Cytomegalovirus Infection in Adult Patients with Inflammatory Bowel Disease: A Literature Review.

Human cytomegalovirus (HCMV) is classified within the Herpesvirales order and is prevalent in 50%‒80% of the general population. Most carriers experience this infection without noticeable clinical symptoms. HCMV causes a lifelong latent infection that can be reactivated due to immune disorders and inflammation. The reactivation of HCMV becomes particularly significant when it coincides with inflammatory bowel disease (IBD). While cytomegalovirus (CMV) colitis in IBD patients was identified years ago, the role of CMV in triggering flare-ups, acute severe colitis, treatment resistance, and other outcomes in IBD patients experiencing CMV reactivation remains a subject of ongoing debate. In this review, we aim to address an updated insight into aspects related to the CMV colitis in IBD patients including epidemiology, risk factors, clinical features, diagnostic tests, histology, place of immunosuppressants and indications for antiviral treatment. We suggest for personalized and thorough assessment based on the disease phase and colitis severity when prescribing drugs to these patients. Furthermore, we emphasize the importance of regular patient follow-up to monitor drug side effects, ensuring treatment success, and minimizing the risk of colectomy.

Adequate antiviral treatment lowers overall complications of cytomegalovirus colitis among inpatients with inflammatory bowel diseases.

BACKGROUND: Cytomegalovirus (CMV) colitis significantly complicates the course of inflammatory bowel disease (IBD), frequently leading to severe flare-ups and poor outcomes. The role of antiviral therapy in hospitalized IBD patients with CMV colitis is currently under debate. This retrospective analysis seeks to clarify the influence of antiviral treatment on these patients. METHODS: We retrospectively reviewed IBD patients diagnosed with CMV colitis via immunohistochemistry staining from colonic biopsies at a major tertiary center from January 2000 to May 2021. The study focused on patient demographics, clinical features, risk factors, prognostic indicators, and antiviral treatment outcomes. RESULTS: Among 118 inpatients, 42 had CMV colitis. Risk factors included hypoalbuminemia and antibiotic use. IBD patients with CMV colitis receiving < 14 days of antiviral therapy had higher complication (72% vs. 43%, p = 0.028) and surgery rates (56% vs. 26%, p = 0.017) compared to those without CMV. Adequate antiviral therapy (≥ 14 days) significantly reduced complications in the CMV group (29% vs. 72%, p = 0.006), especially in Crohn's disease (20% vs. 100%, p = 0.015). Independent predictors of IBD-related complications were CMV colitis (Odds Ratio [OR] 3.532, 90% Confidence Interval [CI] 1.012-12.331, p = 0.048), biological treatment failure (OR 4.953, 95% CI 1.91-12.842, p = 0.001), and adequate antiviral therapy (OR 0.108, 95% CI 0.023-0.512, p = 0.005). CONCLUSION: CMV colitis and a history of biological treatment failure increase complication risks in IBD patients. Adequate antiviral therapy significantly mitigates these risks, highlighting its importance in managing IBD patients with CMV colitis.

The Effects of Endosomal Toll-like Receptor Inhibitors in an EBV DNA-Exacerbated Inflammatory Bowel Disease Mouse Model.

Epstein-Barr virus (EBV), a Herpesviridae family member, is associated with an increased risk of autoimmune disease development in the host. We previously demonstrated that EBV DNA elevates levels of the pro-inflammatory cytokine IL-17A and that inhibiting Toll-like receptor (TLR) 3, 7, or 9 reduces its levels. Moreover, this DNA exacerbated colitis in a mouse model of inflammatory bowel disease (IBD). In the study at hand, we examined whether inhibition of TLR3, 7, or 9 alleviates this exacerbation. Mice were fed 1.5% dextran sulfate sodium (DSS) water and administered EBV DNA. Then, they were treated with a TLR3, 7, or 9 inhibitor or left untreated. We also assessed the additive impact of combined inhibition of all three receptors. Mice that received DSS, EBV DNA, and each inhibitor alone, or a combination of inhibitors, showed significant improvement. They also had a decrease in the numbers of the pathogenic colonic IL-17A+IFN-γ+ foci. Inhibition of all three endosomal TLR receptors offered no additive benefit over administering a single inhibitor. Therefore, inhibition of endosomal TLRs reduces EBV DNA exacerbation of mouse colitis, offering a potential approach for managing IBD patients infected with EBV.

