Cytomegalovirus infection associated with inflammatory bowel disease

doi:10.1016/S2468-1253(16)30159-5

The Lancet Gastroenterology & Hepatology

Volume 2, Issue 5, May 2017, Pages 369-376

https://doi.org/10.1016/S2468-1253(16)30159-5 Get rights and content

Summary

Refractory colitis in patients with inflammatory bowel disease is a complicated clinical disorder that might, in some patients, even necessitate surgery. Hence the diagnosis of additional complications is of utmost importance. Colitis mediated by cytomegalovirus is one such complication. The high seroprevalence and latent nature of cytomegalovirus, with the possibility of viral replication without mediating disease, poses a real challenge for the diagnosis of cytomegalovirus-mediated colitis. The challenge in daily clinical practice is to distinguish cytomegalovirus replication from cytomegalovirus-mediated colitis in patients with inflammatory bowel disease who have refractory colitis. This Review discusses the scientific literature and provides a diagnostic and therapeutic algorithm for clinical practice.

Introduction

Although the repertoire of medical treatment options is continuously increasing, refractory colitis remains a clinical challenge. To avoid surgery, any additional complications, including cytomegalovirus infection, must be excluded. In theory, the diagnosis of cytomegalovirus-mediated colitis should be easy because various methods exist for detection of viral DNA with high sensitivity and specificity. However, the detection of virus replication alone is not sufficient for diagnosis. From a clinical perspective, it is highly relevant to distinguish between simple viral replication and virus-mediated disease.

Colitis can be caused by inflammatory bowel disease, cytomegalovirus infection, or a combination of both. Therefore, unlike other patients with compromised immune systems, the diagnosis of cytomegalovirus-mediated colitis in patients with inflammatory bowel disease is particularly challenging because the intestine is the organ of interest in both cases. In this Review, I propose a pragmatic approach to the diagnosis and treatment of cytomegalovirus-mediated colitis in clinical practice.

Section snippets

Epidemiology

Cytomegalovirus is a DNA virus that belongs to the Herpesviridae family. Human beings are the only reservoir, and salivary and sexual transmission are the dominant paths of cytomegalovirus infection, although congenital infection and infection via organ transplants are also known to occur.1, 2, 3, 4 As with any other herpes virus, cytomegalovirus persists after primary infection. Remarkably, the sites of latency remain largely undefined, but probably include peripheral blood mononuclear cells,

Diagnostic tests and clinical features

A number of diagnostic tests are used in the clinic routinely (table 2),14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 yet it is important to remember that cytomegalovirus can exist in a latent form and that viral reactivation can occur after primary infection. In view of the high prevalence of cytomegalovirus in the general population, serology tests are of limited value. Serology is useful for the identification of a primary cytomegalovirus infection when cytomegalovirus-specific IgG

Cytomegalovirus-mediated colitis or just cytomegalovirus replication: implications for clinical practice

Whereas the diagnosis of a primary cytomegalovirus infection and cytomegalovirus carrier is clearly important, it is crucial to distinguish between a simple cytomegalovirus replication, which is observed frequently, and real cytomegalovirus-mediated colitis, which should be treated with antiviral therapy. Whether or not cytomegalovirus replication in patients with colitis warrants antiviral treatment at all remains to be addressed in future studies.45, 46

Data from numerous studies suggest that

When to start antiviral therapy

A problem with most studies is that cytomegalovirus replication alone is not distinguished from cytomegalovirus-mediated colitis. My colleagues and I have addressed this problem with the development of a local algorithm.⁵⁶ 109 patients who had been admitted to hospital between 2006 and 2009 with moderate-to-severe or steroid-refractory inflammatory bowel disease were tested for cytomegalovirus infection. In patients with systemic or mucosal viral infection, immunosuppressive treatment was not

Treatment of cytomegalovirus-mediated colitis

Due to the low number of patients with cytomegalovirus-mediated colitis, no randomised controlled trials are available. Thus the current recommendations are based on data retrieved from transplantation medicine studies. In line with ECCO guidelines based on expert opinion and various case studies, ganciclovir (5 mg/kg bodyweight twice daily) for 2–3 weeks is the therapy of choice for cytomegalovirus infections. After 3–5 days, a switch to oral valganciclovir (900 mg twice daily) for the

Is it only cytomegalovirus, or is there more?

