Development of Peptic Ulcer following Second Shot of Sputnik V Vaccine: A Case Report and Literature Review of Rare Side Effects of Sputnik V Vaccine

Considering the global spread of the coronavirus disease 2019 (COVID-19), it is expected that vaccination against its causative agent, the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), will reduce the related morbidity and mortality. However, the safety of the COVID-19 vaccines and their potential and unknown side effects are a matter of concern. With the ongoing development and implementation of COVID-19 vaccination programs around the world, the side effects, safety, and effectiveness of these vaccines are gradually being reported, providing researchers with valuable information that can affect the production and utilization of the COVID-19 vaccines. The present study intended to report a case of peptic ulcer disease (PUD) development following vaccination with Gam-COVID-Vac, a vector-based COVID‐19 vaccine containing two recombinant human adenoviruses (rAd26 and rAd5).


Introduction
As a newly emerged disease, the coronavirus disease 2019 (COVID- 19) was frst reported in Wuhan, China, in December 2019.Having been declared a global epidemic by the World Health Organization (WHO) [1], this disease is associated with considerable mortality and signifcant social, psychological, and fnancial impacts globally [2].
Since the outbreak of COVID-19, several treatment protocols have been developed for disease management, with new evidence emerging every day [3].Moreover, many countries have made eforts to develop efective vaccines to stop the extension of the pandemic.Some of these vaccines have received emergency injection licenses from the WHO, while others are being injected with the permission of local health organizations in diferent countries [4,5].
As a COVID-19 vaccine produced by the Gamalia Institute for Epidemiological and Microbiological Research, Sputnik V (Russian: Sпutojl V) was released on August 11, 2020, and was named the Gam-COVID-Vac (Russian: Γan-LPCJE-Cal) by the Russian Ministry of Health.Tis vaccine is an adenovirus-based vector vaccine and is injected in two doses with an interval of 21 days [6].On February 2, 2021, a preliminary analysis of its phase III clinical trial was published in Lancet, reporting an efectiveness of 91.6% with no remarkable side efects [7].However, this vaccine has not yet been licensed for emergency use by the WHO.Terefore, regarding the studies reporting its efectiveness, ambiguities and objections have been raised [8].Until February 2021, twenty-one countries had authorized the emergency use of the Sputnik V vaccine [9].
Te vaccines against the SARS-CoV-2 have been tested in large randomized controlled trials to evaluate their efcacy and safety in all populations.However, the data from these trials have shown several side efects for each COVID-19 vaccine, which is similar to vaccines against other diseases [4].Several studies have found that certain groups of people tend to have a lower humoral immune response to vaccines.Tese groups include older individuals, males, those who are seronegative, and those with underlying health conditions such as end-stage renal disease or diabetes mellitus [10,11].As a result, these individuals may require additional doses of vaccination or a combination of diferent types of vaccines, such as mRNA vaccines with protein vaccines or vector-based vaccines [11].It is important to note that these groups may have a higher risk of experiencing unknown side efects from vaccination compared to others.Some of the commonly reported side efects include myalgia, fever, and headache [12].Moreover, some rare side efects have been reported for these vaccines, mostly the mRNA-based vaccines.Te present study reports a case of peptic ulcer disease (PUD) following the second shot of the sputnik V vaccine in a young woman without any underlying disease and reviews the rare side efects reported for this vaccine.

Case Report
Our patient was a 28-year-old female healthcare provider who had presented to a physician with nausea, vomiting, and epigastric pain 5 days after being vaccinated with the Sputnik V vaccine.Te patient received routine medications (Figure 1).However, her symptoms did not respond to treatment, and she was referred to our healthcare facility for further evaluation.
Te patient did not mention any relevant past medical history, underlying diseases, smoking, or alcohol consumption; also, the patient did not mention any special medication or eating habits.Moreover, she had a blood pressure of 120/80 mmHg, a pulse rate of 65 per min, a body temperature of 37 °C, a respiratory rate of 22 per min, and no other remarkable fnding in her physical examination.Also, she had a high leukocyte count (14,500 per μL, neutrophil percentage: 89%), while other routine tests, including other items of cell blood count (CBC) and diferentiation, renal function tests, liver function tests, blood sugar, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and urine analysis, were reported in the normal range.Furthermore, she had elevated levels of anti-SARS-CoV-2 antibody, while she underwent two polymerase chain reaction (PCR) tests for SARS-CoV-2, which were reported negative.
Regarding intractable vomiting and severe epigastric pain, the patient underwent an endoscopy, which showed severe ulceration and edema in the lower part of the esophagus extending to the whole stomach.Moreover, a large circumferential ulcer was reported in the gastric body and antrum of which multiple biopsies were taken (Figure 2(a)).Also, she was assessed for gastrin levels, which were reported normal, as the Zollinger-Ellison syndrome was suspected.Furthermore, the pathology reported superfcial erosive and ulcerative gastritis, active erosive duodenitis, mild colonization with Helicobacter pylori, no dysplasia or neoplasia, and severe infammation.Moreover, she had leukocyte infltration in the lamina propria, which was polymorphonuclear-dominant with lower levels of lymphocyte and eosinophil and was associated with red blood cell extravasation and multiple foci of hemorrhage (Figure 2(b)).Finally, the patient was treated with high-dose proton pump inhibitor (PPI, pantoprazole 40 mg QDS) and was discharged after 3-4 days with H. pylori eradication medications.
In the following, the patient underwent a follow-up endoscopy three months later due to persistent dyspepsia and epigastric pain.According to the endoscopy report, the esophagus was normal.However, a semicircumferential ulceration with severe edema was reported in the stomach, of which multiple biopsies were taken (Figure 3(a)).Moreover, the pathology reported severe, chronic nonatrophic gastritis with moderate infltration of lymphocytes and neutrophils in the lamina propria, edema without any dysplasia, neoplastic granuloma, and H. pylori infection (Figure 3(b)).
Considering the acute onset of the PUD 5 days after the vaccination and no improvement following treatment for H. pylori or a family history of PUD, the patient's condition was hypothesized to be a rare side efect of the Sputnik V vaccine.Te patient received a high dose of pantoprazole and was advised to skip the third dose of the Sputnik V vaccine.Six months after the frst endoscopy, the patient underwent another endoscopy, which revealed partial healing of the ulcers.

