Acute abdomen following COVID-19 vaccination: a systematic review

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a serious public health threat due to the rapid progression, hospitalization, and death of those infected [1]. As of August 30, 2023, about 6.9 million people have died worldwide because of COVID-19, with a total of 770 million confirmed cases [2]. In response, the U.S. Food and Drug Administration issued the Pfizer-BioNTech vaccine (BNT162b2 messenger RNA [mRNA]), followed by two vaccines, Moderna (mRNA-1273) and Janssen/Johnson (traditional viral vector), for licensure and emergent use [3].

Immunization against SARS-CoV-2 is one of the most important preventive measures to contain the disease because it prevents the spread of the virus and limits the serious consequences of the infection; therefore, for the development of vaccines, three main factors must be considered: efficacy, immunogenicity, and safety, as well as continuous surveillance and research [4]. Currently, the authorization of the emerging use of vaccines against SARS-CoV-2 has been approved, including mainly mRNA technology vaccines, viral vectors, recombinant protein, inactivated, live attenuated, and DNA vaccines [5]. At the time of writing manuscript, approximately 13.5 billion vaccines have been administered worldwide [2].

In general, vaccines have proven to be safe, although rare but potentially serious adverse effects may occur after vaccination [6]. Thus, several studies describe a series of neurological (Guillain-Barré) [7], cardiovascular (myocarditis) [8, 9], hematological (hemolytic anemia) [10], ophthalmological (optic neuritis) [11], endocrinological (Graves’ disease) [12], and other complications, with a possible association with the T-cell immune response that vaccines induce.

Case report and case series studies report the occurrence of acute abdomen such as acute appendicitis [13], acute pancreatitis [14], diverticulitis [15], cholecystitis [16], and colitis [17] as a possible complication of COVID-19 vaccination. These studies are of current interest in surgical and clinical medical practice; therefore, our objective was to perform a systematic review of case reports and case series to describe in detail the possible association, the clinical and demographic characteristics of development of acute abdomen following COVID-19 vaccination.

In this systematic review of case reports and case series on acute abdomen following COVID-19 vaccination, we identified acute pancreatitis as the most common complication, associated with the Pfizer-BioNTech vaccine (mRNA) and the first dose. And the vaccine type and dose were reported, respectively. Of the 17 cases included in this review, the mean age of the cases who developed acute abdomen after receiving the vaccine was 47 years, and 64.7% were females. In our review, most patients showed improvement requiring only supportive medical treatment. Of the patients in our review, 47.06% (n=8) had an established prior diagnosis of comorbidity, with cardiovascular disease (arterial hypertension) being the most frequent.

Acute appendicitis (AA) is the most frequent cause of acute surgical abdomen worldwide [34]. The incidence is estimated to be around 1/10,000 cases per year, with an estimated lifetime risk of 7% to 8% [34, 35]. There is a slight male predominance in a 1.4:1 ratio compared to females, and it most commonly occurs between the ages of 10 and 20 years [36]. The etiology of acute appendicitis is primarily attributed to obstructive processes resulting from follicular hyperplasia and fecalith. Additionally, rare obstructive causes include conditions such as amebiasis, carcinoid tumors, and infestations by parasites like amebiasis, enterobiasis, and ascariasis, among others [37]. Our study found three case reports of AA induced by SARS-CoV-2 vaccination. The mean age was estimated to be 48.6±21.45 years, with a slight predominance by females. AA occurred mainly after administration of Pfizer-BioNTech (mRNA) vaccine (n=2) [13, 21] followed by Moderna (mRNA) (n=1) [22]. In other studies, the Pfizer-BioNTech vaccine was associated with AA with a risk ratio of 1.40 (95% confidence interval, 1.02 to 2.01) in contrast to the Moderna (mRNA) vaccine, where a weak association was found in certain age groups, in both cases demonstrated within 21 days of vaccine administration [38, 39]. The dose was equivalent for all three patients (first [n=1], second [n=1], and third [n=1]). The time elapsed from vaccine administration to onset of symptoms was 10.3±12.49 days. The treatment involved laparoscopic appendectomy in two patients due to perforation, while one patient underwent outpatient treatment with antibiotics and steroids. There was one case that reported the appearance of AA together with fulminant myocarditis [22]. In a retrospective study by Quint et al. [40], the registry of 421 patients with AA was reviewed, leading to the conclusion that AA caused by vaccination resembles classical AA. No deaths were reported, and all patients recovered, being discharged within a few days. The mechanisms by which this association may occur are not fully elucidated. It is known that SARS-CoV-2 vaccines produce an increased type 1 T helper (Th1) cell response [41]. Th1 cells primarily produce cytokines such as interferon-gamma and tumor necrosis factor-alpha; dysregulated levels of Th1 cytokines have been associated with autoimmune inflammation [42]. A study by Rubér et al. [43] found a positive association between gangrenous-type appendicitis and states of Th1-mediated immunity, suggesting that the increased Th1 response may contribute to an uncontrolled inflammatory reaction and the risk of perforation. If vaccines induce an elevated Th1 response, it is plausible that in our two patients who underwent appendectomy due to a perforated phase, this could be attributed to a potential association.

