Cytomegalovirus in IBD: where to biopsy, whom to treat

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Amy Carpenter Aquino

July 2023—Though it’s been suggested that newer drugs have made cytomegalovirus less relevant in patients with inflammatory bowel disease, CMV remains an important opportunistic infection in patients with IBD. Knowing where to biopsy and how many are needed is one of the histologic challenges, said Joseph Misdraji, MD, associate professor of pathology, Yale School of Medicine, in a CAP22 session.

Another is defining high-grade disease. Patients with high-grade disease may be more likely to benefit from antiviral therapy, according to several studies, he said, but there is no standard definition.

CMV is a double-stranded DNA virus in the herpes family that infects 66 to 75 percent of people in Western populations. Primary infection is usually asymptomatic or can resemble Epstein-Barr virus before entering a latent phase.

“What we’re often looking at is CMV reactivation,” Dr. Misdraji said, “either in the population or even in patients with inflammatory bowel disease, where the CMV replication begins in the target organ, such as the colon, and then becomes disseminated after some time into peripheral blood.”

Primary CMV infection in immunosuppressed patients with IBD is a severe illness associated with viremia, tissue damage, pneumonia, and hemophagocytic lymphohistiocytosis. It can be fatal even if treated with ganciclovir, said Dr. Misdraji, who is also director of histology in the Department of Pathology at Yale and associate pathologist at Yale New Haven Hospital. More often seen in pathology practice, he said, is reactivation of CMV promoted by the upregulation of inflammatory mediators in patients with IBD. “This often results in nonresponse to their IBD therapy.”

CMV reactivation occurs more often in patients with ulcerative colitis (38 percent) than in patients with Crohn’s disease (11 percent), Dr. Misdraji said, noting, “The cytokine milieu of ulcerative colitis favors CMV reactivation.” CMV reactivation depends on tumor necrosis factor-α, and in ulcerative colitis TNF-α favors CMV reactivation. In Crohn’s disease, interferon-γ exhibits antiviral properties.

There has long been controversy in the literature, he said, about whether CMV reactivation is a marker of severe inflammatory disease that has no bearing on prognosis or whether it is pathogenic and exacerbates the colitis, with worse outcome. Most studies at this point, though not all, support that CMV in patients with IBD is associated with increased patient mortality, nonresponse to immunosuppressive therapy, higher rates of colectomy, longer hospital stays, and higher costs, and that treating CMV restores steroid responsiveness, reduces the colectomy rate, and improves the outcome, he said.

CMV can exacerbate colitis by promoting proinflammatory cytokine production; replicating in the endothelial cells, resulting in microthrombi and tissue ischemia; and disrupting epithelial tight junctions in the gut, enhancing bacterial translocation.

“Some people have suggested that CMV may not be as relevant today in the age of biologics as it was years ago when everyone was on steroids and thiopurines,” Dr. Misdraji said. Those drugs and cyclosporines do raise the risk for CMV, whereas the newer anti-TNF agents, such as infliximab and adalimumab, are not associated with an increased risk of CMV reactivation.

Dr. Misdraji

“It turns out that the new kid on the block is vedolizumab,” he said, “and that does increase the risk of severe CMV,” by targeting the α4β7 integrin that homes lymphocytes to the gut. “Ultimately, many of these therapies are given sequentially or concurrently, and CMV today remains an important opportunistic infection in this patient population.”

For clinicians, diagnosing CMV disease versus infection in patients with IBD is a challenge, Dr. Misdraji said. “Many of these patients have CMV infection, meaning they’ve already been carrying it and they’re infected with the virus,” he said, “but how do we demonstrate there’s active CMV disease?” Endoscopy is one modality, and some but not all studies have found clinically relevant CMV disease to be associated with deep ulcers. “Serology has very limited utility in reactivation,” he noted. IgM occurs in primary CMV infection, and most patients have an IgG.

CMV antigenemia assays detect pp65 antigen in circulating lymphocytes, he said, and are not entirely predictive of CMV activity in the colon.

CMV PCR in blood leukocytes is a relatively rapid test and thus used frequently, “almost as a screening test,” he said. But since CMV involves the blood only after days or weeks of viral replication in the colon, a positive result is helpful but a negative result may be less so. There will be a positive value in 48 percent of patients with an IHC diagnosis and 60 percent if there are numerous inclusions. A high viral level result supports treatment, but cutoffs have not been established.

PCR in colonic tissue is one of the two gold standards. “High values of quantitative PCR in the colon do correlate with active disease, and the test is usually negative in biopsies that do not have inclusions,” Dr. Misdraji said. The other is histology with immunohistochemistry, which “is a gold standard across numerous white papers. Ultimately, we are the gold standard,” he said.