Identifying recurrence risk factors in CT-confirmed acute appendicitis in adults managed non-operatively during the COVID-19 pandemic

doi:10.21203/rs.3.rs-1400638/v1

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Identifying recurrence risk factors in CT-confirmed acute appendicitis in adults managed non-operatively during the COVID-19 pandemic

https://doi.org/10.21203/rs.3.rs-1400638/v1

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Background/Objective

Acute appendicitis is predominantly managed with appendectomy, but can be treated non-operatively, leading to recurrence risk. Non-operative management has been more common since the COVID-19 pandemic affected the feasibility of performing surgery. This case-control study analyzed non-operatively managed patients in order to identify clinical and radiological factors associated with recurrence risk.

Methods

Over 12 months, 48 adults with CT-proven acute appendicitis managed non-operatively were identified, and followed up for at least 6 further months to assess them for recurrence (reattendance to hospital more than 14 days after discharge and after symptom resolution, requiring treatment for appendicitis). Clinical and CT data were collected and a Cox regression survival analysis was performed to produce hazards ratios.

Results

Of the 48 patients, 12 (25%) experienced a recurrence up until the end of the follow-up period, 8 of whom were then treated operatively.

On the univariate analysis, greater recurrence risk was observed in patients with diabetes mellitus, higher pulse rate (on admission and maximum value during admission), lower white cell count and neutrophils and appendiceal wall thinning on CT. On the multivariate analysis, diabetes mellitus (hazards ratio=7.72, p=0.021) and higher pulse rate (hazards ratio=1.08, p=0.018) were associated with statistically significant greater recurrence risk.

Conclusions

Diabetes mellitus and higher pulse rate on admission are associated with greater recurrence risk of acute appendicitis managed non-operatively. No CT findings were associated with greater risk. Clinicians should therefore consider diabetes mellitus and pulse rate when making decisions on appendicitis management, during the COVID-19 pandemic and beyond.

Acute appendicitis

Non-operative management

Recurrent appendicitis

CT scan

Survival analysis

Acute appendicitis (AA) is the most common surgical emergency, and it has been treated with appendectomy since its first recognized case in 1880 [1]. Advances in surgical techniques and technology have further asserted surgery as the typical management of AA, which is now primarily treated with laparoscopic appendectomy.

An alternative AA treatment is antibiotic therapy which for uncomplicated AA causes less complications and less sick days compared to surgery [2, 3], but leads to a recurrence rate of 27.3% at one year and 39.1% at five years [3]. A 2020 study found that 10 days of antibiotics was non-inferior to surgery for uncomplicated AA according to patient-reported quality of life, but 25% required appendectomy before 90 days [4]. Large meta-analyses recommend that the choice between surgery and antibiotics for uncomplicated AA should be based on consideration of several factors, including patient preference [2, 5, 6].

In cases of AA with abscess there is also the option of draining the abscess radiologically and this has been recommended in cases of abscesses greater than 5cm in diameter [7]. In these cases there is a recurrence risk, as there is with antibiotics alone, as the appendix itself is not removed.

The coronavirus disease (COVID-19) pandemic has led to the limitation of availability of hospital beds (particularly intensive care), theater space, and theater staff. Furthermore, for patients testing positive for COVID-19 peri-operatively, 30-day mortality is 23.8%, and 51.2% have pulmonary complications resulting in a 30-day mortality of 38.0% in this group [8]. There was also initially a concern regarding COVID-19 transmission to theater staff with laparoscopic surgery, although a recent systematic review concluded that there was no clear evidence for this [9]. These factors led to higher rates of AA treated non-operatively [10], therefore providing an opportunity to assess the outcomes of a larger pool of patients treated without surgery. Another study analyzed AA cases across 97 centers during the “first wave” of the pandemic, finding that antibiotics alone was successful in 80% of cases at 90-day follow-up and that it resulted in less complications and less financial cost than surgery [10].

Computed tomography (CT) is the most sensitive and specific diagnostic investigation of AA [11] and it is also faster, more readily available and less operator-dependent than ultrasonography (USG). However, it does involve ionizing radiation equivalent to 2.6 years of background radiation in the case of CT of the abdomen and pelvis which is typically performed to assess for AA [12]. Therefore, it is usually avoided, particularly in younger patients, unless USG is unavailable and the clinical diagnosis is uncertain. CT can however provide objective measures and has therefore been incorporated with clinical measures into the Appendicitis Severity Index (APSI) which accurately predicts complicated AA (perforated or gangrenous) [13]. The measures used are: age over 51 years; fever; symptoms for more than 48 hours; and the following on CT: appendiceal diameter ≥ 14 mm; periappendiceal fluid; extraluminal air; and perityphlitic abscess.

