Introduction

Inflammatory bowel disease physiopathology involves various factors including the host immune system and management often requires immunosuppressive therapy posing, consequently, challenges in the context of vaccination. The advent of vaccines against SARS-CoV-2 a major role in the global flight against the pandemic, however questions regarding efficacy in specific patient populations particularly those with underlying immune-mediated conditions such as Crohn's disease are raised.

Aims & Methods

The aim of our study was to assess the humoral response in patients with CD under conventional immunosuppressive or biotherapies and to compare with healthy controls. We conducted a single-center descriptive study involving CD patients who had received at least one dose of the SARS-CoV-2 vaccine between January and June 2022. Additionally, healthy volunteers (HV) who had received at least one vaccine dose were included. To evaluate the humoral response, we assessed quantitative Anti-SARS-CoV-2 antibodies (using IgM and IgG assays) with the VIDAS® method for all participants.

Results

In total, we collected a total of 58 blood samples (28 patients with CD and 30 HV), the median age was 48.39 years ± 12.14. Regarding medical treatment of CD, 12 patients were on biotherapies: Infliximab (n=9), Adalimumab (n=2) and Ustekunimab (n=1). Twenty-one patients had conventional immunosuppressive: azathioprine (n=19), methotrexate (n=1), corticosteroids > 10 mg/d (n=2). The majority of the patients had received at least 2 doses of the vaccine with a median number of doses in both groups was 2 IC95% [1-4]. There was no statistically significant difference regarding the number or the type of the vaccine between the 2 groups. CD patients had a lower mean level of Ig G against SARS-Cov2 antibodies (20.34 IU +/- 15.57) comparing to healthy controls (32.97+/-10.18) with statically significant difference (p= 0.001). Regarding the type of treatment, there was no significant difference of the level of antibodies between conventional immunosuppressive drugs and biotherapies In CD patients.

Conclusion

This study highlights an altered immune response in patients with Crohn's disease, reflected in a reduced humoral response compared to healthy controls. Assessing the serological response to SARS-CoV2 vaccination in this vulnerable population is of paramount importance for optimizing vaccination strategies and protecting the public.

Clinical Case Summary

Introduction: This case describes a rare complication, triggered by SARS-CoV2 infection in a patient with Crohn’s disease (CD) and a long history of gastrointestinal and extraintestinal manifestations but otherwise stable at the infection onset.
Case Presentation: 25-year old male,non smoker, unvaccinated against COVID-19,with fistulizing and stricturing CD diagnosed at age 12 with multiple extraintestinal complications (articular,ocular, thrombotic, malnutrition). Therapeutic history is marked of various failed attempts over the years, ranging from many courses of steroids, anti-TNFalfa drugs, immunosupresives to holistic approaches until the age of 24 when he presented at our clinic and we initiated treatment with ustekinumab with a good response. During his previous visit,he presented with fever and COVID-19 infection. Radiologic image of the lung was normal but a computed tomography scan was performed to rule out a complication of CD. Both clinical and imaging evaluations confirmed a stable condition with colo-cutaneous fistula in partial remission. Four days later he presented with signs of acute abdomen, extremely distressed, hypotensive,tachycardic.
Tests revealed: leukocytosis, rised inflammatory markers, thrombocytopenia, high D-dimer. The scan suggested a perforation and was taken to surgery where the laparotomy confirmed it, at the level of the transverse colon. He suffered a cardiopulmonary arrest during the surgery and died despite resuscitative efforts.
Discussion: SARS-CoV2 virus binds to the human angiotensin-converting enzyme 2 receptors and triggers direct endothelial lesions and activation of prothrombotic factors resulting in a cascade of microvascular injury and ultimately ischemic tissue damage. Ischemia weakens the bowel wall, increasing risk of ulceration, necrosis,and perforation, especially in Crohn’s patients with fragile mucosa.
Conclusion: The case highlights the potential for fatal outcomes and the importance of close observation in CD patients during SARS CoV2 infection.

