rate of the follow are the strong ways of the study. Exclusion of the cases with appendicolith can be another argument. As previously mentioned presence of appendicolith decreases the success rate and increased recurrence rate concordant with our clinical experiment and literature. Therefore, we suggest nonoperative management of acute appendicitis with approved appendicolith only in cases with high surgical risks. Another limitation is the cost of the treatment is not calculated.
In conclusion, nonoperative management of uncomplicated acute appendicitis with antibiotics has high success rate in patient without appendicolith. Long term follow of nonoperatively managed cases showed low recurrence rate and makes nonoperative management safe and feasible.
Author contributions
• Study conception and design: BS, ND, ÖK
• Acquisition of data: BS, ND
• Analysis and interpretation of data: BS, ÖK
• Drafting of manuscript: BS, ND
• Critical revision of manuscript: ÖK
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
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Associated Data
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Data Availability Statement
No datasets were generated or analysed during the current study.