The association between CMV infection and UC has received increasing attention in recent years. The results of our previous study13 showed that the development of CMV colitis due to CMV infection causes colonoscopic changes in UC patients, presenting as punched-out and longitudinal ulcers. These changes complicate the diagnosis and treatment of patients with active UC. To better understand the influence of CMV infection on the clinical manifestations of UC and related risk factors, we performed a multicenter case-control study to assess the clinical symptoms, complications, biochemical indicators and effect of therapeutic drugs on the development of infection in patients with active UC. The results revealed prominent presentations of abdominal pain, fever, and oral ulcers after CMV infection, whereas the rates of gastrointestinal perforation, gastrointestinal bleeding, and toxic megacolon between the infection and noninfection groups did not appear significantly different. The probability of CMV infection induction increased with the use of glucocorticoids and immunosuppressive agents, whereas biological agents had no effect. Lower Ig levels and the initial onset type appeared more prominent in the CMV infection group than in the non-CMV infection group. Multivariate analysis showed that high-dose glucocorticoid treatment and immunosuppressive agents were independent risk factors for CMV infection, while low albumin and eosinophil levels were also risk factors for CMV infection in UC patients.
The major clinical manifestations of CMV infection are fatigue and fever. If the intestinal tract is involved, watery diarrhea, bloody stool, and abdominal pain might occur. This study analyzed the clinical characteristics of UC patients with and without CMV infection. The percentages of fever and abdominal pain in patients with CMV infection were significantly higher than those in patients without CMV infection, whereas no significant differences were observed in hematochezia and diarrhea incidence between the two groups. One possible reason for this result is that diarrhea and hematochezia are the major clinical manifestations for patients with active UC; therefore, significant differences between the two groups would be difficult to demonstrate.
With regard to complications, this study did not find significant differences in the proportions of complications between the CMV infection and noninfection groups. A recent study14 reported that patients with CMV infection have a worse prognosis and are more prone to complications and increased colectomy rates than noninfected individuals. However, other studies did not support these results, possibly due to different inclusion criteria; for example, some studies enrolled patients with CMV infection, while others enrolled patients with CMV colitis. In addition, the results of this study indicated that patients with extensive colonic UC and severe UC are prone to CMV infection, as CMV exhibits a tendency toward inflammation and can easily infect growing cells in granulation tissues. Moreover, extensive UC is characterized by a wide range of ulcers and more severe inflammation, which may promote CMV reactivation and proliferation15. Therefore, the possibility of CMV infection should be considered for patients in the active stage with fever and abdominal pain that do not conform to the disease condition. In addition, the possibility of CMV infection should always be considered for patients with the E3 type and severe UC in the active stage.
The laboratory analysis results showed multiple abnormal indicators in the CMV infection UC group. The significant increase in hsCRP, an inflammatory indicator, suggests that patients with severe inflammation activity are more prone to CMV infection. This result was consistent with the aforementioned results showing severe UC patients to be prone to CMV infection. The hemoglobin level in the CMV infection group also was decreased compared with that in the noninfection group. Although a significant P value was not obtained (P = 0.054), these results nonetheless indicate that CMV infection can aggravate the condition of UC patients. Furthermore, serum sodium levels in the CMV infection group were decreased, and there are two possible explanations for this result. First, the high inflammatory activity aggravated the disease, and diarrhea caused by CMV infection resulted in hyponatremia. The other explanation addresses diarrhea resulting in hyponatremia, which might be associated with CMV infection. It has been shown that16 hyponatremia will result in cellular immune dysfunction, and abnormal cellular immunity probably promotes CMV infection.