Discussion
Although mass vaccination against COVID-19 is an outstanding achievement, there are several concerns regarding the safety and potential adverse efects of the related vaccines [13].Te common side efects following vaccination against SARS-CoV-2 include injection site reactions, myalgia, headache, fever, and asthenia [13].However, we reported a confrmed case of PUD 5 days after the second dose of the Sputnik V vaccine.
As a benign mucosal and submucosal lesion of the gastrointestinal tract, PUD is often caused by gastritis, H. pylori infection, smoking, and the use of nonsteroidal anti-infammatory drugs (NSAIDs).Moreover, its rare causes include Zollinger-Ellison syndrome, malignancies, and stress.According to studies, H. pylori infection is the main cause of PUD.However, recent studies have shown a relationship between SARS-CoV-2 and peptic ulcers [14,15].Also, the symptoms of PUD include epigastric pain, heartburn, indigestion, and blood in the stool, while the pain usually occurs shortly after eating or when hungry [15].
It has been shown that PUD can also occur without H. pylori infection.Such condition is referred to as the H. pylori-negative PUD, which should be considered if four of the following criteria are met: (i) lack of H. pylori bacteria in triple staining of gastric mucosal biopsies (hematoxylin and eosin, Alcian blue stain, and a modifed silver stain), (ii) a negative H. pylori culture, (iii) a negative IgG test for H. pylori, and (iv) no self-reported history of receiving treatment for H. pylori [16].
In the present study, the patient was diagnosed with H. pylori infection and received the related treatment.However, despite the H. pylori eradication, the PUD was not completely healed after 3 months.According to the results of 2

Case Reports in Infectious Diseases
Receiving the second dose of Sputnik V vaccine First Visit Beginning of nausea, vomiting and epigastric pain, her symptoms did not respond to treatment follow-up endoscopy due to persistant dyspepsia and epigastric pain, the patient underwent an endoscopy, and a semi-circumferential ulceration with severe edema was seen.

Diagnosis and final follow-up
A high dose of pantoprazole was administered, resulting in partial healing of the ulcers.

First endoscopy appointment
There was severe ulceration and edema in the lower part of the esophagus, which extended to the entire stomach, and a large circumferential ulcer was also visible.
The sixth day Case Reports in Infectious Diseases the study by Notarte et al., it is shown that 4-6 months after the injection of the second dose of the vaccine, its serum levels decrease, so there is a possibility that the relative healing of our patient's ulcers after 6 months may be due to a decrease in serum levels of vaccine [17].
According to studies on COVID-19 patients with gastrointestinal bleeding (GIB), the virus can be isolated from gastric biopsies.Moreover, the receptors of the angiotensin 2converting enzyme are expressed in the gastric cells.Terefore, it is possible that SARS-CoV-2 can cause gastritis, PUD, GIB and in rare cases esophagitis dissecans superfcialis [18,19].However, the underlying mechanisms of vaccineinduced PUD are unclear.A convincing explanation recently suggested for this phenomenon is molecular mimicry [20].According to this hypothesis, the cross-reaction caused by the similarity of the amino acid sequences of viral antigens and self-antigens may lead to tissue damage by the cytotoxic antibodies [21].In support of this hypothesis, antibodies against the SARS-CoV-2 spike protein have been reported to show cross-reaction with several human tissue antigens [22].Moreover, given that our patient developed PUD 5 days after the vaccination, memory T cells must had been sensitized to the antigens similar to SARS-CoV-2 antigens before the vaccination because postvaccination antibody production generally requires several weeks [22].
Our team searched the studies published in PubMed/ MEDLINE up to February 22, 2022, to fnd the case reports of the rare side efects of the Sputnik V vaccine.According to our fndings, only 4 related studies were published (Table 1).In all the reported cases, the infection with SARS-CoV-2 was excluded using the real-time PCR (RT-PCR) test, except for one case where the details were not provided [24].Considering our case report, all the cases were older than 18 years.Moreover, they had a mean age of 37.4 years and included 2 men and 3 women.Te developed complications were resolved in all the patients with proper treatment.Also, all the patients had elevated levels of anti-SARS-CoV-2 antibodies after their vaccination, except for one patient with multiple sclerosis (MS) who was treated with rituximab.Despite the acute recurrence of MS in the patient, she was advised to complete her vaccination after the end of her course of treatment with prednisolone (Table 1). 4 Case Reports in Infectious Diseases Considering the abovementioned, it is essential for clinicians and researchers to be aware of the potential side efects of COVID-19 vaccination.Moreover, the present study showed the possibility of PUD in patients presenting with nausea, vomiting, and abdominal pain after vaccination with the adenovirus-based COVID-19 vaccines.Given the lack of a history of gastrointestinal problems, it is very likely that our patient developed PUD and gastritis due to vaccination.

Figure 1 :Figure 2 :
Figure 1: Timeline of the PUD unusual case illustrating the chronological sequence of events.

Figure 3 :
Figure 3: Patient endoscopic fndings after 3 months of follow-up (a) and patient pathology fndings after 3 months of follow-up (b).

Table 1 :
Summary of case reports on Sputnik V vaccines rare side efects.