As cytomegalovirus belongs to the Herpesviridae family,1, 2, 3, 4 whether or not the effect of cytomegalovirus on refractory colitis applies to other family members is a relevant question. The results of a study⁶² confirmed that Epstein-Barr virus causes a similar effect. In this study, control patients, patients with inflammatory bowel disease and refractory disease, and responders were analysed separately, and the presence of either cytomegalovirus or Epstein-Barr virus was analysed on a

Immunosuppressive therapy and cytomegalovirus-mediated colitis

Real cytomegalovirus-mediated colitis is a rare event, and controlled trials have not been done; any therapeutic recommendations are based on weak evidence. The recommendation for use of antiviral therapy is based on data retrieved from transplantation medicine. However, this recommendation does not address how to proceed with the immunosuppressive strategy after or during treatment of cytomegalovirus-mediated colitis. The following considerations are entirely based on mechanistic thoughts and

Conclusion

Real cytomegalovirus-mediated colitis in patients with inflammatory bowel disease is rare. However, cytomegalovirus replication is often seen in patients with steroid-refractory colitis. Because cytomegalovirus-mediated colitis is rare, little evidence is available to support diagnosis and treatment methods. In view of the available scientific literature, this Review offers a diagnostic and therapeutic approach that will allow clinicians to distinguish between cytomegalovirus replication and

Search strategy and selection criteria

PubMed was searched for reports published between Jan 1, 1990, and May 31, 2016, using the terms “CMV”, “Crohn's disease”, “ulcerative colitis”, and “IBD”. Articles were also identified through searches of the author's own files. Only papers published in English were considered. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review.

