Association Between Coronavirus Disease 2019 and Acute Complicated Diverticulitis

Background Gastrointestinal manifestations of coronavirus disease 2019 (COVID-19) are increasingly recognized. Through potentially overlapping pathophysiology, co-occurrence of COVID-19 and first-time acute diverticulitis has been reported. Our study aims to further characterize this association in COVID-19-positive patients within a large tertiary care academic center. Methodology Patients diagnosed with COVID-19 who subsequently developed acute diverticulitis within 30 days were identified between 2020 and 2022. COVID-19 and acute diverticulitis were diagnosed by polymerase chain reaction and computed tomography, respectively. Patients with prior history of acute diverticulitis were excluded. Patient characteristics and comorbid conditions were collected. Characterization of the COVID-19 course (treatment setting, medical/ventilatory therapy) and acute diverticulitis (treatment setting, medical/surgical therapy, complications) was performed retrospectively. Subanalysis was performed by COVID-19 vaccination status, the severity of COVID-19, and the timing of acute diverticulitis diagnosis. Results A total of 81 patients were identified, with a median duration between COVID-19 diagnosis and acute diverticulitis of 13 days (interquartile range = 2.5-21.0), with 44.4% of patients requiring hospitalization for COVID-19. The all-cause complication rate of acute diverticulitis was noted to be 59.3%, most commonly intestinal perforation (39.5%), abscess formation (37.0%), and peritonitis (14.8%). Although a trend toward increased all-cause complications (65.9%), intestinal perforation (43.9%), and peritonitis (19.5%) was noted in unvaccinated patients, this did not reach significance. Although all-cause complication rate did not differ in patients diagnosed with acute diverticulitis at the time of COVID-19 presentation, a significantly elevated incidence of intestinal perforation (55.9% vs. 27.7%, p = 0.01), peritonitis (29.4% vs. 4.3%, p < 0.01), and the need for emergent surgical intervention (38.2% vs. 10.6%, p < 0.01) was noted. Conclusions Our study indicates that patients diagnosed with first-time acute diverticulitis within 30 days of COVID-19 infection have a high complication rate, most commonly intestinal perforation. Additionally, patients diagnosed with acute diverticulitis at the same time as COVID-19 detection had a significantly elevated rate of complications and emergent surgical needs. Given the high complication rate, patients who develop diverticulitis within a short timeframe of COVID-19 infection may benefit from increased clinician vigilance and monitoring.


Introduction
The coronavirus disease 2019 (COVID- 19) pandemic has been at the forefront of public health concern, with over 90 million cases reported to date in the United States. Presenting primarily with fever and respiratory tract symptoms, extrapulmonary manifestations are increasingly being recognized as part of the COVID-19 disease spectrum. Gastrointestinal manifestations occur in a significant proportion of patients with COVID-19, with the most common symptoms being nausea, vomiting, diarrhea, anorexia, and abdominal pain [1][2][3]. While incompletely understood, the multifactorial pathophysiology of gastrointestinal injury in COVID-19 is thought to include a combination of direct virus-mediated tissue damage, diffuse endothelial and submucosal vascular inflammation, intestinal edema, and virus-mediated alterations to the intestinal microbiome [2,4,5]. As such, there are potentially several mechanisms by which COVID-19 may result in gastrointestinal sequela of infection.
Acute diverticulitis is postulated to occur through the obstruction of intestinal diverticula by fecal matter, resulting in low-grade inflammation and mucosal abrasion that eventually lead to bacterial overgrowth and intestinal microperforation [6]. Recent studies have shown an association between chronic inflammatory states, altered gut microbiome, and the development of acute diverticulitis [7,8]. With potentially overlapping pathophysiologic mechanisms, an association between COVID-19 infection and acute diverticulitis has been reported [9][10][11]. However, together representing less than a handful of patients, this association has not been investigated on a larger scale. In the current work, we aimed to investigate the association between COVID-19 infection and the first occurrence of acute diverticulitis in patients with COVID-19 infection. Given the reduction of severe COVID-19 infection in patients vaccinated against COVID-19 [12], vaccinated and unvaccinated patients were compared. Given both direct and inflammationinduced gastrointestinal injury in COVID-19 infection, the authors hypothesize that patients who develop acute diverticulitis shortly after COVID-19 infection may have a more complicated disease course with an elevated risk of complications. Furthermore, given that inflammation is more severe in active COVID-19 infection, we hypothesize that patients who develop acute diverticulitis shortly after COVID-19 infection would have an increased incidence of complications.