References

Images with the colo-cutaneous fistula before and after the treatment with ustekinumab
Ragiologic and computed tomography imaging from his previous visit with the first SARS-CoV2 positive test
Radiologic and computed tomography imaging from his last visit when he presented with acute abdomen

Introduction

Patients with inflammatory bowel disease (IBD) frequently use immunosuppressants and immunobiologicals for maintenance treatment. The humoral responsiveness to COVID-19 vaccines in this group of patients using this drugs is still not fully understood, as the need for more vaccine boosters.

Aims & Methods

Our study aims to evaluate the humoral response to different types of vaccines against SARS-Cov-2 in this population, as well as to compare this response with the healthy population. Patients with IBD enrolled at the Policlinic Piquet Carneiro (UERJ) were prospectively followed with serial blood collection between July 2021 and July 2022. Samples were screened to determine antibody titers, and patients were stratified by demographic and clinical characteristics, naturally occurring infection, vaccination schemes, and IBD medications. Anti-spike IgG antibody titers against the SARS-Cov-2 were determined by ELISA before and one month after the two doses of different vaccination schemes in patients with IBD, regularly followed-up at the outpatient unit. The results were compared with those of a healthy control group during the same period.

Results

In the IBD group (46 individuals), mean antibody titers were 430.3 AU/ml pre-vaccination and 8038.4 AU/ml after the two vaccine doses. In comparison, in the control group (92 individuals), mean antibody titers were 90.5 AU/ml pre-vaccination and 7697.5 AU/ml after the two doses. In both groups, there was a significant increase in the titer of antibodies after the two vaccine doses (p<0.001). When comparing antibody titers one month after the 2nd dose, there was no difference between the two groups (p=0.731). On the other hand, in the IBD group, there was a difference between the vaccination schemes, with higher titers in those who received Pfizer, as well as in younger patients (p<0.005) and in those with previous natural COVID-19 infection (p<0.012). Diagnosis of Crohn’s disease or ulcerative colitis, sex, race, smoking status, clinical variables related to disease localization, extension, behavior, clinical activity, and type of medical therapy did not significantly affect the immune response to vaccines.

Conclusion

The use of immunosuppressants and immunobiologicals does not affect the overall humoral response to the COVID-19 vaccination among patients with IBD. Nevertheless, specific vaccine schemes, age, and previous COVID-19 infection significantly affect antibody titers.

References

1. Ministério da Saúde. Painel Coronavírus. Accessed 01/2023. https://covid.saude.gov.br.
2. Tsang HF, Chan LWC, Cho WCS et al. An update on COVID-19 pandemic: the epidemiology, pathogenesis, prevention and treatment strategies. Expert Rev Anti Infect Ther 2021;19(7):877-888.https://doi.org/10.1080/14787210.2021.1863146.
3. Rahman S, Montero MTV, Rowe K et al. Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence. Expert Rev Clin Pharmacol. 2021;14(5):601-621. https://doi.org/10.1080/17512433.2021.1902303.
4. Chenchula S, Karunakaran P, Sharma S et al. Current evidence on efficacy of COVID-19 booster dose vaccination against the Omicron variant: A systematic review. J Med Virol. 2022;94(7):2969-2976. https://doi.org/10.1002/jmv.27697.
5. Hunt RH, East JE, Lanas A et al. COVID-19 and Gastrointestinal Disease: Implications for the Gastroenterologist. Dig Dis 2021;39(2):119-139. https://doi.org/10.1159/000512152.
6. Neurath MF. COVID-19 and immunomodulation in IBD. Gut 2020;69(7):1335-1342. https://doi.org/10.1136/gutjnl-2020-321269.
7. Quaresma AB, Kaplan GG, Kotze PG, The globalization of inflammatory bowel disease: the incidence and prevalence of inflammatory bowel disease in Brazil. Curr Opin Gastroenterol 2019;35(4):259-264. https://doi.org/10.1097/MOG.0000000000000534.
8. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-78. https://doi.org/10.1056/NEJMra0804647.
9. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019;68(Suppl 3):s1-s106. https://doi.org/10.1136/gutjnl-2019-318484.

Introduction

Patients with chronic liver disease (CLD), particularly those with cirrhosis, exhibit increased risk of developing severe illness when infected with SARS-CoV-2, primarily due to their underlying immune dysfunction and coexisting conditions. As such, vaccination plays a crucial role in safeguarding this population. Here, to fully assess the efficacy COVID-19 vaccination in patients with CLD, we thoroughly characterized the overall and SARS-CoV-2-specific cellular immune response of these patients.