However, there is currently no tool aiming to predict recurrence in AA patients managed non-operatively, meaning with antibiotics alone or interventional radiology drainage (IR-drain) of an abscess. Greater recurrence risk following non-operative management of AA has been shown to be associated with male gender [14] and abscess on CT [15], however to this date no study has analyzed clinical factors and all radiological signs used in the development of the APSI tool. This study aims to analyze AA patients from an ethnically-diverse population in a large urban teaching hospital which has been widely recognized as a high-intensity COVID-19 center. This is in order to further identify clinical and radiological factors which are associated with greater recurrence risk in CT-confirmed AA treated non-operatively. Identifying higher recurrence risk in non-operative management would reasonably support the decision to perform appendectomy. However, the high risk of mortality in patients with peri-operative COVID-19 infection [8] necessitates the clinician to be highly selective of patients for surgical management during the pandemic. Therefore, knowledge of recurrence risk might help surgeons worldwide to rationalize the decision to perform surgery or not, both during the pandemic and beyond.

The objectives were to: identify all adults with non-operatively managed CT-proven AA in a 12-month period; identify which patients had a recurrence; and analyze associations between clinical and radiological factors and the recurrence risk.

All adults diagnosed with AA at our institution from 1st March 2020 to 28th February 2021 were retrospectively identified using the hospital database. Cases which were managed non-operatively were identified and labelled as either managed with antibiotics only or IR-drain. Non-operatively managed patients who underwent a CT scan during their admission but before attempted non-operative management were then identified. For those with multiple admissions, only the initial admission was used in the data analysis. The eligibility criteria were therefore:

age over 18 years,
diagnosed with AA from 1st March 2020 to 28th February 2021,
treated non-operatively,
and underwent a CT scan during their admission but before attempted non-operative management (defined as before more than one dose of antibiotics or before IR-drain).

There were 280 diagnoses of AA within the 1-year period, which occurred in 258 different patients. Of these, 92 (36%) were managed non-operatively on their initial admission. 48 of these patients underwent a CT scan during their admission but before attempted non-operative management. Of these 27 were male and 21 were female, and mean average age was 47.5 years (range 24–97 years). Figure 1 shows the management of AA by month at our institution over the 12-month study period.

The patients had their demographic, clinical and biochemical data reviewed to provide data on age, gender, presenting history, past medical history (PMH), vital signs, blood tests and antibiotic management.

Of the continuous variables, there were several for which the data was significantly skewed so they were converted to the following categorical variables: >2 days of pain on admission, antibiotic course > 7 days, length of admission > 2 days, CRP > 100mg/L and temperature > 37.5°C (fever).

Due to the small number of patients with a history of many comorbidities, several of them were combined into the following groups: cardiovascular risk factors; bowel disease; and hepatobiliary disease.

CT scans were reviewed by a radiologist and assessed for the same signs which were used in the development of the APSI [13]. These were: appendiceal diameter; appendiceal wall thickness; thinning of appendiceal wall; periappendiceal fat stranding and fluid; intraluminal and extraluminal air; cecal wall thickening > 3mm; appendicolith; and periappendiceal abscess. The assessor was blinded to clinical, biochemical and outcome data.

Patients were followed up until 6 months after the study period (up to September 2021) and assessed for recurrence using the hospital systems and by telephone in case they had presented to a different hospital. AA recurrence was defined as reattendance to hospital requiring treatment for appendicitis more than 14 days after discharge and after resolution of symptoms. Therefore, the patients were categorized as recurrent, or non-recurrent. Reattendance within 14 days was considered persistent appendicitis rather than recurrence. The time to recurrence was noted for the recurrent group and for the non-recurrent group it was the time to end of follow-up for the purposes of the survival analysis.

The data was then analyzed using IBM SPSS Statistics. A Cox regression survival analysis was performed to correct for the variation in follow-up times between patients. This compared each variable with time to recurrence, producing recurrence hazards ratios (HRs) and p-values. Statistical significance on the univariate analysis was defined as p-value < 0.20. The significant measures were then included in a multivariate analysis to evaluate their impact on recurrence risk independent of each other, therefore correcting for any potentially confounding variables. P-value < 0.05 was deemed statistically significant on this multivariate analysis.

There was missing data for the following variables: appendix diameter (4 patients); appendix wall thickness (12 patients); thinning of appendiceal wall (20 patients); periappendiceal fat stranding (1 patient); periappendiceal fluid (2 patients); appendiceal intraluminal air (4 patients); extraluminal air (3 patients); caecal wall thickness (7 patients); appendicolith (1 patient); use of intravenous antibiotics (1 patient); length of antibiotic course (5 patients). The missing data was not included in the analysis.