Patient selection
Institutional Review Board approval was obtained to collect de-identified patient information through a retrospective chart review at a large tertiary care academic center in the United States (Mayo Clinic Institutional Review Board, approval number: 21-005645). Patients were selected by filtering International Classification of Diseases 10 (ICD10) codes for confirmed positive COVID-19 diagnosis (U07.1) and crossreferences with ICD10 codes for the diagnosis of acute diverticulitis within the subsequent 30 days (K57.*) to obtain the initial patient cohort. The time frame of the retrospective review was January 1, 2020, to August 30, 2022. The diagnosis of COVID-19, COVID-19 vaccination status, and acute diverticulitis was then confirmed through a detailed retrospective chart review. A confirmed positive COVID-19 infection was defined as a positive reverse transcription polymerase chain reaction (RT-PCR) assay on samples taken from the patients' nasopharynx. The diagnosis of acute diverticulitis was defined based on previously reported computed tomography (CT) imaging criteria. Specifically, the diagnostic criteria used included imaging findings of colonic wall thickening (wall thickness greater than 3 mm on luminal short axis) and pericolonic fat stranding [13]. Patients were excluded if a diagnosis of COVID-19 or acute diverticulitis could not be confirmed. Patients with a prior history of acute diverticulitis were excluded. Patients whose diagnosis of acute diverticulitis occurred more than 30 days after the initial positive COVID-19 diagnosis were also excluded.

Data collection
Clinical, laboratory, and imaging data were obtained through a retrospective review. The following demographic data were collected: age, gender, ethnicity, and body mass index (BMI). Clinical variables included common comorbid conditions (diabetes mellitus, hypertension, hyperlipidemia, obesity, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, and diverticulosis). Current or previous alcohol and tobacco history were also collected. COVID-19-related variables were collected, including the date of diagnosis, vaccination status at the time of diagnosis, COVID-19-directed medical therapy, COVID-19-related hospitalization and length of stay, need for intubation, mechanical ventilation duration, use of non-invasive positive pressure ventilation (NIPPV), and use of high-flow oxygen supplementation. Data regarding acute diverticulitis was also collected, including date of acute diverticulitis diagnosis, treatment setting (outpatient vs. inpatient), hospital length of stay, and complications related to acute diverticulitis (abscess formation, perforation defined by abdominal free air, fistula formation, peritonitis, and the need for emergent surgical intervention).

Statistical analysis
Statistical analysis was performed using SPSS statistical software version 25.0 (IBM Corp., Armonk, NY, USA). The data were summarized using descriptive statistics. Values are reported as the median and interquartile range (IQR) or fractions and percentages, as appropriate. Wilcoxon rank sum and Fisher's exact tests were used to compare baseline characteristics and incidence of acute diverticulitis complications between groups.

Variable
All patients Baseline patient characteristics, COVID-19-associated variables, and incidence rates of acute complicated diverticulitis are detailed. Patients were divided into those who were vaccinated versus those not vaccinated for COVID-19 at the time of acute diverticulitis presentation as well as by COVID-19 hospitalization status. Wilcoxon rank sum and Fisher's exact tests were used for statistical analysis. No significant differences were noted between vaccinated and unvaccinated patients on demographic as well as comorbid conditions. Similarly, no significant differences were noted in patients hospitalized versus those not hospitalized for COVID-19. Regarding complications of acute diverticulitis, the overall rate of all-cause complications was similar between vaccinated and unvaccinated patients. Although a higher incidence of perforation, peritonitis, and the need for emergent surgery was noted in unvaccinated patients, which did not reach significance. For patients who required hospitalization for COVID-19, the incidence of peritonitis and the need for emergent surgery was significantly elevated. COVID-19 hospitalized patients also had a non-significant trend toward a higher incidence of all complications, abscess formation, perforation, and fistula formation. *: p < 0.05.   Baseline patient characteristics, COVID-19-associated variables, and incidence rates of acute complicated diverticulitis are detailed. Patients were divided into those diagnosed with acute diverticulitis at the time versus those after the detection of COVID-19. Wilcoxon rank sum and Fisher's exact tests were used for statistical analysis. No significant differences were noted in demographic and comorbid conditions. Regarding complications of acute diverticulitis, the overall rate of all-cause complications was similar between patients diagnosed with acute diverticulitis at the time versus after the detection of COVID-19. The incidence of intestinal perforation, peritonitis, and the need for emergent surgery was significantly elevated in patients diagnosed with acute diverticulitis at the time of COVID-19 detection. Although a higher incidence of abscess and fistula formation was noted, this difference did not reach significance. *: p < 0.05.

