Peptic ulcer disease (PUD) affects >4 million people yearly and is associated with life-threatening complications such as bleeding, perforation, and obstruction1. Perforated peptic ulcer (PPU) is the second most prevalent complication, occurring in 2%–14%. This condition is fatal and associated with increased morbidity and mortality of patients1,2.
Several risk factors have been associated with the development of PPU. Helicobacter pylori and nonsteroidal anti-inflammatory drugs consumption have been considered the main risk factor of PPU. As the number of H. pylori has plummeted in recent years, other factors such as psychological stress cannot be ignored3. Previous study has found that psychological stress significantly increases the risk of PUD4,5 and PPU6 independently to H. pylori infection and nonsteroidal anti-inflammatory drugs consumption. Psychological stress can also alter a person’s behavior that may increase health risks related to the development of PPU7.
The first case of coronavirus disease 2019 (COVID-19) was reported in December 2019. Since then, the disease has spread throughout the world, including Indonesia. The Indonesian government declared a national infectious disease outbreak in March 2020 and adopted an emergency health policy with a quarantine program, social and individual restrictions to prevent transmission of the virus8. This causes a drastic change in people’s daily lives in multiple aspects. This COVID-19 pandemic causes fear and uncertainty and has been proven to be associated with a significant increase in psychological stress9 and perceived stress10. This study aims to analyze the effect of COVID-19 pandemic high psychological stress as a risk factor for developing PPU.
Methods
A cross-sectional study was conducted on all adult patients diagnosed and underwent surgery for PPU from July 2017 to March 2021 at a tertiary hospital in Indonesia. Patients with perforation due to tumor, endoscopy, or trauma were excluded. Patients are then divided into nonpandemic group and pandemic group. The nonpandemic group consists of patients who underwent PPU surgery from July 2017 to February 2020 and the pandemic group from March 2020 to March 2021. The Ethics Committee approved ethical clearance before the study. The research was registered with Research Registry with a registration number researchregistry7571.
We extract electronic medical records to obtain patients’ demographical data. Perceived stress is then collected from the patient during the follow-up visit using an Indonesian version of the Perceived Stress Scale (PSS-10) questionnaire. PSS-10 score of 0–13 was defined as low-stress, 14–26 as moderate-stress, and 27–40 as high stress. Comorbidity in this study is defined as any concomitant disease during the admission of PPU. This includes pulmonary disease, cardiovascular disease, autoimmune disorders, and malignancy in the patient history.
χ2 test of independence was used to analyze categorical data. Fischer exact test was used if χ2 test criteria were not met. An Independent t test is used to analyze numerical data if normally distributed; otherwise, the Mann-Whitney U test is used. The Indonesian version of PSS-10 was analyzed for validity using the Pearson correlation test and reliability using Cronbach α test. All P were 2-sided with statistical significance defined as P<0.05. Statistical analyses were performed with SPSS version 20.
Results
Patient characteristic
During the 45 months, a total of 53 patients with PPU underwent surgery in our hospital. Twenty-five patients from the nonpandemic period with an average incidence of 0–1 patient each month and twenty-eight patients during the pandemic period with an average of 3–4 patients each month in the first 6 months, then 1–2 patients the following months. Two patients from the pandemic group were positive of COVID-19 via oropharyngeal/nasopharyngeal PCR swab. Patient characteristics are shown in Table 1. The pandemic group is predominantly female compared with the nonpandemic group, which is predominantly male. H. pylori infection were found in only 2 subjects in the nonpandemic group and none in the pandemic group. No subject in the study smoked or drank alcohol.
Table 1 -
Patient characteristic.