Approval from an ethics committee was not deemed necessary as this was a retrospective study where the patient-identifying data has been anonymized, but approval was granted by the Audit and Quality Improvement Department. Since the selection of patients and definition of recurrence were based on objective criteria being met, selection and recall bias were minimalised.

Of the 48 patients of interest, there were 12 (25%) who had experienced a recurrence up until the end of the follow-up period. Table 1 shows the demographic data for recurrent and non-recurrent groups. 2 patients in the non-recurrent group underwent interval appendectomy in the follow-up period.

Table 1

Patient demographics and number of patients with each comorbidity in their medical history.
		Total (n = 48)	Recurrent (n = 12)	Non-Recurrent (n = 36)
Mean age in years (range)		47.5 (21–97)	46.1 (24–66)	48 (21–97)
Male		27	6	21
Female		21	6	15
Diabetes mellitus		6	3	3
Cardiovascular risk factors	Any	8	3	5
	Hypertension	5	1	4
	Ischemic heart disease	2	0	2
	Obesity	2	1	1
	Chronic kidney disease	3	1	2
Bowel disease	Any	8	2	6
	Inflammatory bowel disease	1	0	1
	Colitis	1	0	1
	Bowel malignancy	2	1	1
	Chronic constipation	2	0	2
	Irritable bowel syndrome	2	1	1
Hepatobiliary disease	Any	5	2	3
	Gallstones	2	1	1
	Cholecystitis	2	0	2
	Portal hypertension	1	1	0
	Liver cirrhosis	1	1	0

The recurrence analysis for the clinical factors is shown in Table 2. There was no significant impact of age or gender on recurrence risk. Lower recurrence risk was observed in IR-drain patients compared to those treated with antibiotics alone but this was not significant. Recurrence risk was greater in those admitted for > 2 days, those treated with antibiotics for > 7 days, and those treated with intravenous antibiotics, but these results are likely to have been confounded by other factors affecting the management decisions regarding length of admission and antibiotic therapy.

Table 2

Recurrence analysis for demographic and clinical factors. Unadjusted hazards ratios refer to the univariate analysis and the adjusted hazards ratios refer to the multivariate analysis.
Variable	Unadjusted Hazards Ratio	p-value	Adjusted Hazards Ratio (95% CI)	p-value
Age	0.997	0.852
Male	ref	n/a
Female	1.38	0.581
Antibiotics only	ref	n/a
IR-drain	0.498	0.508
> 2 days of pain on admission	1.10	0.876
Admitted for > 2 days	1.70	0.367
Antibiotic course > 7 days	1.02	0.975
Intravenous antibiotics	2.10	0.34
Diabetes mellitus	2.96	0.105*	7.72 (1.36–43.7)	0.021*
Bowel disease	1.10	0.907
Hepatobiliary disease	2.39	0.271
Cardiovascular risk factors	1.63	0.466
^a Maximum CRP > 100	1.72	0.357
^a Admission CRP > 100	0.984	0.978
Febrile anytime during admission	0.989	0.987
Febrile on admission	0.354	0.321
^b Maximum WCC	0.927	0.386
^b Admission WCC	0.86	0.104*
Maximum neutrophils	0.879	0.215
Admission neutrophils	0.821	0.075*	0.842 (0.621–1.14)	0.267
Maximum pulse rate	1.03	0.094*
Admission pulse rate	1.05	0.017*	1.08 (1.01–1.47)	0.018*
a CRP = C-reactive protein, b WCC = white cell count. *denotes statistically significant results.

Greater recurrence risk was observed in patients with diabetes mellitus (DM) (unadjusted HR = 2.96, p = 0.105) and this was significant so included in the multivariate analysis. Bowel disease and hepatobiliary disease increased recurrence risk but this was not statistically significant.

Maximum CRP > 100mg/L was associated with greater recurrence risk but admission CRP > 100mg/L was associated with lower recurrence risk. Higher admission WCC (unadjusted HR = 0.860, p = 0.104) and admission neutrophils (unadjusted HR = 0.821, p = 0.075) were associated with lower recurrence risk and were statistically significant.

Maximum pulse rate (PR) during admission (unadjusted HR = 1.03, p = 0.094) and PR on admission (unadjusted HR = 1.05, p = 0.017) were both associated with statistically significantly greater recurrence risk.

Table 3 shows the recurrence analysis for the CT data. Thinning of appendiceal wall on CT (unadjusted HR = 2.67, p = 0.129) was associated with significantly greater recurrence risk. However, none of the other radiological outcome measures were statistically significant. Fat stranding was present in all 47 patients in which it could be assessed for.

