4. DISCUSION
In the present systematic review of case reports and case series of acute abdomen following COVID-19 vaccination, we found that acute pancreatitis, Pfizer-BioNTech vaccine (mRNA) and first dose were the most common complication, vaccine type and dose 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. Sixty-four-point seven percent were female and 35.3% were male. 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 worldwide34. 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 predominance of males in a 1.4:1 ratio with respect to females and it occurs most frequently between the ages of 10 and 20 years36. The etiology of acute appendicitis is mainly due to obstructive processes due to follicular hyperplasia and fecalith. In addition, rare obstructive causes such as amebiasis, carcinoid tumor, infestation by parasites such as amebiasis, enterobiasis, ascariasis, and others37. Our study found 3 case report 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 Modern (mRNA) (n=1)22. In other studies, the Pfizer-BioNTech vaccine was associated with AA with a RR of 1.40 (CI: 1.02 to 2.01) in contrast to the Modern (mRNA) vaccine, where a weak association was found in certain age groups, in both cases demonstrated within 21 days of vaccine administration38,39. The dose was equivalent for all 3 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. Treatment was surgical in 2 patients (laparoscopic appendectomy) due to being in the perforated phase and outpatient in 1 patient (antibiotics and steroids). There was one case that reported the appearance of AA together with fulminant myocarditis22. A retrospective study by Quint et al. reviewed the registry of 421 patients with AA, concluding that AA caused by vaccination is like classical AA40. There was no case of death, all patients recovered and were 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 Th1 cell response41. Th1 cells primarily produce cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), dysregulated levels of Th1 cytokines have been associated with autoimmune inflammation42. A study by Rubér et al, found that gangresone-type appendicitis has a positive association with states of Th1-mediated immunity, this could explain the increased th1 due to uncontrolled inflammatory reaction and risk of perforation43. If vaccines induce increased Th1 response, it is possible that in our two patients appendectomized for perforated phase, it is due to this possible association.
Acute pancreatitis (AP) is one of the most frequent gastrointestinal causes and its incidence continues to increase worldwide44. Gallstones (45%) and alcohol abuse (20%) are the most frequent causes of AP. Medication, endoscopic retrograde cholangiopancreatography (ERCP), hypercalcemia, hypertriglyceridemia, infection, genetics, autoimmune diseases and (surgical) trauma are other less frequent associated causes45. AP has previously been associated with several vaccines reported in the literature, vaccines against human papillomavirus46,47, hepatitis A and B48,49, measles, mumps, and rubella (MMR)50,51, varicella52, and typhoid fever and cholera53. Our study found 9 case report 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 by females. AP occurred mainly after administration of Pfizer-BioNTech (mRNA) vaccine (n=7)23,27 followed by Sinopharm (n=1)28 and Johnson & Johnson / Jassen (n=1) vaccines29. The dosing for the 9 patients was (first (n=6), second (n=2) and third (n=1). The time from vaccine administration to onset of symptoms was 13.97 ± 28.82 days. Treatment was medical and supportive in all patients, there was no surgical procedure. There was one case that reported the appearance of AP together with hemolytic anemia and thrombocytopenia30, in addition, there was one case associated with systemic lupus erythematosus27. There was a case of AP after administration of the Pfizer-BioNTech vaccine in a patient at 31 weeks of gestation, after which on the second day she had a spontaneous vaginal delivery because of the inflammatory process triggered by AP25. There was no case of death, all patients recovered and were 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 the host antigens, a mechanism called molecular mimicry25,28. This mimicry is due to the cleavage of the FURIN peptide identical to that of the human epithelial sodium channel, present in different organs such as the intestine, pancreas, and lungs. These data suggest pancreatic injury due to an autoimmune reaction induced by the mRNA vaccine26,54.
Diverticulitis is the third most common gastrointestinal disease and the main indication for elective colon resection55. It is predominantly seen in men until the sixth decade of life and is related to multiple risk factors such as: obesity, single consumption of red meat, smoking and medications such as non-steroidal anti-inflammatory drugs56. Our study found only 1 case report of diverticulitis induced by SARS-CoV-2 vaccination. This was a 41-year-old male patient who developed diverticulitis 1 day after receiving the third dose of Modern (mRNA) vaccine15. Treatment was medical and supportive, and he was discharged with subsequent follow-up colonoscopy. Diverticulitis can be caused by genetic factors, environmental factors, dysmotility of the colon and recent studies associate it with specific immune responses of the host and the microbiome57. It is hypothesized that the Modern 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 dysbiosis15.
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 illness58. 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 activation59. Our study found 2 case report reports of SARS-CoV-2 vaccination-induced cholecystitis, both cases were diagnosed as acute acalculous cholecystitis (no presence of gallstones). The mean age was calculated to be 40.5 ± 11.5 years, observed in one female patient and one male patient. Acute cholecystitis occurred after administration of Pfizer-BioNTech (mRNA)16 and Johnson & Johnson/ Janssen (Viral vector) vaccine31. It occurred in the first and third doses respectively. The time from vaccine administration to symptom onset was 28 ± 20 hours. Treatment was medical and supportive, 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 elucidated60. The association between the vaccine and the appearance of acalculous cholecystitis is not known, a possible molecular mimicry reaction is suggested16.
Eosinophilic colitis is a rare condition characterized by an elevated eosinophilic infiltrate in the colon walls, and commonly presents as abdominal pain or diarrhea61. The pathophysiology of eosinophilic colitis involves a variety of agents such as food allergens, parasitic infections, and drugs62. Ischemic colitis is characterized by a deficit of blood supply to the colon, caused by some drugs, pathogenic microorganisms, coagulation disorders, obesity, smoking and iatrogenic63. Our study found 2 case report reports of colitis induced by SARS-CoV-2 vaccination, both cases were diagnosed as eosinophilic colitis and ischemic colitis. The mean age was estimated to be 60 ± 12 years, observed in one female patient and one male patient. Eosinophilic colitis occurred after administration of Pfizer-BioNTech (mRNA) vaccine32 and ischemic colitis by Sinopharm vaccine17. It occurred in the first and second doses, respectively. The time from vaccine administration to symptom onset was 15 ± 9 hours. Treatment was medical in ischemic colitis, and there was spontaneous resolution for the case of eosinophilic colitis. Patients had a favorable recovery. The mechanisms by which this association occurs is not clear. For ischemic colitis, it is proposed that vaccines induce inflammation and immune reaction, which could generate a state of hypercoagulability and alter the arterial blood supply to the colon17.
Our study has some limitations. First, the systematic review only includes case report 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 generate a potential risk of bias. Third, although we performed an exhaustive literature search, we did not rule out the possibility that we missed some studies related to this topic. 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 development of acute abdomen following vaccination against COVID-19 is of great interest in clinical and surgical medical practice. Therefore, the planning and elaboration of cohort and cross-sectional studies is encouraged 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.