Activation of Nod2 signaling upon norovirus infection enhances antiviral immunity and susceptibility to colitis.

Over 90% of epidemic non-bacterial gastroenteritis are caused by human noroviruses (NoVs), which persist in a substantial subset of people allowing their spread worldwide. This has led to a significant number of endemic cases and up to 70,000 children deaths in developing countries. NoVs are primarily transmitted through the fecal-oral route. To date, studies have focused on the influence of the gut microbiota on enteric viral clearance by mucosal immunity. In this study, the use of mouse norovirus S99 (MNoV_S99) and CR6 (MNoV_CR6), two persistent strains, allowed us to provide evidence that the norovirus-induced exacerbation of colitis severity relied on bacterial sensing by nucleotide-binding oligomerization domain 2 (Nod2). Consequently, Nod2-deficient mice showed reduced levels of gravity of Dextran sodium sulfate (DSS)-induced colitis with both viral strains. And MNoV_CR6 viremia was heightened in Nod2-/- mice in comparison with animals hypomorphic for Atg16l1, which are prone to aggravated inflammation under DSS. Accordingly, the infection of macrophages derived from WT mice promoted the phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1) and NOD2's expression levels. Higher secretion of Tumor Necrosis Factor alpha (TNFα) following NOD2 activation and better viral clearance were measured in these cells. By contrast, reduced levels of pSTAT1 and blunted downstream secretion of TNFα were found in Nod2-deficient macrophages infected by MNoV_S99. Hence, our results uncover a previously unidentified virus-host-bacterial interplay that may represent a novel therapeutic target for treating noroviral origin gastroenteritis that may be linked with susceptibility to several common illnesses such as Crohn's disease.

Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10-/- mouse model of inflammatory bowel disease.

BACKGROUND: Following viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain-specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-10-/-) model derived from the SvEv mouse, had evidence of increased Mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wild type. MMTV is endemic in several mouse strains as an endogenously encoded Betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut-associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10-/- model. RESULTS: Viral preparations extracted from IL-10-/- weanling stomachs revealed augmented MMTV load compared to the SvEv wild type. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4-97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10-/- spleen encoded the MTV-9 superantigen that preferentially activates T-cell receptor Vß-12 subsets, which were expanded in the IL-10-/- versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10-/- splenocytes with amplified interferon-γ production versus the SvEv wild type. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12-week treatment versus placebo. The combination antiretroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL-10-/- mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis. CONCLUSIONS: This study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain-specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis. Video Abstract.

Cytomegalovirus Colitis in Immunocompetent and Immunocompromised Children: A 2-Center Study.

BACKGROUND: Data about cytomegalovirus (CMV) colitis in children are scarce. We aimed to describe the characteristics of childhood CMV colitis in terms of risk factors, clinical symptoms, diagnosis, therapeutic approaches, and outcomes. METHODS: Inflammatory bowel disease (IBD) and non-IBD patients with CMV colitis diagnosed by histology and tissue CMV PCR at 2 tertiary centers between January 2017 and November 2019 were studied. Clinical and laboratory data were retrieved from medical records. Underlying conditions, immune status, response to therapy and outcomes were described and followed up to 6 months after diagnosis. RESULTS: A total of 16 children (8 non-IBD, 7 ulcerative colitis and 1 Crohn's disease) with CMV colitis were included. All patients had persistent diarrhea (bloody in 13 cases). There was a significant age difference between IBD and non-IBD children (P < 0.05). The final diagnosis in 1 patient was immunodeficiency with a mutation in JAK1 gene. Three children were categorized as apparently immunocompromised and 4 children as apparently immunocompetent. Ulcer was not visible in 2 children from the non-IBD group. The mean fecal calprotectin level of IBD children was significantly higher than that of non-IBD children (376.12 ± 231.21 µg/g vs. 160.96 ± 69.94 µg/g, P < 0.05). After follow-up, 1 patient died because of another reason. Ganciclovir was used in 14 of 16 children for 3 weeks and the treatment was continued with valganciclovir in selected 6 children. CONCLUSIONS: CMV colitis is a rare but overlooked cause of prolonged diarrhea in immunocompetent and immunocompromised children. CMV colitis might present without any ulcer formation at colonoscopy in infants.

