Continuing Education Activity

Cytomegalovirus (CMV) is a member of the Herpesviridae family, which has the largest genome of any herpes virus. It is spread through bodily fluids such as during the perinatal period or sexual contact. Although immunocompetent individuals can be infected, the serious disease typically only manifests in those with immunocompromised states such as patients with AIDS, organ transplant recipients, and patients on chemotherapy. CMV can affect many organs, including the eyes, stomach, colon, but the focus of this discussion is on the esophagus. This article goes into the etiology, presentation, diagnosis, and treatment of cytomegalovirus esophagitis. It highlights the population most likely to be afflicted with the disease and introduces interprofessional team to ways to best recognize and care for patients affected by CMV esophagitis.

Objectives:

• Identify the etiology of cytomegalovirus esophagitis.
• Describe the evaluation of cytomegalovirus esophagitis.
• Outline the management options available for cytomegalovirus esophagitis.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care and improve outcomes for strategies for patients affected by cytomegalovirus esophagitis.

Introduction

Cytomegalovirus (CMV) is a member of the Herpesviridae family, which has the largest genome of any herpes virus. It is spread through bodily fluids, such as during the perinatal period or sexual contact.[1] Although immunocompetent individuals can be infected, the serious disease typically only manifests in those with immunocompromised states, such as patients with AIDS, organ transplant recipients, and patients on chemotherapy.[1] CMV can affect many organs, including the eyes, stomach, and colon, but this discussion focuses on the esophagus. CMV esophagitis is the second most common gastrointestinal (GI) tract manifestation of CMV disease, the first being colitis.[2] The typical manifestation of CMV esophagitis is odynophagia and dysphagia, and finding of large ulcer or ulcers in the middle to distal esophagus. Standard diagnosis requires biopsy and pathologic verification.[1] Current treatment still consists of antivirals ganciclovir and valganciclovir, but research for alternatives is ongoing.[1][3][4] Nonetheless, esophageal disease of CMV infection carries a poor prognosis, recurrence risk, and high rate of one-year morbidity and mortality.[5]

Etiology

CMV is a member of the Herpesviridae family of viruses.[6] CMV may be acquired in the perinatal period or during adulthood via sexual contact.[1] Those at the highest risk for the active disease are immunocompromised patients, most notably patients with acquired immunodeficiency syndrome (AIDS), solid organ and bone marrow transplant recipients, and those receiving immunosuppressive therapy and chemotherapy for cancer treatment.[5] There have been very few cases reported of CMV esophagitis affecting immunocompetent individuals.[5] Acute CMV infection is often asymptomatic and is one of the most common human viral infections. Once the infection is acquired, there is lifelong viral latency coupled with the risk of intermittent reactivation.[1]

Epidemiology

CMV is a common human viral infection, affecting 40 to 100 percent of adults.[1] About 70 percent of the global human populations have latent CMV infections, and the prevalence of seropositivity for CMV highly correlates with socioeconomic status, ethnicity, and geographic region.[7] CMV is the most common viral opportunistic infection in the AIDS population.[8] The esophagus is the second most common site of CMV-caused GI tract involvement, the first being the colon.[2]

Pathophysiology

CMV can infect a large variety of cell types.[6] It is also able to remain latent in bone marrow progenitor cells after primary infection, and it can replicate in different cells and tissues.[7] Highly conserved glycoproteins M and B (gM and gB, respectively) binding to the host cell’s heparin-sulfate proteoglycans is the first step in CMV infection.[6] Glycoprotein B is also crucial for the spread of CMV from cell to cell.[6]

In the immunocompetent, CMV replication is kept under control through antibodies against key viral surface glycoproteins and cell-mediated immune response carried out by NK cell, CD4, and CD8 T cells. Disease in the immunocompromised can result from reactivation of the latent virus, newly acquired infection, or reinfection with a new strain. Reactivation in immunocompromised patients is the result of dysfunction in cell-mediated immunity rather than humoral immunity. Patients typically have enough anti-CMV antibodies.[1] It is their poorly functional CD4 and CD8 T cell responses to mono and polyfunctional cytokine production, which fail to control CMV replication.[7] Moreover, the virus itself is also able to encode proteins that interfere with class I and class II HLA response, NK cell activities, the cell cycle, apoptotic and inflammatory pathways that typically act to contain this pathogen.[7]

Mucosal infection by CMV leads to inflammation and tissue necrosis, vascular endothelial involvement, and, ultimately, ischemic mucosal injury. The occlusion of vasculature contributes largely to the cause of tissue injury and ulcer formation.[1]

