a b s t r a c t

Objective: There is insufficient research on digestive symptoms and outcomes following coronavirus disease (COVID-19) vaccination. We aimed to investigate digestive symptoms and related complications among South Koreans who were administered COVID-19 vaccines.

Methods: Forty-six patients (men: 22, women: 24) with a median age of 68 years (interquartile range:55.5, 73.8 years) who experienced digestive symptoms following COVID-19 vaccination between March 1 and July 30, 2021, were included. This retrospective single-center study collected information on clinical symptoms, labora- tory tests, Imaging results, comorbidities, complications, treatment type, and prognosis.

Results: Thirty-three (71.7%), nine (19.6%), and three (6.5%) patients were administered AZD1222 (AstraZeneca), BNT162b2 (Pfizer/BioNTech), and JNJ-78436735 (Johnson and Johnson) vaccines, respectively. Patients were classified with mild (25 patients, 54.3%), moderate (five patients, 10.9%), and severe (16 patients, 34.8%) based on disease severity. Digestive symptoms included abdominal pain, diarrhea, dyspepsia, and nausea, which usu- ally developed within 1 day (78.3%) following the first vaccination. In total, 14 (30.4%) patients experienced only Gastrointestinal symptoms, whereas 32 (69.6%) experienced non-gastrointestinal symptoms. Complications included enterocolitis (76%), acute kidney injury (9%), anaphylactoid reaction (2%), and duodenal perforation (2%).

Conclusions: COVID-19 vaccines caused digestive symptoms and other complications that ranged from mild to se- vere. While further validation is required, our results suggest that monitoring digestive symptoms following COVID-19 vaccination can help detect rather severe complications that require medical intervention.

(C) 2022 Published by Elsevier Inc.

1. Introduction

The World Health Organization declared the coronavirus disease (COVID-19) outbreak a global pandemic in March 2020 [1]. COVID-19 vaccines are the primary defense against the pandemic; they reduce disease severity and mortality [2]. Four COVID-19 vaccines have been approved for use [3] in South Korea: AZD1222 (AstraZeneca), BNT162b2 (Pfizer-BioNTech), JNJ-78436735 (Janssen), and mRNA- 1273 (Moderna); they are currently in use as of August 20, 2021. These vaccines are effective in preventing COVID-19 infection and are generally safe to use with a low incidence of adverse events (AEs) [4-9,10]. How- ever, rare and critical complications such as encephalomyelitis [11],

* Corresponding authors.

E-mail addresses: [email protected] (D.S. Lee), [email protected] (J.W. Kim), [email protected] (K.L. Lee), [email protected] (Y.J. Jung), [email protected] (H.W. Kang).

anaphylaxis [12], vesiculo-bullous rash [13], acute kidney injury [14], in- travascular thrombosis, and thrombocytopenia [14-16] have been re- ported following vaccine administration.

Most AEs following COVID-19 vaccination are mild and transient. The common side effects include headache, Muscle pain, chills, diarrhea, and pain at the inoculation site. Previous studies reported that digestive symptoms following COVID-19 vaccination were not severe AEs, and they could be managed without medical treatment [17,18]. However, some critical complications were identified in patients with digestive symptoms in the emergency department (ED). There is insufficient in- formation regarding the clinical characteristics of digestive symptoms following the vaccination. Therefore, we aimed to investigate the clini- cal characteristics and outcomes of patients experiencing digestive symptoms following COVID-19 vaccination.

https://doi.org/10.1016/j.ajem.2022.05.044 0735-6757/(C) 2022 Published by Elsevier Inc.

1. Methods
   1. Design

This retrospective single-center study was conducted at the Seoul National University Boramae Medical Center in Seoul, South Korea, from March 1 to July 30, 2021. The study protocol was approved by the Institutional Review Board of the Seoul National University Boramae Medical Center (approval number 30-2021-113). The requirement for informed consent was waived because of the retrospective nature of the study.

