Patterns of abdominal pain during COVID-19: an observational study

In the present study, the prevalence of patients with abdominal pain during COVID-19 was higher than in the reported literature (23.7 versus 14.5%).8. This may be explained by the fact that abdominal pain has been largely captured manually from medical records since the onset of COVID-19 symptoms and also throughout the hospital course. This strategy was adopted because the temporal evolution of this symptom remains uncertain. Unlike other studies, history and physical examination were considered. Although this strategy may overestimate abdominal pain, special care was taken to eliminate patients with abdominal pain of other obvious etiologies (eg, coprostasis, gallbladder disease, etc.) and adjusted our analysis for abdominal surgery. As a quality control of the registration process, we calculated that the median time from pain symptoms to diagnosis of SARS-CoV2 infection was 0 (interquartile range 7) days, indicating that a majority of abdominal pain was captured early during SARS-CoV2 infection.

In this work, we unveiled the patterns of abdominal pain related to COVID-19 that had never been realized before, to our knowledge. Patients presented with the highest frequency of spontaneous or induced pain in the upper abdomen with a predominance of the epigastric and upper right regions. However, 17.1% of patients had a history of pain in the lower right region and 21.7% abdominal tenderness in the lower left region. We hypothesized that these two features could be hallmarks of a manifestation of COVID-19 that may involve the small intestine and/or colon instead of the liver. Unfortunately, as we did not collect transit data, we do not know if this pattern of abdominal pain was preferentially associated with diarrhoea, nausea or vomiting.

Using these pain patterns in our analysis, we then demonstrated an association between Murphy’s sign and right upper region tenderness and severe COVID-19 outcomes. The adjustment was based on putative confounders but did not dramatically change the strength or significance of the association. This primary analysis was limited by the ability to adjust for BMI and alcohol consumption due to missing data and possible other unknown confounders. Therefore, we performed a secondary analysis as a sensitivity analysis of adding BMI and alcohol consumption into the model (Table S1). In this secondary analysis, the previously mentioned associations did not change. However, epigastric point sensitivity, which showed an inverse association with the composite outcome and was no longer statistically significant after adjustment in the primary analysis, was again statistically significant in our secondary analysis. The p-value for this association in this secondary analysis was close to 0.05 and this result might be a Type I error. Additionally, pain in the bile duct or liver can be felt in both the right hypochondria and in the epigastric region, but tenderness is more precisely localized in the upper right region after percussion, palpation or Murphy’s sign test. Indeed, localized epigastric tenderness in COVID-19 could be related to gastritis and not liver or bile duct injury. Of note, a history of abdominal pain or tenderness in other areas of the abdomen and diffuse pain were not associated with serious COVID-19-related findings.

The association between 5× the higher level of transaminases (250 IU) and abdominal pain was first studied using a double-entry table at different time points (transaminases at baseline, maximum value during first 7 days or maximum value during the first 30 days after admission) (data not shown). This analysis showed an association with the maximum value of transaminases only during the first 30 days. As many factors can increase LFT during hospitalization (for which we could not adjust), we decided to consider only the baseline value of transaminases and perform logistic regression to adjust for confounding factors. . Thus, we demonstrated different associations with AST and ALT and history of pain in the upper region, but not with any pattern of abdominal point tenderness with the exception of Murphy’s sign.

Indeed, SARS-CoV2 has been shown to induce both alternating hepatic blood flow, as a systemic response to infection, with sinusoidal thrombi and direct virus replication in liver tissue.6. These two features could indicate two distinct pathophysiological processes (a systemic reaction with activation of coagulation and direct damage to the liver). Angiotensin-converting enzyme 2 (ACE2) receptors, which allow SARS-CoV2 entry into cells, are predominant in liver tissue, particularly on bile duct cells9 but the virus can replicate in both hepatocytes10.11 and bile duct cells12. This could partly explain the elevation of LFT observed during COVID-19 when the cytolytic pattern of lesions is more common than cholestasis13. LFT elevation is multifactorial in COVID-196 and in the present study, we remain focused on the baseline LFT using a strict threshold of 5 × the upper level of transaminases (the hallmark of viral hepatitis14) to reduce the likelihood of considering drug cytolysis. On the other hand, we excluded patients with mild transaminase elevation induced by COVID-19, which has been frequently reported.1. However, while some authors suggest a distinction between COVID-19-induced hepatitis and mild cytolysis, our analysis did not demonstrate a multimodal but unimodal and left-skewed distribution of transaminases, an observation previously reported.15.