Histopathology

There is no pathognomonic endoscopic feature for CMV esophagitis, and definitive diagnosis depends heavily on biopsy findings. Histopathological diagnosis can be made by identifying CMV inclusion bodies with standard H&E staining, called a cytomegalic cell. These cells appear 25 to 35 micrometers with basophilic intranuclear inclusion, occasionally surrounded by a clear halo. There can also be intracytoplasmic inclusions.[1] The task of finding these cytomegalic cells can be tedious and requires an astute pathologist and a sufficient number of biopsy samples for evaluation.[1] The advent of immunohistochemical staining via anti-CMV monoclonal antibodies has allowed for more modalities to help aid in diagnosis. However, immunohistochemistry has not proven to be more sensitive than routine pathology.[1][9]

History and Physical

Although immunocompetent patients may be infected with CMV, it rarely causes active disease in such patients. In healthy adults, most primary CMV infections are either asymptomatic or present as a mild mononucleosis-like syndrome.[1] The active disease almost always occurs through reactivation or reinfection in the immunocompromised since the virus itself is so prevalent universally that most have been previously infected. Disease from CMV most commonly affects patients with AIDS, especially when their CD4 cell count drops to less than 100/mm3. CMV also notoriously leads to disease in recipients of organ transplants.[1] The most common finding is the large, distal solitary esophageal ulcer in the symptomatic cases, which will present as odynophagia or constant substernal chest pain in AIDS and transplant patients.[1] However, other studies have also cited ulcers to be multiple in the majority of patients.[10] Dysphagia can occur as well.[11] Other symptoms include nausea, vomiting, abdominal pain, weight loss, diarrhea.[2] Rare presentations include gastrointestinal bleeding and stricture formation.[1]

Evaluation

There are many noninvasive options for diagnosis; however, the most reliable modality is still endoscopy and biopsy.[5] Because CMV can remain latent or be asymptomatic in immunocompetent hosts, the detection of CMV in tissue or body fluids does not equate to disease. Serology in detecting levels of anti-CMV antibodies is not useful as disease correlates with defective cell-mediated immunity and not humoral immunity. Anti-CMV IgM indicates a recent infection, and anti-IgG can be present in most adults who have previously been infected. Blood and oropharyngeal viral culture, even if obtained from patients with risk factors such as organ transplant recipients, can help identify those at high risk for developing the disease but are not sensitive or specific for identifying active disease.[1]

The endoscopic appearance of CMV esophagitis ulcers is well-demarcated, vertical, or horizontal linear shallow ulcers at the mid to distal esophagus.[2] Ulcerations can be single or multiple, can be deep resembling cavitations, and have associated features such as mucosal edema and nodularity.[5] Intervening mucosa between the ulcers is typically normal.[10] There is no pathognomonic endoscopic or pathologic feature for CMV disease, and finding cytomegalic cells with the CMV inclusion bodies is critical. The success of this aforementioned task relies heavily on there being an adequate number of samples and the diligence of the examining pathologist.[1] Immunohistochemistry to label specific CMV antigens is a useful adjunct when inclusion bodies are difficult to identify, but it does not need to be used upfront.[9]

Treatment / Management

The mainstay of CMV esophagitis treatment day is ganciclovir and valganciclovir.[7] Treatment of active disease should begin with induction therapy with intravenous (IV) ganciclovir at a dose of 10-15 mg/kg per day in 2-3 divided doses daily for 3 to 6 weeks, depending on clinical circumstances.[1][3] Maintenance therapy with IV ganciclovir at 5 mg/kg daily is indicated in cases with concurrent retinitis or recurrent gastrointestinal disease after discontinuation of induction therapy. Relapse is unfortunately common as the patients affected by the disease have baseline severely persistent immune deficiency most of the time, and treatment only suppresses the infection but does not eliminate it.[1] If recurrence occurs, repeat induction should be done, followed by maintenance therapy. Foscarnet is an alternative to ganciclovir if resistance to the first-line treatment occurs. Failure of monotherapy calls for an attempt at combination therapy with IV ganciclovir and IV foscarnet.[1]

Differential Diagnosis

Cytomegalovirus esophagitis more commonly presents as a single, isolated large ulcer in the distal esophagus but can also manifest as diffuse esophagitis.[1] The diffuse presentation can be difficult to distinguish from other disorders such as herpes simplex virus (HSV) esophagitis and acid peptic disease. The differentiating factor is that HSV esophagitis typically presents as multiple, small, shallow ulcerations more so than large ulcerations. HSV esophagitis also affects the entire esophagus, whereas CMV esophagitis more commonly affects the mid to distal esophagus.[10]

