This study provides a valuable contribution to the existing literature regarding recurrent AA following non-operative management, by identifying further risk factors. Previous studies have found greater recurrence risk in patients of male gender , and those with abscess on CT , but this study has identified greater PR on admission and DM as significant factors to be considered by the clinician. This is the first study to analyze the relationship of a large number of radiological factors as well as clinical factors, with AA recurrence risk, in an ethnically diverse urban population. A large Taiwanese study found that AA recurrence risk was greater in males, those under 18 years old, and those treated with a percutaneous drain . However, it included children, did not analyze any CT data and also is not likely to have the same ethnic diversity as the population evaluated here. This study has assessed the impact on recurrence of all the CT findings used to develop the APSI , whereas other studies which involved CT findings did not incorporate as many of them [14, 15, 17]. Multiple CT factors have been incorporated in one study previously which found that risk was greater in patients with an appendicolith , but the authors did not differentiate between recurrent AA and persistent AA, which is an important distinction.
In this study higher PR on admission was associated with significantly greater recurrence risk on the multivariate analysis. PR is not currently used in tools to predict complicated AA  or diagnose AA , possibly due to concerns around it being caused by pain or anxiety. However, it has been shown to predict perforated AA , and this study adds to the evidence that a higher PR should be treated with caution when deciding on AA management. DM was also associated with greater recurrence risk on multivariate analysis, and therefore it may be appropriate to manage diabetic patients surgically in order to prevent an AA recurrence. This is in keeping with another study which has shown that diabetic women have a greater recurrence risk than non-diabetic women . Gender did not impact recurrence risk in this study so was not included in the multivariate analysis.
CRP > 100g/L at any time during the admission was associated with greater recurrence risk but notably CRP > 100mg/L on admission was not. This is in line with the delayed rise in CRP or “lag” which is known to be associated with inflammation generally, and also highlights that admission to hospital to monitor CRP during non-operative management may be beneficial, in order to not be falsely reassured by a lower CRP on admission. Higher WCC was not associated with a greater recurrence risk which is in keeping with the APSI study which found that WCC did not predict complicated AA . High WCC is a well-documented feature in AA, and incorporated into sensitive and specific diagnostic scoring tools . However, in this study high WCC was associated with a lower recurrence risk, as was presence of fever although this result was not statistically significant. Histologically-proven complicated AA has been associated with high CRP and high procalcitonin levels independently . A systematic review of biomarkers in AA found that procalcitonin and interleukin-6 levels were predictive for perforated appendix but procalcitonin lacked sensitivity and both were high in cost . Therefore, these biomarkers are unlikely to provide affordable insight into AA recurrence risk.
Thinning of the appendiceal wall was associated with greater recurrence risk but none of the other CT findings were. AA is primarily a clinical diagnosis but imaging plays a vital role in cases of diagnostic uncertainty, with USG being considered the first-line modality . This study provides little evidence to suggest that performing more CTs would be valuable in order to predict recurrence, especially given the radiation exposure involved. However, in cases where a CT has been performed a thin appendiceal wall should alert the clinician that recurrence risk may be greater. Abscess on CT has been shown to be associated with greater recurrence risk  and CT findings are used to predict complicated AA , so it is likely that CT could play a role in prediction of recurrence that would warrant further investigation. CT has also been shown to be useful pre-operatively, markedly reducing the negative appendectomy rate, defined as the pathologically normal appendix removed from the patient for suspected appendicitis. Other studies have shown that this reduction is as much as from 22–7% , and from 13–5% . These figures might indicate that 5–7% of patients in this study may have been misdiagnosed as AA on CT.
In summary, this study has shown that greater recurrence risk of AA managed non-operatively is observed in adults with a greater PR on admission and those with DM. Therefore, the on-call surgeon should be more inclined to perform appendectomy on tachycardic and diabetic patients on the initial admission rather than treating non-operatively and offering an interval appendectomy later on. Caution should also be taken in patients with a thinned appendiceal wall on CT, although this study provides little evidence to suggest that a CT should be performed to assess for risk of recurrence in the future.
Figure 1 shows that a greater proportion of cases of AA were managed non-operatively during May 2020 and January to February 2021. Inpatients in the UK testing positive for COVID-19 peaked during April 2020 and January 2021  so the trend of non-operative management highlights a greater preparedness of this surgical department for the so-called “second wave” of the pandemic. This is compared with the “first wave” when the high mortality associated with operating on COVID-19 patients was not yet well published . Of the 12 patients who experienced a recurrence, 8 of them were treated surgically for their second episode, and the other 4 were treated with antibiotics alone. It remains to be seen whether there will be repeated COVID-19 waves requiring more cases of AA to be managed non-operatively in the future. If this is the case, this would enhance the relevance of the findings presented here which aid the surgeon in deciding which cases would require surgery at initial presentation, and which should be treated non-operatively before being offered interval appendectomy.
Statistical significance on the univariate analysis was defined as p < 0.20 due to a relatively small sample size, which is a limitation of this study. The associations presented here, particularly on the multivariate analysis, could be further evaluated in a larger study either over a greater time period or across multiple centers. It is likely that at least 50 patients in both recurrent and non-recurrent groups would be required for the training data to design a model to reliably predict recurrent AA. There was also no power calculation in this study and it has been suggested that at least five events (recurrent cases) per predictor variable are needed for problems to be uncommon when using a Cox regression model . Larger sample size would also allow more robust analysis of the comorbidities that were grouped together due to small prevalence in our population, such as hypertension and obesity. Therefore, a larger multicenter study is planned to investigate further the risk factors of AA recurrence over a longer follow-up period.
AA is a variable and multi-faceted disease with many factors affecting its severity, making its course relatively difficult to predict. It is therefore challenging to confidently decide whether certain patients would be reasonably treated non-operatively. This highlights the importance of involving patients in discussions regarding their management decisions, as the large meta-analyses have previously suggested [2, 5, 6]. The work presented here has shown an association of greater AA recurrence risk with DM and higher PR on admission, which will aid the clinician in being highly selective of patients for surgical management despite the risks during the pandemic, such as high mortality if infected with COVID-19. The results will also be of relevance to the debate on AA management beyond the pandemic which is ongoing as recent studies have found that non-operative management, although resulting in a recurrence risk, may lead to less complications, less sick days, and less financial cost compared with surgery [2, 3, 10]. This is the first study to analyze multiple clinical and CT findings in a highly-diverse AA population, and therefore provides valuable findings to aid on-call emergency surgeons working in similar centers across the globe.