Cytomegalovirus in pediatric inflammatory bowel disease patients with acute severe colitis.

BACKGROUND: The prevalence and significance of cytomegalovirus (CMV) colitis in pediatric acute severe colitis is unknown. The aim of this study was to determine the prevalence of CMV in colonic mucosa of children with acute severe refractory colitis and compare the clinical characteristics and outcomes of CMV positive and negative patients. METHODS: In a case-control study, colonic biopsy specimens from children with severe refractory colitis were tested for CMV, and matched with non-refractory IBD controls. We characterized CMV positive patients by assessing laboratory values, concurrent medications, and need for surgery as compared with CMV negative refractory colitis patients. RESULTS: Colonic biopsies from 96 patients were evaluated for CMV; 48 with severe refractory colitis, and 48 non-refractory controls. There was an increased prevalence of CMV in severe refractory colitis [7/48 (14.6%), P < 0.0001]; all were previously CMV negative. Viral DNA burden on immunohistochemistry was not predictive of response to antiviral therapy or need for surgery at 12 months. Lymphopenia was seen in all CMV positive patients, but this did not demonstrate statistical significance (P = 0.09). We did not see an association between azathioprine or infliximab use and the need for surgery at 12 months. CONCLUSIONS: There is an increased prevalence of CMV in colonic biopsies of pediatric patients with severe refractory colitis. Viral burden does not predict clinical outcomes or subsequent need for colectomy.

Epidemiology and Natural History of Elderly-onset Inflammatory Bowel Disease: Results From a Territory-wide Hong Kong IBD Registry.

BACKGROUND: Elderly-onset inflammatory bowel disease [IBD], defined as age ≥60 at diagnosis, is increasing worldwide. We aimed to compare clinical characteristics and natural history of elderly-onset IBD patients with those of adult-onset IBD patients. METHODS: Patients with a confirmed diagnosis of IBD from 1981 to 2016 were identified from a territory-wide Hong Kong IBD registry involving 13 hospitals. Demographics, comorbidities, clinical features, and outcomes of elderly-onset IBD patients were compared with those of adult-onset IBD patients. RESULTS: A total of 2413 patients were identified, of whom 270 [11.2%] had elderly-onset IBD. Median follow-up duration was 111 months (interquartile range [IQR]: 68-165 months). Ratio of ulcerative colitis [UC]: Crohn's disease [CD] was higher in elderly-onset IBD than in adult-onset IBD patients [3.82:1 vs 1.39:1; p <0.001]. Elderly-onset CD had less perianal involvement [5.4% vs 25.4%; p <0.001] than adult-onset CD. Elderly-onset IBD patients had significantly lower cumulative use of immunomodulators [p = 0.001] and biologics [p = 0.04]. Elderly-onset IBD was associated with higher risks of: cytomegalovirus colitis (odds ratio [OR]: 3.07; 95% confidence interval [CI] 1.92-4.89; p <0.001); herpes zoster [OR: 2.42; 95% CI 1.22-4.80; p = 0.12]; and all cancer development [hazard ratio: 2.97; 95% CI 1.84-4.79; p <0.001]. They also had increased number of overall hospitalisations [OR: 1.14; 95% CI 1.09-1.20; p <0.001], infections-related hospitalisation [OR: 1.87; 95% CI 1.47-2.38; p <0.001], and IBD-related hospitalisation [OR: 1.09; 95% CI 1.04- 1.15; p = 0.001] compared with adult-onset IBD patients. CONCLUSIONS: Elderly-onset IBD was associated with increased risk of infections and cancer development, and increased infection- and IBD-related hospitalisations. Specific therapeutic strategies to target this special population are needed.

A network of immune and microbial modifications underlies viral persistence in the gastrointestinal tract.