IQR = interquartile range; BMI = body mass index; COVID-19 = coronavirus disease 2019
Of the 81 patients, 53 (65.4%) had a history of current or former alcohol use, with 30 (37.0%) currently consuming more than two alcoholic beverages per week at the time of COVID-19 diagnosis. Regarding tobacco usage, 40 (49.4%) patients had a history of current or former tobacco usage, with seven (8.6%) currently using tobacco products at the time of COVID-19 diagnosis. No significant differences were noted between vaccinated and unvaccinated patients or COVID-19 hospitalized versus non-hospitalized patients were noted (Table 1). Similarly, no significant differences were noted between patients diagnosed with acute diverticulitis at the time of COVID-19 detection versus after COVID-19 detection ( Table 2).

Acute diverticulitis
The median duration between the diagnosis of COVID- 19

Overall Complication Rate
As detailed in Table 1

Comparison of Complication Rate by COVID-19 Hospitalization Status
Patients with COVID-19 who required hospitalization for treatment had a trend toward a higher incidence of acute complicated diverticulitis (66.7% vs. 53.5%). However, this did not reach significance (p = 0.26  Table 1.

Comparison of Complication Rate by Time of Acute Diverticulitis Diagnosis
As detailed in Table 2

Discussion
This study investigated the complication rate of first-time acute diverticulitis in patients diagnosed with COVID-19 between January 2020 and August 2022. Patients presented with varying complaints leading to RT-PCR-confirmed COVID-19 diagnosis, with 44.4% of patients requiring hospitalization due to symptom severity. Of the patients hospitalized for COVID-19, close to 40.7% required escalation of oxygen therapy beyond the use of a nasal cannula, with the average hospitalization length being close to 11 days. Comparing COVID-19 vaccinated versus unvaccinated patients, unvaccinated patients were significantly more likely to require hospitalization (56.1% vs. 32.5%) and advanced oxygen therapy (65.9% vs. 40.7%). The median duration between the diagnosis of COVID-19 and acute diverticulitis was 13 days, with 40% of patients found to have acute diverticulitis at the time of their initial COVID-19 diagnosis. Although COVID-19 vaccinated versus unvaccinated patients did not differ in this regard, patients requiring hospitalization for COVID-19 were more likely to have acute diverticulitis at their initial presentation to the emergency department (69.4% vs. 17.8%).
Approximately 60% of patients were diagnosed with acute complicated diverticulitis upon diagnosis, with the most common overall complications being intestinal perforation (39.5%) and abscess formation (37%). Furthermore, a substantial number of patients required emergent surgical intervention for acute diverticulitis (22.2%), likely reflecting the higher perforation incidence. When comparing COVID-19 vaccinated versus unvaccinated patients, a trend toward increased all-cause complications was noted.
Although not significant, this trend was mainly driven by an elevated incidence of intestinal The above results suggest a high complication rate in COVID-19-positive patients who develop acute diverticulitis. The noted 59% overall incidence rate of acute complicated diverticulitis in patients diagnosed with COVID-19 represents a marked increase above the published overall incidence rate of 9-25%; however, this should be taken in the context of a more ill patient population in the acute and immediate post-acute infectious setting [14,15]. When examining the literature-reported incidence of individual complications of acute diverticulitis (abscess formation: 16-17%, intestinal perforation: 10%, peritonitis: 1-2%), patients who developed acute complicated diverticulitis within 30 days of COVID-19 infection were noted to have an elevated incidence (abscess formation: 37.0%, intestinal perforation: 39.5%, peritonitis: 14.8%), with intestinal perforation and abscess formation being the most common [14,16,17]. On subanalysis, the overall complication rate was found to be further elevated in patients with severe COVID-19 infection (indicated by the need for hospitalization) or those diagnosed with acute diverticulitis at the time of COVID-19 infection.
In the two aforementioned groups, the incidence of intestinal perforation and peritonitis is of particular concern, especially when noting the elevated incidence of emergent surgical intervention. While one cannot directly compare the incidence of acute complicated diverticulitis in acute and post-acute COVID-19 patients to literature-reported rates, the current data suggest that patients diagnosed with COVID-19 who develop acute diverticulitis have a high risk of developing complications, in particular, intestinal perforation and peritonitis. Furthermore, our data indicate that patients with severe COVID-19 or those who are diagnosed with acute diverticulitis at the time of COVID-19 diagnosis are at a particularly high risk of complications.