| Variable |
Pandemic (n=28), n (%) |
Nonpandemic (n=25), n (%) |
PR |
95% CI |
P
|
| Sex |
| Female |
17 (60.7) |
4 (16) |
|
|
0.001*
|
| Male |
11 (39.3) |
21 (84) |
3.79 |
1.47–9.77 |
|
| Age, mean (y) |
63 |
53 |
|
−10.30, 1.84 |
0.167† |
| Age group (y) |
| >65 |
13 (46.4) |
7 (28) |
1.66 |
0.79–3.49 |
0.167*
|
| <65 |
15 (53.6) |
18 (72) |
|
|
|
| Comorbidity |
| Yes |
26 (92.8) |
12 (48) |
1.94 |
1.27–2.95 |
0.000*
|
| No |
2 (7.2) |
13 (52) |
|
|
|
| Boey score |
| 0–1 |
8 (28.6) |
14 (56) |
|
|
|
| 2–3 |
20 (71.4) |
11 (44) |
1.62 |
0.98–2.98 |
0.043*
|
| PULP score |
| 1–7 (low risk) |
13 (46.4) |
15 (60) |
|
|
|
| ≥8 (high risk) |
15 (53.6) |
10 (40) |
1.4 |
0.74–2.42 |
0.323*
|
| ASA score (mean) |
| 3 |
21 (75) |
24 (96) |
|
|
|
| 4 |
7 (25) |
1 (4) |
6.25 |
0.83–47.34 |
0.033*
|
| Current NSAID exposure |
| Yes |
24 (80) |
20 (80) |
1.07 |
0.83–1.37 |
0.719‡
|
| No |
4 (20) |
5 (20) |
|
|
|
| Shock |
| Yes |
6 (21.4) |
2 (8) |
2.67 |
0.59–12.08 |
0.256‡
|
| No |
22 (78.6) |
23 (92) |
|
|
|
*χ2.
†Independent t test.
‡Fisher exact.
ASA indicates American Society of Anesthesiologists; NSAID, nonsteroidal anti-inflammatory drugs; PR, prevalence ratio; PULP, peptic ulcer perforation.
Patient outcome
Patient during the pandemic shows a significant increase in post-operative complication or morbidity rate [78.5% vs. 52%; prevalence ratio (PR): 1.51, 95% confidence interval (CI): 0.99–2.31; P=0.041] and increase in mortality (46.4% vs. 28%; PR: 1.66, 95% CI: 0.79–3.49; P=0.167) (Table 2). The average length of stay for PPU patients was longer in the pandemic group compared with the nonpandemic group (23.6 vs. 16.2 d; 95% CI: 2.23–16.87, P=0.002).
Table 2 -
Morbidity and mortality rate of pandemic and nonpandemic patients with PPU.
| Variable |
Pandemic (n=28), n (%) |
Non-pandemic (n=25), n (%) |
PR |
95% CI |
P
|
| Morbidity |
| Yes |
22 (78.5) |
13 (52) |
1.51 |
0.99–2.31 |
0.041 |
| No |
6 (21.5) |
12 (48) |
|
|
|
| Mortality |
| Yes |
13 (46.4) |
7 (28) |
1.66 |
0.79–3.49 |
0.167 |
| No |
15 (53.6) |
18 (72) |
|
|
|
χ2 test.
CI indicates confidence interval; PR, prevalence ratio.
In the pandemic group, 22 patients have a postoperative complication, with 3 patients with multiple complications. The most common complication in the pandemic group is pneumonia (32.1%) and superficial surgical site infection (29.4%). In the nonpandemic group, the most common complication is also pneumonia (24%) and superficial surgical site infection (12%) (Table 3).
Table 3 -
Postoperative complication of pandemic and nonpandemic patients with perforated peptic ulcer.
| Complication |
Pandemic |
% |
Nonpandemic |
% |
| Intra-abdominal abscess |
1 |
3.5 |
1 |
4 |
| Superficial surgical site infection |
5 |
29.4 |
3 |
12 |
| Pneumonia |
9 |
32.1 |
6 |
24 |
| Sepsis |
6 |
21.4 |
2 |
8 |
| Cardiovascular complication |
2 |
7.1 |
1 |
4 |
| Repair site leak |
2 |
7.1 |
0 |
0 |
Association between pandemic versus nonpandemic group and stress level
The Indonesian version of the PSS-10 Questionnaire validation was done before the study. The analysis resulted in a valid questionnaire with high reliability (α=0.942). Stress level were higher in PPU patients in the pandemic group compared with the nonpandemic group (42.1% vs. 5.6%; PR: 7.58; 95% CI: 1.05–54.69; P=0.006) (Table 4).