• Achalasia
• Acid peptic disease
• Aphthous ulcers
• Barrett esophagus and Barrett ulcer
• Candidiasis
• Cryptococcosis
• Drug-induced dysphagia
• Epstein-Barr virus infection
• Esophageal cancer
• Gastroesophageal reflux disease
• Herpes simplex esophagitis
• Histoplasmosis
• Tuberculosis

Prognosis

Upper gastrointestinal CMV disease in immunocompromised individuals carries significant morbidity and mortality, to as high as 25% one-year mortality in some studies.[5] Hoversten et al. conducted what was the largest case study of CMV esophagitis in the non-HIV immunocompromised population and demonstrated that 28% died within one year of CMV esophagitis diagnosis. This one-year risk of mortality is further perpetuated by having more than one risk factor such as congenital or acquired immunodeficiency, history of transplant, active malignancy, immunosuppressive cytopenia, recent use of systemic steroids, and non-steroid immunosuppressive medications or chemotherapy.[11] In some cases, where the cause of immunocompromise may be reversed by the removal of the corticosteroid, cancer chemotherapy agent, or immunosuppressive agent, patients may have a resolution of their CMV disease.[1] In the immunocompetent population where the disease is self-limited, supportive therapy will suffice to provide symptom relief, without poor prognostic outcome.[1] 

Complications

Malnutrition can develop in the setting of dysphagia and odynophagia, which can be devastating in the setting of severe illnesses such as AIDS and organ failure requiring a transplant.[2] If the ulcerations that develop become extensive and deep enough, perforation and massive GI bleeding can occur spontaneously or as a complication during endoscopy.[5][1] Stricture formation, while uncommon, has been reported to occur despite undergoing treatment with ganciclovir and foscarnet and even as the initial presentation of CMV esophagitis without prior ulcers.[8] One case report noted stricture formation severe enough to cause complete obliteration of the esophageal lumen in a patient who completed anti-viral treatment and had post-treatment pathology samples negative for CMV and HSV, demonstrating that strictures can form despite disease treatment and resolution.[8]

Deterrence and Patient Education

CMV can infect and remain latent in a large number of people, even if they are immunocompromised. Immunocompetent individuals will not typically manifest with symptomatic disease. Patients receiving chemotherapy, patients with advanced age, newborns, AIDS patients, and organ transplant patients are also at increased risk. 

CMV infection can be acquired through bodily fluids such as during the perinatal period, contact with contaminated blood products, and sexual contact.

Patients should discuss their symptoms with the physician managing the cause of their immunocompromise, such as infectious disease specialists for AIDS patients, rheumatologists for autoimmune disease, and oncologists for patients on chemotherapy. Ultimately, patients should be seen by a gastroenterologist for upper endoscopy with biopsy. The biopsy samples will then be reviewed by pathologists to give the final diagnosis. 

Antiviral drugs such as ganciclovir, valganciclovir, foscarnet are available to suppress viral replication. However, CMV can remain latent and thus recur in the future.

Enhancing Healthcare Team Outcomes

The first step of improving the outcome for patients affected by CMV esophagitis is to recognize the at-risk population. Primary care physicians for patients with immunocompromised status should educate their patients about the potential diseases that they may face, including CMV esophagitis. The same should be done for patients soon to become immunocompromised, such as patients with newly diagnosed cancer, about to undergo chemotherapy, or patients who are about to begin immunosuppressive therapies for autoimmune disorders. Primary care physicians should educate patients regarding symptoms such as odynophagia, dysphagia, and chest pain. They should also emphasize the importance of HAART medication compliance for patients with HIV to avoid low CD4 count putting them at risk for CMV esophagitis. Patients should be educated about taking universal precautions when coming into contact with bodily fluids.  

If there is suspicion for CMV esophagitis, patients should be assessed by primary care physicians for a thorough history, physical and evaluate for the presence of risk factors. Patients should be referred to gastroenterologists for an upper endoscopy, with biopsy samples obtained and to be reviewed by pathologists. The results should be reviewed by the primary care physician with the patient. The primary care physician should also initiate induction treatment and follow-up with the patient. Infectious disease specialists should also be involved in the discussion if difficulties in treatment were to occur.