Acute pancreatitis (AP) is among the most prevalent gastrointestinal causes, and its incidence continues to rise globally [44]. Gallstones (45%) and alcohol abuse (20%) represent the most common causes of AP. Other less frequent associated causes include medication, endoscopic retrograde cholangiopancreatography, hypercalcemia, hypertriglyceridemia, infection, genetics, autoimmune diseases, and (surgical) trauma [45]. AP has been previously associated with several vaccines reported in the literature, including vaccines against human papillomavirus [46, 47], hepatitis A and B [48, 49], measles-mumps-rubella [50, 51], varicella [52], as well as typhoid fever and cholera [53]. Our study identified nine case reports of AP induced by vaccination against SARS-CoV-2. The mean age was estimated to be 46.3±26.79 years, with a predominance of females. AP predominantly occurred after the administration of the Pfizer-BioNTech (mRNA) vaccine (n=7) [23, 27], followed by Sinopharm (n=1) [28], and Johnson & Johnson/Janssen (n=1) vaccines [29]. Dosing for the nine patients included the first dose (n=6), second dose (n=2), and third dose (n=1). The time from vaccine administration to the onset of symptoms was 13.97±28.82 days. Treatment was medical and supportive in all patients, with no surgical procedures reported. One case mentioned the appearance of AP together with hemolytic anemia and thrombocytopenia [30]. Additionally, one case was associated with systemic lupus erythematosus [27]. There was a case of AP following the administration of the Pfizer-BioNTech vaccine in a patient at 31 weeks of gestation. On the second day, she underwent spontaneous vaginal delivery due to the inflammatory process triggered by AP [25]. No deaths were reported, and all patients recovered, being discharged in the following days. The mechanisms by which post-vaccination AP occurs are not clear. An autoimmune reaction is suggested due to the similarity of amino acids between the vaccine and host antigens, a mechanism known as molecular mimicry [25, 28]. This mimicry is attributed to the cleavage of the Furin peptide, identical to that of the human epithelial sodium channel, present in various organs such as the intestine, pancreas, and lungs. These data imply pancreatic injury due to an autoimmune reaction induced by the mRNA vaccine [26, 54].

Diverticulitis ranks as the third most common gastrointestinal disease and stands as the primary indication for elective colon resection [55]. It predominantly affects men until the 6th decade of life and is associated with various risk factors, including obesity, single consumption of red meat, smoking, and the use of medications such as non-steroidal anti-inflammatory drugs [56]. Our study identified only one case report of diverticulitis induced by SARS-CoV-2 vaccination. This involved a 41-year-old male patient who developed diverticulitis one day after receiving the third dose of the Moderna (mRNA) vaccine [15]. The treatment administered was medical and supportive, and he was discharged with a subsequent follow-up colonoscopy. Diverticulitis can result from genetic factors, environmental factors, and colon dysmotility, with recent studies associating it with specific immune responses of the host and the microbiome [57]. It is hypothesized that the Moderna vaccine (mRNA), once injected into the host, is translated into a viral spike protein. This protein could bind in a manner like SARS-CoV-2, to cells of the gastrointestinal tract inducing an inflammatory process and dysbiosis [15].