We collected cases of patients who visited the ED for digestive symp- toms following COVID-19 vaccination. Only those that had an associa- tion between vaccination and digestive symptoms were included in the study. The inclusion criteria were as follows: (1) newly developed gastrointestinal symptoms after vaccination (symptom onset is mea- sured after vaccination) and no gastrointestinal symptoms prior to vac- cination; (2) gastrointestinal symptoms requiring medical treatment;

(3) gastrointestinal symptoms result in a major portion of the patient’s discomfort; (4) patients visiting the ED for gastrointestinal symptoms. The exclusion criteria were as follows: (1) gastrointestinal symptoms prior to vaccination; (2) no history of recent COVID-19 infection;

(3) positive real-time Polymerase chain reaction test results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); and (4) no history of medications that can cause indigestion.

• 1. Data collection

Clinical data were collected from medical records by trained re- search assistants according to the stipulated guidelines [19]. Investiga- tors retrieved data regarding comorbidities, clinical characteristics, Laboratory test results, radiological findings, vaccine brand, and out- comes from electrical medical records. Reviewers who were clinical physicians reviewed clinical data from electronic medical records; dis- crepancies among them were resolved by the investigators. diagnostic information was acquired sequentially based on medical history, phys- ical examination, and categories according to the 10th Revision of the In- ternational Statistical Classification of Diseases and Related Health Problems (ICD-10; Version 2019) [20].

• 1. Outcome measures

Digestive symptoms, including abdominal pain, diarrhea, and indi- gestion, were defined as the main symptoms. Other symptoms such as dyspnea, generalized weakness, headache, and decreased conscious- ness levels were considered additional symptoms. Patients were classi- fied into three groups based on disease severity according to the Korean Food and Drug Administration guidelines regarding symptoms, labora- tory results, medical treatment, hospitalization, and recovery period [21,22]. Patients in the mild group had stable vital signs and normal C- reactive protein (CRP) levels, whereas those in the moderate group had stable vital signs and abnormal CRP levels; they required medical treatment. Patients in the severe group had unstable vital signs, abnor- mal laboratory results, and an extended recovery period, requiring hos- pitalization.

• 1. Statistical analysis

Descriptive and categorical variables are reported as medians (inter- quartile ranges [IQRs]) and frequencies (percentages), respectively. Sta- tistical significance was set at P < 0.05. Statistical analyses were performed using SPSS version 20 (IBM Corp, Armonk, NY, USA).

1. Results
   1. Baseline characteristics

Seventy-four patients were preliminarily screened for digestive symptoms following COVID-19 vaccination. We excluded 28 patients whose digestive symptoms exhibited no definite causal relationship with COVID-19 vaccination (Fig. 1). Finally, we analyzed 46 patients (men: 22, women: 24). Fig. 1 shows the flowchart of patient inclusion. Table 1 presents the patients’ baseline characteristics (median age: 68 years; IQR: 55.5, 73.8 years). COVID-19 vaccines from three different brands were used; 33 patients received AZD1222 (AstraZeneca), nine received BNT162b2 (Pfizer/BioNTech), and three received JNJ- 78436735 (Johnson and Johnson). The median time for the onset of di- gestive symptoms after vaccination was 1 (1,1) days. Most digestive symptoms appeared following the administration of the first dose of the vaccine. Comorbidities included hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and musculoskeletal disease (Table 1).

• 1. Symptoms and outcomes

In total, 14 (30%) patients experienced digestive symptoms only (Table 2). These included abdominal pain, diarrhea, dyspepsia, nausea, hematochezia, and melena. Patients (70%) experienced additional symptoms, including fever and poor oral intake (Table 2). Abdominal pain, diarrhea, fever, and inadequate oral intake were frequently ob- served in severe cases.

The following abnormal laboratory findings were commensurate with Symptom severity: aspartate aminotransferase >38 IU/L, alanine aminotransferase >45 IU/L, CRP > 1 mg/dL, white blood cell count

>10,000 cells/uL, segmented neutrophils >70%, and lymphocyte count

<1200 cells/uL (Table 2). Complications included enterocolitis, anaphy- lactoid reaction, acute kidney injury, and duodenal perforation (Table 3). Sixteen patients (35%) were critical cases. The median recov- ery period was 5.0 (3.0, 7.0) days. Medical treatment included intrave- nous fluid resuscitation, antibiotic agents, antiviral agents, and corticosteroids. Sixteen patients (35%) received antibiotic agents, and one received antiviral agents (Table 3).