COVID-19 infection has come to be associated with multiple organ dysfunction. This is thought to be secondary to the production of an acute inflammatory state [18]. While most commonly manifesting as a respiratory disease, there has been increased recognition of COVID-19-related gastrointestinal manifestations [1][2][3]. While the pathophysiology of acute diverticulitis in itself is currently incompletely understood, longstanding theories postulate that obstruction of intestinal diverticula by fecal matter results in low-grade inflammation and mucosal abrasion, subsequently leading to bacterial overgrowth and microperforation [6]. However, more recent studies have demonstrated an association between chronic inflammatory states, altered intestinal microbiome, and the development of acute diverticulitis [7,8]. As such, it is possible that the generalized inflammatory state associated with COVID-19 infection could predispose, and potentially worsen, the development of acute diverticulitis through inflammation-mediated tissue damage. Indeed, histopathological evidence has demonstrated that COVID-19 infection is associated with the infiltration of lymphocytes and plasma cells into the intestinal lamina propria, resulting in diffuse submucosal endothelial inflammation, microvascular injury, and mesenteric ischemia [4]. Furthermore, the COVID-19-induced intestinal inflammatory cell infiltrate has also been associated with substantial intestinal edema [19]. As such, it is conceivable that the intestinal inflammation and edema may predispose to obstruction of pre-existing intestinal diverticula, facilitating bacterial overgrowth and potentially precipitating acute diverticulitis. Furthermore, the combination of COVID-19-associated microvascular injury and mesenteric ischemia may represent the underlying pathomechanism contributing to the increased rate of diverticular perforation and peritonitis noted in the present study. As such, it seems that not only do COVID-19-infected patients who develop acute diverticulitis have a high overall incidence of complications, they are more likely to develop more severe complications of intestinal perforation and peritonitis.
Our study has several limitations that warrant discussion. First, our study used a retrospective approach to investigate the disease course of acute diverticulitis in patients who were diagnosed with COVID-19 in the 30 days prior at a singular institution. Although the current methodology allows for detailed review within one health system with consistent documentation, patient numbers are limited. Furthermore, our study population consisted of mostly Caucasian individuals with a median age of over 65. As such, our results must be interpreted in the setting of this older population with more comorbidities. Nevertheless, comorbid conditions and demographic data did not differ significantly between our investigated groups (vaccinated versus unvaccinated, hospitalized versus non-hospitalized, diagnosis at versus after COVID-19 diagnosis). Furthermore, given that the mean age at presentation for diverticulitis is often above 60 years, our data remain applicable to the at-risk population. To address the current limitations, future studies should seek to include multi-institutional data or leverage available data from national databases for further investigation, as this would allow for a larger and more heterogeneous population. Furthermore, it would be of interest for future studies to investigate if ethnic or socioeconomic differences exist in clinical outcomes for patients with COVID-19 who develop acute diverticulitis.

Conclusions
Using a retrospective approach at a large tertiary care academic institution, this study found that patients diagnosed with first-time acute diverticulitis within 30 days of COVID-19 infection had an all-cause complication rate of nearly 60%, with the most common complication being intestinal perforation. Although a trend toward an elevated incidence of complicated diverticulitis was noted in COVID-19 unvaccinated patients, this was not found to be significantly different from COVID-19 vaccinated patients. In patients with severe COVID-19 infection or those who were found to have acute diverticulitis upon initial COVID-19 diagnosis, an elevated incidence of all-cause complications was noted, in particular, intestinal perforation and peritonitis. These findings have potential clinical implications for hospital and primary care physicians faced with COVID-19-positive patients who develop acute diverticulitis during or shortly after infection. Given the high incidence of abscess formation, intestinal perforation, and peritonitis in this patient group, patients may benefit from increased clinician vigilance and monitoring for the development of complications.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Mayo Clinic Institutional Review Board issued approval 21-005645. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.