Cytomegalovirus (CMV) enteritis is traditionally thought to be a self-limited infection in immunocompetent individuals. Consequently, current guidelines recommend against treating nonimmunocompromised patients with antiviral therapy. Conversely, recent data suggests that spontaneous resolution occurs less frequently than previously believed; furthermore, mortality rate in immunocompetent individuals is similar to that of the immunosuppressed. We present a case of a 43-year-old male who was simultaneously diagnosed with CMV ileitis and Crohn's Disease. When discovered concomitantly, there is no guidance in the current medical literature regarding the benefit of antiviral treatment of the CMV infection prior to initiating biologic therapy versus the risks of withholding treatment, as is currently recommended for nonimmunosuppressed individuals.
Cytomegalovirus (CMV) is in the Herpesviridae family and often remains latent after primary infection. The virus later reactivates, often triggered by immunosuppression, either endogenous such as acquired immunodeficiency syndrome (AIDS) or iatrogenic, such as patients undergoing treatment for inflammatory bowel disease (IBD) [
In immunocompetent hosts, primary infection is either asymptomatic or presents as an undifferentiated mononucleosis-like syndrome. CMV infection of the gastrointestinal tract most commonly involves the rectum or esophagus, only rarely affecting the small bowel. In immunocompetent patients, CMV enteritis is traditionally thought to be a self-limited infection, thus current guidelines recommend supportive management only, without antiviral therapy. However, guidance is lacking regarding whether treatment of active CMV infection is recommended prior to initiation of biologic therapy. The only guidelines addressing diagnosis and treatment of CMV prior to immunosuppressing therapy are chemotherapy guidelines for cancer patients.
A 43-year-old African American male was referred to the Gastroenterology clinic for a 12-month history of alternating diarrhea/constipation, intermittent sharp rectal pain, as well as a 6-week history of pencil-thin stool and staining with defecation. He denied any other constitutional symptoms such as fever, chills, weight loss, or fatigue. A diagnostic colonoscopy was attempted, but limited due to a severe anal stricture.
Computed Tomography (CT) and subsequent Magnetic Resonance Imaging (MRI) of the abdomen/pelvis showed a diffusely distended colon and dilated ileum concerning for ileus or enterocolitis, likely infectious or inflammatory in etiology (Figure 1). Rectal exam under anesthesia was notable for a functional narrowing of the anus and two large ulcers at the posterior anal canal. Anal biopsies revealed granuloma formation and positive immunohistochemical staining for CMV. Ileocolonoscopy performed under sedation and monitored anesthesia care demonstrated extensive circumferential ulcerations and inflammation of the terminal ileum (TI) with endoscopically normal colon (Figure 2). Nearly all TI biopsies were positive for scattered CMV-infected cells in a background of diffuse histopathologic effect and ulceration (Figure 3). Unfortunately, a plasma CMV viral load was not checked during his admission as it was unlikely to change management at time; however it would have been useful to demonstrate extent of disease burden and response to treatment.
PHOTO (COLOR): CT, MR Imaging. (a) Coronal CT, irregular wall thickening of the TI (long orange arrow), and mild RLQ lymphadenopathy (short orange arrow). (b) MRE, wall thickening of TI (yellow arrow).
PHOTO (COLOR): Colonoscopy images. Extensive involvement of the terminal ileum with circumferential ulcerations and inflammation (left). Detailed view of erosions and inflammation seen throughout the ileum (right).
PHOTO (COLOR): Biopsies from terminal ileum. (a) 200x and 500x (inset) H&E stained appearance of CMV-infected cells. (b) 400x H&E stain showing a cell with CMV cytopathic effect. (c) 500x H&E stain showing a cell with another variation of CMV cytopathic effect. (d) 500x H&E stain with another example of CMV cytopathic effect. The nucleus contains a viral inclusion.
During his hospitalization, the patient had persistent, frequent bloody bowel movements associated with significant abdominal pain. On hospital day 2, the patient became septic, manifested by fever, tachycardia, tachypnea, leukocytosis of 20.82 x10
Given the severity of illness, we had significant concerns about initiating immunosuppressive therapy for his Crohn's Disease in the setting active CMV infection. Given the unremarkable workup for underlying immunodeficiency, the infectious disease team recommended against antiviral therapy, in accordance with current guidelines [
CMV is a common latent infection that can reactivate during times of severe immunosuppression, such as in acquired immunodeficiency syndrome, transplant patients or patients undergoing immunosuppressing chemotherapy. When the GI tract is involved, CMV classically affects the esophagus or colon. CMV ileitis is rare, especially in young, immunocompetent individuals. In patients with known IBD, baseline elevation of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), promotes reactivation of latent CMV and can subsequently lead to IBD exacerbation [
CMV infection in immunosuppressed individuals is associated with severe sepsis and high mortality rates. Though CMV infection is believed to be self-limited in immunocompetent hosts, prior studies note that spontaneous resolution of CMV colitis occurred in only 50% of immunocompetent individuals without other comorbidities [
Biologic therapy commonly used to treat moderate to severe Crohn's Disease includes TNF-α inhibitors, such as infliximab, adalimumab, and certolizumab pegol. TNF-α is produced by activated macrophages and T-cells. It is important for macrophage activation, neutrophil chemotaxis, granuloma formation, and maintenance of granuloma structure. The American College of Gastroenterology recommends anti-TNF agents be used in combination with immunomodulatory therapy (such as thiopurines) in moderate to severe Crohn's Disease, as combination therapy is more effective than either treatment class alone in patients naïve to such agents [
Although anti-TNF agents offer a more targeted strategy than traditional nonspecific immunosuppressive agents, such as corticosteroids, methotrexate, and azathioprine, multiple adverse effects, including risk of serious infections, have been reported. Consensus amongst experts recommends screening for certain infections prior to initiation of anti-TNF therapies, including tuberculosis, hepatitis B, and hepatitis C. Furthermore, the American College of Rheumatology recommends against initiation of anti-TNF agents if active or recent bacterial, herpes zoster, or invasive fungal infection or nonhealing skin ulcer [
Current medical literature is limited regarding treatment of active CMV infection prior to initiation of biologic therapy. Existing guidelines only pertain to treatment of CMV prior to chemotherapy in cancer patients. National Comprehensive Cancer Network (NCCN) guidelines recommend screening for and treatment of CMV infection prior to immunosuppressive treatments due to the risk of disseminated CMV after starting chemotherapy [
This case was presented as a poster at the American College of Gastroenterology Annual Scientific Meeting on October 7, 2018, in Philadelphia, PA.
We have no conflicts of interest to disclose.
Thanks are due to Dr. Ryan Schwope, Department of Radiology, Brooke Army Medical Center, San Antonio, TX.
By Kendra T. Stilwell; Jason Estes; Maria T. Kurtz; James M. Francis; David T. Lynch and Anish A. Patel