1. Discussion

SARS-CoV-2 causes digestive complications and can invade several digestive organs by binding to angiotensin-converting enzyme-2 recep- tors, abundant in several gastrointestinal organs [23]. Patients with COVID-19 frequently experience digestive symptoms such as abdomi- nal pain, vomiting, anorexia, diarrhea, and nausea [24,25]. Additionally, there are reports of various complications, including acute liver disease, acute acalculous cholecystitis, acute pancreatitis, intestinal obstruction, acute colon pseudoobstruction, and Mesenteric ischemia [26-30].

Adverse reactions following COVID-19 vaccination are rather similar to complications in COVID-19 patients. These have been described as “Vaccine-Induced COVID-19 Mimicry” Syndrome, a condition caused by COVID-19 vaccines [31]. However, compared to patients with COVID-19 [32-34], vaccinated individuals had a faster onset of symp- toms, a higher rate of asymptomatic infections, and lower severity and mortality [2].

In this study, the most common digestive symptoms were abdominal pain and diarrhea, whereas the most common complication was enterocolitis. Digestive symptoms mainly occurred following administration of the first vaccine dose, with symptom onset usually occurring within one day. Among the mild cases, the proportion of women was high, and the proportion of men was high among the se- vere cases. AZD122 resulted in more adverse reactions after vaccination than BNT162b2. These results were quite similar to those from our pre- vious study [22].

Patients admitted to the emergency department with gastrointestinal symptoms after COVID-19 vaccination (n = 74)

Excluded patients (n = 28):

• Preexisting gastrointestinal symptoms prior to vaccination (n = 21)
• Minor gastrointestinal symptoms related to other symptoms (n = 3)
• History of recent COVID-19 infection (n = 2)
• Positive real-time polymerase chain reaction test results for SARS-CoV-2 (n = 2)

Patients included in the study (n = 46)

Mild (n = 25)

Moderate (n = 5)

Severe (n = 16)

Fig. 1. Patient inclusion flowchart.

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

There was a high incidence of complications in older patients with Multiple comorbidities. Patients with prerenal acute kidney injury fre- quently experienced diarrhea and poor oral intake.

Patients with severe complications had to be hospitalized for appro- priate treatment. Anaphylactoid reaction was treated with intravenous volume infusion and epinephrine. Enteritis generally improved with ad- equate intravenous fluid resuscitation. Spontaneous bowel peritonitis was treated with antibiotics. Acute kidney injuries improved with

Table 1

Baseline characteristics of the study population (n = 46)

fluid resuscitation. Acute cholangitis was treated with antibiotics and Endoscopic retrograde cholangiopancreatography. Patients with duode- nal ulcer perforation underwent laparoscopic Primary repair. Severe complications were more prevalent in patients with abdominal pain, di- arrhea, old age, cardiovascular disease, endocrine disease, and elevated CRP levels than those without these factors. These results were similar to those of our previous study [35].

To the best of our knowledge, this is the first study focusing on diges- tive symptoms after COVID-19 vaccination. However, this study has some limitations. First, it was a retrospective single-center study with a small sample size. Considering the results of our previous study [22], actual adverse events may have a higher incidence. Second, there

Characteristics Mild

n = 25

Moderate

n = 5

Severe

n = 16

Total

N = 46

ings of the study population (n = 46)

Age (years), median [IQR] 60 [50, 72] 42 [37, 50] 71 [62, 77] 68 [56, 74] Table 2
<=40	6	1	1	8 Symptoms and laboratory find
41-60	5	2	2	9 Clinical symptoms
61-80	12	1	10	23
81-90	2	1	3	6
Sex				Gastrointestinal symptoms