Aims & Methods

Blood samples were systematically collected from patients with CLD (n=22) and healthy volunteers (n=12) at various intervals spanning one year after the initial administration of the BNT162b2 vaccine. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with a panel of 22 surface markers and a viability dye, allowing for the detection of 28 immune cell subsets. In parallel, we analysed the presence of cells specific against SARS-CoV-2 peptide tetramers. Samples were analysed by flow cytometry with acquisition on a four-laser Cytek Aurora® spectral analyzer.

Results

Prior to vaccination, patients with CLD patients were already displaying fewer T cells and an increased number of B cells, comparing to healthy subjects. Within the T cell subsets, differences were significant for CD4+ T cells and the Naïve and Central Memory CD4+ subsets. At both 6-months and 1- year after vaccination, variances between groups were no longer observed. Rather, at 1-year postvaccination, T, CD8+ and CD4+ cells, as well as monocytes were found increased in both groups, suggesting that the vaccination is critical for inducing a strong cellular immune response. Analysis of SARS-CoV-2 epitope-specific cells demonstrated significantly lower frequencies of monocytes, CD4+ and CD8+ T cells, B cells, NK T cells, and NK cells including the regulatory and cytotoxic subsets recognizing the peptide tetramers in CLD patients, in comparison with healthy controls.

Conclusion

Together, these results indicate that CLD patients are capable of mounting a satisfactory immune cellular response following COVID-19 vaccination. However, the SARS-CoV-2-specific response is significantly weaker in CLD patients comparing with healthy individuals. These results reinforce the need for prioritization and/or booster vaccination for CLD patients. (Supported by 2022.08837.PTDC, FCT).

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with a variety of complications, including liver damage. However, its impact on chronic liver disease (CLD) and its association with cholestasis remains unclear. This retrospective cohort study aimed to investigate the incidence of cholestasis and its impact in patients with CLD after SARS-CoV-2 infection.

Aims & Methods

We retrospectively analyzed medical records of 428 patients followed in a tertiary center Liver Unit who were diagnosed with SARS-CoV-2 infection between March 2020 and September 2022. Patients were stratified as having no CLD, non-advanced CLD (NACLD) or advanced CLD (ACLD). Liver chemistries before and several times after SARS-CoV-2 infection were registered. The incidence of cholestasis and its associated risk factors were analyzed using multivariate logistic regression.

Results

A total of 428 patients were included, 357 (66.1% males) with CLD (NACLD in 198 and ACLD in 159 patients). Alcohol-associated liver disease (ALD) was the main etiology (30.8%), closely followed by metabolic-associated fatty liver disease (MAFLD) (24.6%). SARS-CoV-2 infection-related cholestasis was higher in patients with ACLD than in patients with NACLD (39.6% vs. 5.6%, p<0.001). No patient without CLD developed cholestasis. The incidence of decompensation episodes, such as ascites, hepatic encephalopathy and variceal bleeding was significantly higher in patients with cholestasis (32.4%, 32.4% and 17.6% vs. 0.3%, 0.3% and 0%, respectively; p<0.001). Additionally, patients with cholestasis had a longer hospital stay (median/IQR 17/12 vs. 10.5/9 days, p=0.483) and a significantly higher mortality rate (23.0% vs. 0.6%, p<0.001) than those without cholestasis. Patients with ACLD (vs. NACLD) presented higher global mortality (10.7% vs. 0%, p<0.001) and liver-related mortality (10.1% vs. 0%, p<0.001). Multivariate logistic regression analysis showed that ACLD and decompensated disease were independent risk factors for cholestasis in patients with SARS-CoV-2 infection (p=0.031 and p<0.001, respectively).

Conclusion

Our study suggests that SARS-CoV-2 infection is a risk factor for cholestasis in patients with CLD, especially in those with ACLD or decompensated disease. Clinicians should be aware of the potential for cholestasis in these patients with underlying liver disease and closely monitor liver function tests. Further studies are needed to investigate the underlying mechanisms of SARS-CoV-2-induced cholestasis and develop appropriate management strategies for these patients.