Table 4 -
Stress levels of pandemic and nonpandemic patients with perforated peptic ulcer.
| Stress |
Pandemic (n=19), n (%) |
Nonpandemic, (n=18), n (%) |
PR |
95% CI |
P
|
| High |
8 (42.1) |
1 (5.6) |
7.58 |
1.05–54.69 |
0.006
|
| Low-moderate |
11 (57.8) |
17 (94.4) |
|
|
|
Bold is significant value.
Fisher exact test.
CI indicates confidence interval; PR, prevalence ratio.
Discussion
In this study, we found that before the pandemic, PPU were predominantly male. Previous research before the pandemic period has also shown males were more at risk of developing a complicated peptic ulcer, especially in a developing country11,12. During the pandemic, PPU were predominantly female. A study by Fenollar-Cortés et al13 shows females have a higher psychological stress level than men during the beginning pandemic. We suspect this may be attributed to increased psychological stress during the pandemic that more affects females.
H. pylori were only found in 2 subjects in the nonpandemic group and none in the pandemic group. Since the use of H2 blockers, proton pump inhibitors, and eradication of H. pylori, the number of patients with uncomplicated PUD has decreased in recent decades, but the number of complications of PPU has not decreased1,14. Perforation at our center increased when compared with the nonpandemic period. There are 2 possibilities regarding the increase in incidence, the first due to increased risk factors during the pandemic related to severe psychological stress. Secondly, due to the increasing PPU referrals to our center as a tertiary hospital because of the lack of readiness in peripheral hospitals in dealing with the pandemic situation.
In this study, the mortality rate in the pandemic and the nonpandemic group was 28% pandemic 46.4%, higher compared with the previous study15,16. This may be attributed to more comorbidity, higher ASA, higher boey score, and peptic ulcer perforation score during the initial presentation compared to other studies. Higher complications were found in the patient in the pandemic group. This may be attributed to the initial presentation of patients in the pandemic group with a higher level of comorbidity, higher boey score, and higher ASA score.
The Association between PPU and COVID-19 disease is not yet fully understood. Only a few serial studies show patients with COVID-19 presenting with PPU17–19. Gastrointestinal manifestations of COVID-19 are symptoms including nausea, vomiting, and diarrhea20. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade host cells. Theoretically, tissues with greater expression of ACE2 would be a potential target for the SARS-CoV-221. Gastrointestinal tissue is shown to express a high level of ACE2 mRNA22. Two patients from the pandemic group in this study were positive for COVID-19. This may show an association between PPU and COVID-19.
There is a significant trend that the COVID-19 pandemic group has a more severe psychological stress effect on PPU patients compared with the nonpandemic group. The COVID-19 pandemic not only causes respiratory disease syndromes but also has effects on psychological stress9. Psychological stress can increase PPU risk through increased acidity, the effect of activation of the hypothalamic-pituitary-adrenal axis, changes in blood flow, or cytokine-mediated disruption of mucosal defenses23,24.
Limitations in this study are based on obtaining primary data and their possibility of recall bias. PSS-10 questionnaire data is also extracted during the follow up of study that may not be represent perceived stress in the initial presentation of the patient.
Despite the limitation, this research is the first to study COVID-19 related psychological stress as a risk factor for PPU. We believe this research complements the surgical management of PPUs so that comprehensive surgical management is not only physical but involves psychological factors.
Conclusion
This study shows that the COVID-19 pandemic impacts psychological stress, consequently increasing the risk of perforated peptic ulcers and increasing morbidity.
Ethical approval
This study has been approved by the Ethics Committee of Faculty of Medicine Universitas Indonesia-Cipto Mangunkusumo National Hospital KET-436/UN2.F1/ETIK/PPM.00.02.2021. All methods were performed in accordance with the relevant guidelines and regulations.
Sources of funding
None.
Authors contribution
E.R. conceptualize, does formal analysis of the data, provided research data, and has a major contribution in drafting, and writing the manuscript. Y.M. supervise the research, provided the research resource data, and has a major contribution in drafting and writing the manuscript. I.K. supervise the research, provided the research resource data, has a major contribution in writing the manuscript. T.J.M.L. supervise the research, provided the research resource data, and has a major contribution in writing the manuscript.
Conflicts of interest disclosure
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
researchregistry7571.
Guarantor
Eko Ristiyanto.
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