Mild

n= 25

Moderate n = 5

Severe n= 16

Total

N= 46

Male	8	2	12	22	Dyspepsia	4	2	4	10
Female	17	3	4	24	Abdominal pain	15	1	10	28
Comorbidities					Nausea	10		1	11
Cardiovascular disease	5	2	9	16	Diarrhea	13	5	7	25
Endocrine disease	4	2	5	11	Hematochezia	1			1
Digestive disease		2	6	8	Melena	1			1
Respiratory disease	1		2	3	Non-gastrointestinal symptoms
Malignancy		1	1	2	Fever	4	4	5	13
Allergy			1	1	Headache	11	1	1	13
Muscular skeletal disease	3	1	3	7	General myalgia	1		2	3
Vaccine brand General weakness 2							3	2	7
AZD1222	16	3	14	33	Poor oral intake	6		4	10
BNT162b2	6	2	1	9	Dizziness	8	1	1	10
JNJ-78436735	2	1		3	Epistaxis	1			1
AZD1222 + BNT162b2	1			1	None	8	3		11
Number of vaccinations					Gastrointestinal symptoms only	8		6	14
Dose 1	18	9	9	36	Non-gastrointestinal symptoms	17	5	10	32
Dose 2	7	1	2	10	Laboratory test results
Symptom onset after	1 [1,1]	1 [1,2]	1 [1, 1]	1 [1, 1]	AST > 38 IU/L or ALT >45 IU/L	1	1	3	5
vaccination (days), median					C-reactive protein >1 mg/dL		3	16	19
[IQR]					White blood cell count >10,000 cells/uL	3	3	16	22
1	22	3	15	40	Segment neutrophils >70%	9	4	16	28
2	2	2		4	Lymphocyte count <1200 cells/uL	9	4	16	29
3	1		1	2	None	5	3		8

IQR, interquartile range. AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Table 3

Complications observed in the study population (n = 46)

Declaration of Competing Interest

Characteristics	Mild (n = 25)	Moderate (n = 5)	Severe (n = 16)	Total (N = 46)	None.
Complications Enterocolitis	25	5	5	35	Acknowledgments

Anaphylactoid reaction 1 1

We would like to thank Editage (https://www.editage.co.kr) for the

Acute kidney injury after enterocolitis

^{4 4} assistance in English language editing.

Duodenal perforation 1 1

Acute exacerbation of chronic obstructive pulmonary disease

_{1 1} References

Spontaneous bacterial peritonitis 1 1

Acute hepatitis 1 1

Acute cholangitis 1 1

Meningitis 1 1

Recovery period, days, median [IQR] 3 [3, 5] 5 [5, 5] 7 [7, 8] 5 [3, 7] Medical treatment

Intravenous fluid resuscitation	25	5	16	46
Antibiotic agent	3	5	8	16
Antiviral agent			1	1
Corticosteroids			2	2

IQR, interquartile range.

could be difficulties in defining the causal-temporal relationship be- tween COVID-19 vaccination and several complications. Third, only the patients who visited the ED were considered, and outpatients were not included in this study. However, the study population was well-balanced in terms of age, comorbidities, symptoms, severity, and outcomes, which facilitates the appropriate evaluation of post- vaccination adverse reactions. Therefore, future large-scale studies are required to support our findings.

1. Conclusions

We found that digestive symptoms and complications after COVID- 19 vaccination are similar to those faced by real COVID-19 patients. While further research is required, our results suggest that digestive symptoms following COVID-19 vaccination can help detect severe com- plications requiring medical treatment.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Source of support

None.

CRediT authorship contribution statement Dong Seok Lee: Writing - review & editing, Writing - original draft,

Visualization, Validation, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptual- ization. Ji Won Kim: Writing - review & editing, Writing - original draft, Validation, Supervision, Methodology, Formal analysis, Data curation, Conceptualization. Kook Lae Lee: Validation, Supervision, Methodol- ogy, Data curation. Yong Jin Jung: Validation, Supervision, Methodol- ogy, Data curation. Hyoun Woo Kang: Validation, Supervision, Methodology, Data curation.

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