Clinical Case Summary

SARS-COV2 infection has accumulated more than 670 million cases since its onset in 2019. Its clinical spectrum varies from asymptomatic patients to bilateral pneumonia with a mortality rate of 1%. Digestive symptoms include nausea, abdominal pain and diarrhea. Multiple complications as hepatitis, pancreatitis, cholecystitis, mesenteric ischemia or venous thrombosis have also been described.
We present the case of a 60-year-old woman who came to ER for abdominal pain. A CT showed acute cholecystitis with a 30mm liver abscess and choledocholithiasis. It was treated with empirical Piperacillin-Tazobactam, thromboprophylaxis and drainage by ERCP. During admission the patient presented bilateral SARS-COV2 pneumonia requiring Dexamethasone and Remdesivir. Due to the reappearance of abdominal discomfort, an US was performed showing a new left portal thrombosis. Given these findings, a coagulation study was performed, with no genetic or cytological alterations. Finally it was decided to maintain antibiotic for 6 weeks and anticoagulation, performing outpatient US control, with deferred surgical treatment.
The portal thrombosis is a complication mostly related to chronic liver diseases and hepatic tumors, being much rarer the septic portal thrombophlebitis associated with abdominal infections or related to proliferative neoplasms. On the other hand, SARS-COV2 infection triggers an inflammatory reaction after binding to ACE-II receptor that leads to a generalized prothrombotic environment. In relation to this process, PTE, DVT and in multiple other locations has been described. One of the the most infrequent locations is abdominal, with very few cases described in the literature.
The scarce clinical repercussion of portal thrombosis and the serious complications derived from it, added to the high prevalence of SARS-COV2, means that we should early rule out this process in patients with abdominal infections with regular evolution and active or recent SARS-COV2 infection.

Introduction

SARS-CoV-2 exhibits an extra-pulmonary tropism, with up to 70% of COVID-19 patients experiencing at least one gastrointestinal (GI) symptom. Persistent viral presence has been observed in intestinal biopsies months after the virus has been cleared from the respiratory tract, which has been implicated in the development of long COVID symptoms. Despite these observations, the dynamics of SARS-CoV-2 infection within the intestine, as well as its potential to act as a viral reservoir and source of ongoing pathogenesis, remain largely unknown.

Aims & Methods

We recently established a robust mouse model to study the dynamics of intestinal SARS-CoV-2 infection by exposing the distal ileum of mice through ventral laparotomy and administering the virus directly into the lumen.

Results

In wild-type (WT) C57Bl/6 mice, after perfusion, viral RNA was detected throughout the GI tract at 7 days post infection (dpi), not only at the site of initial infection, but also in other regions such as the esophagus, stomach, duodenum, jejunum, colon, and rectum. Moreover, viral RNA was also found in extra-intestinal sites, including the salivary gland, liver, and brain. In Stat1^-/- mice with impaired type I, II, and III interferon signaling, the levels of viral RNA as well as nucleocapsid antigens in the GI tract were 10 to 100 times higher than those in WT mice. Virus also successfully disseminated to systemic organs such as the heart, lung, kidney, brain, and spleen. Viral shedding in feces was observed from 3 to 7 dpi in Stat1^-/- mice but not WT mice. Notably, rapid secretory diarrhea was observed in these mice, marking the first instance of diarrhea induced by SARS-CoV-2 infection in a mouse model. Additional studies are ongoing to further characterize these findings, including the assessment of the timing of viral replication, titration of infectious viruses, detailed histological analysis, and immunological profiling.

Conclusion

These results emphasize the usefulness of this mouse model in exploring the mechanisms underlying the impact of SARS-CoV-2 on the intestines locally and systemically. The study also underscores the critical role of interferon signaling in restricting intra-intestinal replication and preventing the virus from spreading to other organs. This has important clinical implications, particularly for individuals taking JAK inhibitor medications, which could affect the interferon response and potentially increase susceptibility to more severe outcomes from SARS-CoV-2 infection.

Disclosure

M.S.D. is a consultant for Inbios, Vir Biotechnology, Ocugen, Topspin Therapeutics, GlaxoSmithKline, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, and Moderna.