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Epstein-Barr Virus-Positive Mucocutaneous Ulcers Complicate Colitis Caused by Immune Checkpoint Regulator Therapy and Associate With Colon Perforation
2020, Clinical Gastroenterology and Hepatology
Citation Excerpt :
Regarding the presence of CMV, similar macroscopic appearance of punched-out ulcers could be observed in CMV-mediated colitis in the context of ulcerative colitis. However, CMV infection in these circumstances does not result in a characteristic pattern of circumscribed lymphoproliferation, as seen with EBVMCUs.32,33 Although aspects of immunosurveillance over EBV and CMV, both latent herpesviruses, are similar, the pathogenesis of tissue damage, respectively, is different and beyond the scope of this study.
Cancer therapy with immune checkpoint inhibitors can cause colitis and colon perforation. We investigated whether infection with Epstein Barr virus (EBV) associates with development and severity of colitis in patients receiving immune checkpoint inhibitor therapies.
We performed a retrospective analysis of fixed colon tissues from 16 patients (12 men, 4 women, median age, 69.5 y) with colitis after immune checkpoint inhibitor therapy (9 patients treated with anti-CTLA4, 3 patients treated with anti-PD1, and 4 patients received a combination). Ten tissue samples were biopsies and 6 were collected during resection (4 surgeries for colon perforation). Patients were treated between 2010 and 2018 in the United Kingdom. The tissues were analyzed by pathology, in situ hybridization (to detect EBV-encoded small RNAs [EBERs]), and immunohistochemistry. Clinical data were also collected.
Colon tissues from 4 of the 13 patients who received anti-CTLA4 (alone or in combination, 4 with colon perforation) had EBV-positive lymphoproliferations that manifested as florid ulcers associated with polymorphous infiltrates containing EBV-positive blasts (CD30+ or CD30-negative, CD20+, CD3-negative, and EBER+), plasma cells (CD138+, CD20-negative, and EBER+ or EBER-negative), and small B cells (CD20+, CD3-negative, and EBER+ or EBER-negative), consistent with EBV-positive mucocutaneous ulcers (EBVMCUs). In analyses of biopsies collected from 2 patients with EBVMCUs over multiple time points, we found that earlier biopsies had no or only a few EBV-positive cells, whereas 1 later biopsy had EBVMCU and co-infection with cytomegalovirus. EBVMCUs were associated with steroid-refractory colitis (100% of EBV-positive patients vs 12.5% of EBV-negative patients; P = .008) and colon perforation (100% of EBV-positive patients vs no EBV-negative patients; P = .001).
We found that colon tissues from 4/13 patients with colitis after anti-CTLA4 therapy (4/6 patients who underwent resection and 4/4 patients with colon perforation) contained EBVMCUs. EBVMCUs seem to arise secondarily in areas of inflamed colon due to immunosuppressive treatment for colitis. EBVMCUs are associated with steroid-refractory colitis and colon perforation.
Management of acute severe ulcerative colitis in Spain: A nationwide clinical practice survey
2019, Gastroenterologia y Hepatologia
La colitis ulcerosa es una enfermedad crónica del tracto digestivo, y hasta el 20-30% de los pacientes sufren un brote grave durante su evolución. Aunque existen guías nacionales e internacionales sobre el tratamiento de la colitis ulcerosa aguda grave, desconocemos cómo se manejan en la práctica clínica estos pacientes en nuestro medio.
Realizamos una encuesta electrónica y anónima entre los miembros del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU), compuesta por 51 preguntas con respuestas predefinidas.
Participaron 164 miembros (20%), en su mayoría especialistas de aparato digestivo (95%). El 59% trabajaban en hospitales terciarios, atendiendo a una mediana de 5 pacientes al año (RIC: 3-8) con un brote grave de colitis ulcerosa. El 86% realizan un estudio endoscópico rutinario, habitualmente al ingreso (62%). El corticoide más empleado es la metilprednisolona, habitualmente a una dosis de 60 mg/día, y se evalúa su respuesta pasados 3 días (mediana, RIC: 3-5). El tratamiento de rescate usado con más frecuencia es infliximab, tanto en pacientes naïve como refractarios a tiopurinas. El 55% han indicado en alguna ocasión una dosis de infliximab mayor de 5 mg/kg durante la inducción, y el 73% han adelantado alguna de las sucesivas infusiones.
El manejo de la colitis ulcerosa aguda grave en nuestro entorno se ajusta en general a las recomendaciones de tratamiento actuales. El tratamiento de rescate más frecuentemente prescrito es el infliximab, y no es excepcional el empleo de pautas intensificadas o aceleradas de este biológico.
Ulcerative colitis (UC) is a chronic disease of the digestive tract and up to 20-30% of UC patients may suffer a severe flare-up during the course of the disease. Although there are national and international recommendations about its clinical management, there is not enough information about the treatment of acute severe UC in clinical practice.
An electronic and anonymous survey with 51 multiple-choice questions was performed among all the members of the Spanish Crohn's Disease and Ulcerative Colitis Working Group (GETECCU).
Out of the 164 responders (20%), most were gastroenterologists (95%), with 59% from tertiary hospitals treating a median of 5 patients per year (IQR: 3-8) with a severe flare-up of ulcerative colitis. An endoscopic examination was routinely performed in 86% of patients (62% at admission). The most commonly used corticosteroid was methylprednisolone, usually at a dose of 60 mg/day, and its response was assessed after a median of 3 days (IQR: 3-5). Both in thiopurine-naïve and thiopurine-refractory patients, infliximab was the drug most frequently prescribed as rescue therapy. Half of responders (55%) had ever prescribed a first dose of infliximab higher than 5 mg/kg, and a higher proportion (73%) had ever prescribed an earlier dose of infliximab in the second or third infusion.
Acute severe UC is generally managed according to current treatment guidelines in our setting. The rescue therapy most commonly prescribed is infliximab, and the use of intensified or accelerated regimens with this biological drug is not unusual.
Differential diagnosis of inflammatory bowel disease: imitations and complications
2018, The Lancet Gastroenterology and Hepatology
Citation Excerpt :
After 3–5 days, a switch to oral valganciclovir can be considered for the rest of the 2–3 week course. Alternatively, in cases of resistance or myelotoxicity, foscarnet can be used20 in patients with or without IBD.73 During the course of Crohn's disease, approximately 30% of patients develop at least one fistulising episode.74
Inflammatory bowel disease (IBD) is characterised by episodes of relapse and periods of remission. However, the clinical features, such as abdominal pain, diarrhoea, and rectal bleeding, are not specific. Therefore, the differential diagnosis can include a broad spectrum of inflammatory or infectious diseases that mimic IBD, as well as others that might complicate existing IBD. In this Review, we provide an overview of ileocolitis of diverse causes that are relevant in the differential diagnosis of IBD. We highlight the importance of accurate patient profiling and give a practical approach to identifying factors that should trigger the search for a specific cause of intestinal inflammation. Mimics of IBD include not only infectious causes of colitis—and particular attention is required for patients from endemic areas of tuberculosis—but also vascular diseases, diversion colitis, diverticula or radiation-related injuries, drug-induced inflammation, and monogenic diseases in very-early-onset refractory disease. A superinfection with cytomegalovirus or Clostridium difficile can aggravate intestinal inflammation in IBD, especially in patients who are immunocompromised. Special consideration should be made to the differential diagnosis of perianal disease.
Novel score predicts risk for cytomegalovirus infection in ulcerative colitis
2018, Journal of Clinical Virology
Citation Excerpt :
In UC patients, loss of successful immune surveillance can lead to symptomatic end-organ involvement, such as CMV colitis. The diagnostic challenge to distinguish between clinically irrelevant (bystander) CMV reactivation and CMV mediated disease is further complicated by the fact that a multitude of techniques have been proposed to monitor CMV infections [7–11]. Current guidelines suggest histology and immunohistochemistry for CMV antigens or polymerase chain reaction (DNA PCR) for detection of CMV in the blood, however, the optimal method for detecting clinically relevant CMV infection in patients with colitis has not been established yet [12,13].
Cytomegalovirus (CMV) infection is associated with relapse and exacerbation of ulcerative colitis (UC), especially in immunosuppressed patients.
The aim of this study was to identify risk factors for CMV colitis and to develop a predictive risk score to estimate the probability of CMV colitis in UC patients supporting clinical decision making.
A cohort of 239 UC-patients was retrospectively analyzed. Univariate and multivariate regression analysis identified several independent risk factors for CMV colitis and a predictive risk score was established using ROC analysis.
CMV colitis is common in patients with severe ulcerative colitis. Clinical UC activity, disease duration and extent as well as the use of steroids and anti-TNF-α agents were identified as risk factors (p < 0.05 each). Based on five predictive parameters, a web-based risk score was developed. A strong correlation between the predicted and actual rates of CMV colitis was found (AUC: 0.855; 95% CI 0.79-0.92; p < 0.0001).
Our study supports the pathogenic relevance of CMV in UC. The predictive risk score estimates the risk of CMV colitis and might aid in clinical decision making, especially when timely modifications of therapeutic regimens are needed and reliable diagnostic tools are not readily available.
An Intestinal Th17 Subset is Associated with Inflammation in Crohn's Disease and Activated by Adherent-invasive Escherichia coli
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Updated S3 guideline for ulcerative colitis (Version 6.1) - February 2023 - Association of Scientific Medical Societies in Germany (AWMF) register number: 021-009
2023, Zeitschrift fur Gastroenterologie