Many pathogens subvert intestinal immunity to persist within the gastrointestinal tract (GIT); yet, the underlying mechanisms that enable sanctuary specifically in this reservoir are unclear. Using mass cytometry and network analysis, we demonstrate that chronic LCMV infection of the GIT leads to dysregulated microbial composition, a cascade of metabolic alterations, increased susceptibility to GI disease, and a system-wide recalibration of immune composition that defines viral persistence. Chronic infection led to outgrowth of activated Tbet-expressing T reg cell populations unique to the GIT and the rapid erosion of pathogen-specific CD8 tissue-resident memory T cells. Mechanistically, T reg cells and coinhibitory receptors maintained long-term viral sanctuary within the GIT, and their targeting reactivated T cells and eliminated this viral reservoir. Thus, our data provide a high-dimensional definition of the mechanisms of immune regulation that chronic viruses implement to exploit the unique microenvironment of the GIT and identify T reg cells as key modulators of viral persistence in the intestinal tract.

Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection.

Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. Type I IFN signaling caused tight junction dysregulation in IECs, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both type I IFN receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrates that infection with a virus that persistently replicates in the intestinal mucosa increases epithelial barrier permeability and reveals type I IFNs and CD8 T cells as causative factors of intestinal leakage during chronic infections.

Respuesta de autores a: A propósito de la carta científica «Sospecha de abdomen agudo como manifestación extrapulmonar de infección COVID-19» / Authors response to: «About the scientific letter: Suspected Acute Abdomen as an Extrapulmonary Manifestation of Covid-19 Infection»

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Colitis inducida por dasatinib: descubriendo los efectos secundarios de la inmunoterapia / No disponible

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COVID-19, coronavirus, SARS-CoV-2 and the small bowel

Although SARS-CoV-2 may primarily enter the cells of the lungs, the small bowel may also be an important entry or interaction site, as the enterocytes are rich in angiotensin converting enzyme (ACE)-2 receptors. The initial gastrointestinal symptoms that appear early during the course of COVID-19 support this hypothesis. Furthermore, SARSCoV virions are preferentially released apically and not at the basement of the airway cells. Thus, in the setting of a productive infection of conducting airway epithelia, the apically released SARS-CoV may be removed by mucociliary clearance and gain access to the GI tract via a luminal exposure. In addition, post-mortem studies of mice infected by SARS-CoV have demonstrated diffuse damage to the GI tract, with the small bowel showing signs of enterocyte desquamation, edema, small vessel dilation and lymphocyte infiltration, as well as mesenteric nodes with severe hemorrhage and necrosis. Finally, the small bowel is rich in furin, a serine protease which can separate the S-spike of the coronavirus into two “pinchers” (S1 and 2). The separation of the S-spike into S1 and S2 is essential for the attachment of the virion to both the ACE receptor and the cell membrane. In this special review, we describe the interaction of SARS-CoV-2 with the cell and enterocyte and its potential clinical implications

Sospecha de abdomen agudo como manifestación extrapulmonar de infección por Covid-19 / Suspected acute abdomen as an extrapulmonary manifestation of Covid-19 infection

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Colitis por citomegalovirus en paciente anciano inmunocompetente / Cytomegalovirus colitis in an immunocompetent elderly patient

La afectación del tracto gastrointestinal por citomegalovirus es una entidad que se suele dar en pacientes inmunocomprometidos, no obstante es más raro verlo en pacientes inmunocompetentes. La edad media recogida en una serie de casos es de 68 años y los síntomas acompañantes son diarrea (76%), dolor abdominal (52%) y hematoquecia o melena (27%). A continuación describimos el caso de un paciente de 85 años sin ningún estado inmunocomprometido que se identificase que desarrolló una colitis por CMV

Gastrointestinal tract involvement due to cytomegalovirus infection is a condition that usually occurs in immunocompromised patients, but is uncommon in immunocompetent patients. In a review of 33 cases, the median age was 68 years, and the accompanying symptoms were diarrhoea (76%), abdominal pain (52%), and haematochezia, or melena (27%). The case is presented of ctyomegalovirus colitis in an 85 year-old man with no previously identified immunocompromised states