While the pathophysiology of SARS-CoV2 infection on liver tissue has been studied, little is known about the effects of the virus on the gut and its role in abdominal pain. 2. The virus could replicate directly in epithelial and glandular cells at various locations along the intestinal tract16.17 and it is speculated that the gastrointestinal symptoms of COVID-19, including abdominal pain, are induced by an intestinal viral infection1. However, abdominal pain during COVID-19 could also be induced by hepatitis or bile duct inflammation and we have previously detected the presence of SARS-CoV2 RNA in gallbladder tissue from a patient with COVID-19. alithiasic cholecystitis.5. In the present study, the majority of patients described pain in the upper abdominal regions, but a significant proportion also had a localized pain pattern in the lower abdomen. This could indicate that abdominal pain during COVID-19 is either induced by liver injury or an intestinal infection.

In order to assess the hypothesis that COVID-19 induces two different manifestations on the gastrointestinal system with opposite results, we finally compared the location of abdominal pain and the presence of dyspnea in a post hoc analysis. Using paired analysis, we showed that dyspnea was greater in patients with upper abdominal pain. According to our results, we built the hypothesis that two forms of COVID-19 may exist and could be characterized by different gastrointestinal manifestations and different outcomes (Fig. 3). The first form or liver-COVID-19 could be identified by elevated transaminases, abdominal pain localized preferentially in the upper right region, dyspnea and a higher probability of being admitted to the IMCU, intensive care or dying during hospitalization. The second form or gut-COVID-19 could be characterized by pain in the stomach and in the lower hemi-abdomen and could be associated with less severe outcomes regarding MICU, ICU admission or death and less dyspnea.

picture 3

Proposed hypothesis of two forms of COVID-19 gastrointestinal symptoms: liver and intestine COVID-19. Hepatic COVID-19 may be associated with upper abdominal pain, dyspnea and more severe clinical outcomes, while intestinal COVID-19 with lower abdominal pain and less severe outcomes .

This work was limited by its retrospective design and the number of missing data for some variables. Data was lacking due to a lack of accuracy in medical records, but also due to limitations in research methods. These missing data had considerable consequences and we could not analyze other LFTs such as alkaline phosphatase, bilirubin and γ-glutamyltransferase. Moreover, gastrointestinal symptoms are not limited to abdominal pain. Anorexia, diarrhea, nausea and/or vomiting, and gastrointestinal bleeding have been commonly identified during COVID-191. We deliberately choose not to search for them in order to reduce the number of variables we were looking for manually. Indeed, as the study focused on abdominal pain and liver damage, we did not expect when preparing the protocol that other gastrointestinal symptoms would be of interest. Gut-COVID-19 could be associated with other gastrointestinal symptoms. Collecting observational studies in a meta-analysis, Mao et al. demonstrated that only patients with abdominal pain had severe COVID-19 while other gastrointestinal symptoms such as diarrhea, vomiting, or nausea were not associated with severe outcomes3. Additionally, frequent use of antibiotics and antivirals (hydroxychloroquine, ritonavir) could be a cause of gastrointestinal symptoms and a potential co-founding factor for this study as a patient with severe COVID-19 could have been preferentially selected. for experimental therapies.18. However, experimental treatments were introduced in our hospital, only in patients with severe COVID-19, most of whom were already intubated in the ICU, making reporting abdominal pain unlikely. Additionally, other causes of abdominal pain could have incorrectly suggested an association with COVID-19 such as diaphragmatic irritation or enteral nutrition, but we judged their effect to be limited. Considering that pain in the upper left region was rarely reported both during history and physical examination (respectively 5.5% and 6.6% cf. Fig. 2), it is unlikely that COVID-19 pneumonia induced extra-digestive abdominal pain exclusively on the right side, sparing the left side. The effect of enteral nutrition was also negligible, as abdominal pain appeared early in the disease course (as noted previously) and enteral nutrition was primarily limited to intensive care patients on invasive mechanical ventilation unable to accurately report pain. Thus, this project merits further studies with a prospective design to verify our results and hypotheses.

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