Table 3

Recurrence analysis for the CT factors. Unadjusted hazards ratios refer to the univariate analysis and the adjusted hazards ratios refer to the multivariate analysis.
Variable	Unadjusted Hazards Ratio	p-value	Adjusted Hazards Ratio (95% CI)	p-value
Appendix diameter (mm)	1.13	0.377
Appendiceal wall thickness (mm)	1.37	0.411
Thin appendiceal wall on CT	2.67	0.129*	1.86 (0.319–10.9)	0.489
Periappendiceal fat stranding	n/a	n/a
Periappendiceal fluid on CT	1	1
Intraluminal air on CT	0.565	0.589
Extraluminal air	0.037	0.349
Caecal wall thickness > 3mm	0.475	0.22
Appendicolith	1.17	0.799
Abscess	0.452	0.309
*denotes statistically significant results.

The multivariate analysis is also shown in Tables 2 and 3. Admission WCC and maximum PR were not included in the analysis due to their strong association with other more significant variables (admission neutrophils and admission PR, respectively). When adjusted for the impact of the other variables DM was shown to be associated with an even greater recurrence risk and this was statistically significant (adjusted HR = 7.72, p = 0.021). This also applies to admission PR (adjusted HR = 1.08, p = 0.018). The other variables were shown to not be significant on the multivariate analysis.

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 [14], and those with abscess on CT [15], 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 [16]. 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 [13], 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 [17], 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 [13] or diagnose AA [18], possibly due to concerns around it being caused by pain or anxiety. However, it has been shown to predict perforated AA [19], 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 [20]. 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 [13]. High WCC is a well-documented feature in AA, and incorporated into sensitive and specific diagnostic scoring tools [18]. 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 [21]. 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 [22]. 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 [23]. 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 [15] and CT findings are used to predict complicated AA [13], 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% [24], and from 13–5% [25]. 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 [26] 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 [8]. 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 [27]. 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.

Acknowledgements

We would like to extend our special thanks to the Health Informatics Development Group and Clinical Coding Team (both at Guy’s and St. Thomas’ NHS Foundation Trust), and the King’s College London Statistical Consultancy Service.

Compliance with Ethical Standards

Dr Chris B Richards, Dr Laura K Pendower, Dr Pinky D Kotecha, Dr Karl Elmqvist, Dr Fungayi N Chinaka, and Mr Ivan Tomasi declare that they have no conflict of interest.

All procedures performed in studies involving human participants were in accordance with the standards of the institution. The study has been discussed with and approved for submission by the institutional Director of Research Delivery. It was also formally approved by the Audit and Quality Improvement Department, as per the attached certificate (project number 12014). The study was initially an audit of the management of acute appendicitis during the COVID-19 pandemic, however the authors then saw the potential of conducting a retrospective research study to add to the literature on conservatively managed appendicitis, therefore approval from a formal ethics committee was not applied for and could not be granted retrospectively. In the UK for a retrospective study where all patient data are anonymised and there is no potential impact on the patient management, formal ethical approval is not normally required.

This article does not contain any studies with animals performed by any of the authors.

i. Funding (information that explains whether and by whom the research was supported) – No funding was received.

ii. Conflicts of interest/Competing interests (include appropriate disclosures) – No conflicts of interest.

iii. Ethics approval (include appropriate approvals or waivers) - All procedures performed in studies involving human participants were in accordance with the standards of the institution. The study has been discussed with and approved for submission by the institutional Director of Research Delivery. It was also formally approved by the Audit and Quality Improvement Department, as per the attached certificate (project number 12014). The study was initially an audit of the management of acute appendicitis during the COVID-19 pandemic, however the authors then saw the potential of conducting a retrospective research study to add to the literature on conservatively managed appendicitis, therefore approval from a formal ethics committee was not applied for and could not be granted retrospectively. In the UK for a retrospective study where all patient data are anonymised and there is no potential impact on the patient management, formal ethical approval is not normally required.

iv. Consent to participate (include appropriate statements) - Not applicable.

v. Consent for publication (include appropriate statements) – Not applicable.

vi. Availability of data and material (data transparency) – Data is available upon request.

vii. Code availability (software application or custom code) – IBM SPSS Statistics.

viii. Authors' contributions - Chris B Richards, Ivan Tomasi and Fungayi N Chinaka contributed to the study conception and design. Material preparation and data collection were performed by Chris B Richards, Laura K Pendower, Pinky D Kotecha, and Karl Elmqvist. Analysis was performed by Chris B Richards. The first draft of the manuscript was written by Chris B Richards and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Identifying recurrence risk factors in CT-confirmed acute appendicitis in adults managed non-operatively during the COVID-19 pandemic

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Abstract

Figures

Introduction

Methods

Results

Discussion

Declarations

References

Supplementary Files

Status:

Version 1