The results of this study showed significant reductions in immunoglobulin (IgG, IgM, and IgA) levels in the CMV infection group. Immunoglobulins (Ig) comprise a group of globulins with immune functions that can interact with specific antigens, and studies17, 18 have shown that hypoimmunoglobulinemia is closely associated with refractory CMV disease. A reduction in Ig levels can increase susceptibility to CMV infection and promote the occurrence and aggravation of CMV infection. CMV infection also affects the stability of immune function and the balance of T cell subsets, and the presence of lymphokine-activated killer (LAK) cells will significantly decrease the activity of natural killer (NK) cells and aggravate reductions in Ig levels19. Studies20, 21 in recent years have indicated that a reduction in serum Ig levels is common in adults and children with IBD, with one report20 showing low IgG, IgG1, IgA, and IgM levels in 22.7%, 23.4%, 7.9%, and 10.9% of IBD patients, respectively. IgAs, which are distributed on the surface of cells in the eyes and in the respiratory, gastrointestinal, and genitourinary tracts, are secretory Igs and the first-line defense against microorganisms. Although studies on the association between IgA and IBD are scarce, Zhou et al19 showed a significant reduction in serum IgA levels in patients infected with CMV in combination with other viruses. The results of this study suggest that attention should be paid to changes in Ig levels in research. Unfortunately, Ig was not included in the multivariate analysis due to missing data. Further expanding the sample size may help to obtain meaningful results.
Our study found increased rates of CMV infection in patients who received glucocorticoids and immunosuppressive agents. These results are similar to those of the majority of studies22, 23.
Similar to the results of another study24, we did not find an increased risk of CMV infection due to the use of tumor necrosis factor (TNF) inhibitors because TNF inhibitors suppress TNF, an important cytokine that promotes CMV reactivation.
After removing confounding factors from the multivariate analyses, high-dose glucocorticoid treatment and immunosuppressive agents were shown to be independent risk factors for CMV infection in UC patients, increasing the risk of CMV infection in UC patients by 13.55-fold and 11.23-fold, respectively.
Relatively few studies on the risk of CMV infection in UC patients with eosinopenia have been published. The eosinophil results are another highlight of our study, as the risk of CMV infection in UC patients was shown to decrease by 80.8% (1-0.192) with every 0.1*10^9/L increase in the peripheral blood eosnophil level. In general, more attention should be paid to an increased eosinophil level because this phenomenon can promote gastrointestinal inflammation and the release of cytokines, chemical factors, and lipid regulators. An increase in eosinophils is also associated with IBD and some gastrointestinal diseases. Studies25 in recent years have shown that eosinophils, a component of the innate immune system, have the capacity to respond to pathogen-related molecules and are closely associated with infection, and a significant reduction in peripheral blood eosinophil numbers usually occurs during the clearance of infection. In addition, eosinopenia is associated with acute infection26, and studies27, 28 have also shown that a reduction in eosinophils is a sensitive and reliable indicator for distinguishing between infection- and noninfection-related sepsis in intensive care units (ICUs).
The multivariate analyses suggested the following: long-term treatment with glucocorticoids at a high dose and immunosuppressive agents should be avoided; patients’ normal immune statuses should be maintained; Ig treatment should be properly applied for severe infections; and UC patients with low eosinophil levels should be monitored for CMV infection. Furthermore, the risk of CMV infection should be considered for patients with high hsCRP levels and low serum albumin levels. A few studies2, 7, 29, 30 have indicated that albumin is a nutritional and inflammatory marker that reflects the potential for infection or disease activity. Increasing albumin levels might have a protective effect against CMV infection in UC patients.
The limitation of this study is that due to its case-control nature, whether the indicators are the causes or results of CMV infection cannot be determined. Therefore, to confirm these risk and protective factors, cohort studies will be required for further investigation.
In summary, CMV infection may occur at the active stage of UC due to changes in the immune status or disease condition; in turn, CMV infection aggravates the condition of UC patients, making the inflammatory disease difficult to control. For patients with extensive UC, treating inflammation, correcting anemia and hyponatremia, improving immunoglobulin function and monitoring low serum and eosinopenia levels may help prevent CMV infection and lead to a better prognosis. Furthermore, the molecular mechanisms underlying the association between Ig, eosinopenia and UC combined with CMV infection are worthy of further study.