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ReviewCytomegalovirus infection associated with inflammatory bowel disease

Summary

Introduction

Section snippets

Epidemiology

Diagnostic tests and clinical features

Cytomegalovirus-mediated colitis or just cytomegalovirus replication: implications for clinical practice

When to start antiviral therapy

Treatment of cytomegalovirus-mediated colitis

Is it only cytomegalovirus, or is there more?

Immunosuppressive therapy and cytomegalovirus-mediated colitis

Conclusion

Search strategy and selection criteria

Antiviral Res

Transplant Rev (Orlando)

Gastroenterology

Lancet

Dig Liver Dis

Pathology

J Clin Virol

J Virol Methods

Dig Liver Dis

J Crohns Colitis

J Clin Virol

Dig Liver Dis

Am J Transplant

Am J Gastroenterol

Clin Gastroenterol Hepatol

Clin Gastroenterol Hepatol

Am J Gastroenterol

Prevention of congenital cytomegalovirus complications by maternal and neonatal treatments: a systematic review

Rev Med Virol

Seroprevalence of cytomegalovirus infection in the United States, 1988–1994

Clin Infect Dis

Epidemiology of cytomegalovirus infections

Rev Infect Dis

Complement-fixing antibodies against cytomegalovirus in different parts of the world

Bull World Health Organ

Incidence and clinical significance of colonic cytomegalovirus infection in idiopathic inflammatory bowel disease requiring colectomy

Gut

Cytomegaloviral enterocolitis: clinical associations and outcome

Dis Colon Rectum

Infection by cytomegalovirus in patients with ulcerative colitis requiring colonic resection

Med Clin (Barc)

Cytomegalovirus infection in patients who required colectomy for toxic megacolon or severe steroid-refractory ulcerative colitis

Dig Dis Sci

Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant

Clin Microbiol Rev

Clinical and immunologic aspects of cytomegalovirus infection in solid organ transplant recipients

Transplantation

Multicenter comparison of the digene hybrid capture CMV DNA assay (version 2.0), the pp65 antigenemia assay, and cell culture for detection of cytomegalovirus viremia

J Clin Microbiol

Prevention and treatment of cytomegalovirus infection in solid organ transplant recipients

Curr Opin Infect Dis

Evaluation of the AMPLICOR cytomegalovirus test with specimens from human immunodeficiency virus-infected subjects

J Clin Microbiol

Cytomegalovirus excretion as a predictor of cytomegalovirus disease after marrow transplantation: importance of cytomegalovirus viremia

J Infect Dis

Recent advances in the diagnosis of cytomegalovirus infection

Ann Biol Clin (Paris)

Review
Cytomegalovirus infection associated with inflammatory bowel disease