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.