Cholecystitis is an acute inflammatory disease, often associated with gallstones (90% to 95%) and approximately 5% to 10% of patients are due to acalculous cholecystitis, defined as acute inflammation of the gallbladder without gallstones, typically in the context of severe critical illness [58]. The mechanisms by which cholecystitis mainly occurs are due to physical obstruction by gallstones, resulting in increased pressure and cholestasis within the gallbladder, which induces infectious mediator activation [59]. Our study identified two case reports of cholecystitis induced by SARS-CoV-2 vaccination. Both cases were diagnosed as acute acalculous cholecystitis, indicating the absence of gallstones. The mean age was calculated to be 40.5±11.5 years, involving one female patient and one male patient. Acute cholecystitis occurred following the administration of the Pfizer-BioNTech (mRNA) vaccine [16] and the Johnson & Johnson/Janssen (viral vector) vaccine [31]. It occurred after the first and third doses, respectively. The time from vaccine administration to symptom onset was 28±20 hours. Treatment was medical and supportive, and patients were discharged a few weeks later. Acalculous or alliasic cholecystitis is characterized by acute necrotizing inflammation without calculi. The mechanisms by which this association occurs are not fully elucidated [60]. The link between the vaccine and the onset of acalculous cholecystitis is not known, and a possible molecular mimicry reaction is suggested [16].

Eosinophilic colitis is a rare condition characterized by an elevated eosinophilic infiltrate in the colon walls and commonly presents as abdominal pain or diarrhea [61]. The pathophysiology of eosinophilic colitis involves various agents such as food allergens, parasitic infections, and drugs [62]. Ischemic colitis is characterized by a deficit of blood supply to the colon, caused by factors like drugs, pathogenic microorganisms, coagulation disorders, obesity, smoking, and iatrogenic factors [63]. Our study identified two case reports of colitis induced by SARS-CoV-2 vaccination. The mean age was estimated to be 60±12 years, involving one female patient and one male patient. Eosinophilic colitis occurred following the administration of the Pfizer-BioNTech (mRNA) vaccine [32], and ischemic colitis occurred after the Sinopharm vaccine [17]. It occurred after the first and second doses, respectively. The time from vaccine administration to symptom onset was 15±9 hours. Treatment was medical for ischemic colitis, and there was a spontaneous resolution for the case of eosinophilic colitis. Both patients experienced a favorable recovery. The mechanisms by which this association occurs are not clear. For ischemic colitis, it is proposed that vaccines induce inflammation and immune reactions, which could generate a state of hypercoagulability and alter the arterial blood supply to the colon [17]. Our study has some limitations. First, the systematic review only includes case reports and case series studies due to the limited number of original studies on the development of acute abdomen following COVID-19 vaccination, as of the date of writing the manuscript. Case reports and case series are not indicative studies, so the information should be interpreted with great caution. Second, the limited number of reported studies regarding the development of these complications could introduce a potential risk of bias. Third, despite conducting an exhaustive literature search, we acknowledge the possibility that some studies related to this topic might have been overlooked. Finally, our eligibility criteria included manuscripts published in English, Portuguese, and Spanish. Therefore, it is possible that there are several studies published in other languages and countries.

The emergence of acute abdomen following COVID-19 vaccination is of significant interest in clinical and surgical medical practice. Therefore, there is encouragement for the planning and execution of cohort and cross-sectional studies to evaluate this association with greater precision. To observe the evolution of patients through clinical monitoring with possible risk of developing these complications once any type of vaccination against COVID-19 is applied.

In conclusion, the present systematic review is of great interest in clinical and surgical medical practice because it presents the development of acute abdomen after vaccination against COVID-19. However, few studies related to this association have been reported, so they are infrequent and occur in a minority of vaccinated individuals. Despite this, patients responded adequately to treatment, and no deaths related to these complications were reported. Importantly, the study involved a small sample of patients, and future observational studies are required. These studies could elucidate the various pathophysiological mechanisms by which this association occurs and provide more robust information on the safety of SARS-CoV-2 vaccines. Ultimately, the cases included and studied in this review indicate that instances of acute abdomen are minimal following vaccination. Therefore, vaccines generally do not seem to develop acute abdomen. However, despite this, physicians should monitor patients with a history of risk factors and observe the evolution of patients through clinical follow-up with a possible risk of developing these complications after any type of vaccination against COVID-19.

Supplementary material is available at Clinical and Experimental Experimental Vaccine Research website (http://www.ecevr.org).

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