Cytomegalovirus Esophagitis Overview of CMV

Esophagitis is the second most common gastrointestinal (GI) manifestation of cytomegalovirus (CMV) infection after colitis. CMV esophagitis has been reported in patients who have undergone transplantation, patients undergoing long-term renal dialysis, patients with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), and patients with other debilitating diseases.

CMV GI disease was first described in the 1960s. The average time to development of CMV esophagitis after solid organ transplantation is 5-7 months. Patients undergoing bone marrow transplantation may develop CMV disease much earlier, at an average of 2-3 months with symptoms occurring as early as 10 days after allogenic bone marrow transplantation.^[1]

Patients with CMV esophagitis may have superimposed CMV colitis (in which case, care at a skilled nursing facility may be necessary).

Patients with HIV infection are at increased risk because their CD4⁺ lymphocyte counts fall to less than 100 cells/µL. In patients with HIV infection or AIDS, CMV infection is an opportunistic infection that signals a decline in patient immunity.

CMV esophagitis has been described in only 3 patients who had been immunocompromised by conditions other than transplantation, HIV infection, or AIDS. No cases have been reported in healthy hosts.

CMV is a member of the Herpesviridae family, along with herpes simplex viruses (HSVs) 1 and 2, Epstein-Barr virus, varicella-zoster virus, and others. CMV is a double-stranded deoxyribonucleic acid (DNA) virus with a protein coat and lipoprotein envelope.

Similar to other herpesviruses, CMV is icosahedral and replicates in the host's nucleus. Like the other members of this family, CMV has the ability to produce a latent infection. Replication in the host cell is typically represented by large, intranuclear inclusion bodies and smaller cytoplasmic inclusions. An inclusion body is seen in the image below.

Studies have shown that 50-80% of the world's population is seropositive for CMV. The 2 peaks for primary CMV infection occur in preschool children and young adults. With the advent of immunosuppressive medications and the increased incidence of HIV infection and AIDS in the early 1980s, a new class of CMV infection has been described.

CMV retinitis, adrenalitis, pneumonia, colitis, and esophagitis are some of the conditions observed in immunocompromised hosts.^[2] CMV is the third most common pathogen in patients with AIDS, superseded only by Pneumocystis carinii and Candida.

Patterns of CMV infection

Three major patterns of CMV infection are described.

The first is primary infection, in which the patient has never been exposed to the pathogen but becomes infected by a patient who is seropositive for the virus. This pattern accounts for 60% of cases. Primary infection in immunocompetent hosts causes few or no symptoms. Studies with in situ hybridization have shown that CMV DNA can persist in a latent form in most organs of the body.

The second pattern, reactivation, occurs in a patient who is seropositive with a latent virus that becomes reactivated when the host's immune system becomes compromised. This occurs in 10-20% of cases.

The third pattern is superinfection, which occurs in 20-40% of cases. In this, a patient is seropositive for CMV and receives latently infected cells from another seropositive patient. The resulting CMV infection is from the latent donor cells, not the recipient cells.

Once a patient becomes infected, CMV can persist in the host tissues indefinitely. Humoral and cellular mechanisms work in concert to control CMV infections and maintain the latent phase. However, if the host's T-cell response becomes compromised by disease or iatrogenic causes, the latent virus can be reactivated to cause a variety of syndromes.

Risk factors that predispose individuals to cytomegalovirus esophagitis include the following:

• HIV infection or AIDS
• High- or low-dose corticosteroid therapy
• Immunosuppressive therapy following transplant
• History of blood transfusion
• Advancing age
• Anything that can decrease an individual’s immunity

Potential complications of cytomegalovirus esophagitis include the following:

• Stricture formation
• Perforation (rarely)

Approximately 8-28% of patients with AIDS who undergo esophagogastroduodenoscopy (EGD) for dysphagia or odynophagia are found to have cultures positive for CMV. Approximately 38% of bone marrow transplant patients who undergo EGD for unexplained nausea and vomiting are positive for CMV esophagitis and/or small intestine involvement.

Morbidity and mortality in CMV esophagitis

Because CMV esophagitis occurs in immunocompromised hosts, the morbidity and mortality attributed to the esophagitis itself is difficult to quantitate.

Patients with CMV esophagitis may report severe dysphagia and/or odynophagia, preventing the already undernourished patient from obtaining much-needed nutrients. This can result in a progressive worsening of the patient's condition.

As the patient's condition worsens, the risk of disseminated CMV infection increases. Historically, the mortality rate associated with CMV disease in transplantation patients has been 85%. With the advent of the antiviral drug ganciclovir, however, this rate has been markedly reduced.

Race, sex, and age predilections in CMV esophagitis

CMV esophagitis has no race or documented sex predilection.

No reports on age-related predilection have been published. However, because immunocompetence generally decreases with age, older patients are at higher risk for developing CMV disease than are younger patients.

Mimics of the symptoms of CMV esophagitis include the following:

• Achalasia
• Barrett Esophagus and Barrett Ulcer
• Candidiasis
• Cryptococcosis
• Esophageal Cancer
• Gastroesophageal Reflux Disease
• Herpes Simplex
• Histoplasmosis
• Tuberculosis

The following conditions should also be considered in the diagnosis:

• Aphthous/idiopathic ulcers (commonly seen in patients with AIDS)
• Drug-induced dysphagia
• Epstein-Barr virus infection

Patients with CMV esophagitis may present with symptoms in other organs or systems (eg, colon, eyes, liver, lungs). Therefore, patients may present with multiple symptoms unrelated to the esophagitis.

Unlike HSV infection, patients present with a more gradual onset of symptoms.^[3] Nausea, vomiting, fever, epigastric pain, diarrhea, and weight loss are nonspecific symptoms but are more typical of CMV infection. In contrast, patients with HSV infection present with an abrupt onset of symptoms consisting of retrosternal chest pain and painful, difficult swallowing.

Keep in mind that CMV can coexist with HSV or any other cause of esophagitis; therefore, patient presentation may vary. Solid organ transplant recipients develop CMV disease 7-9 months after transplantation, while bone marrow transplant recipients develop disease after 2-3 months.

Presenting symptoms of patients with CMV esophagitis include the following:

• Difficult or painful swallowing (ie, dysphagia, odynophagia, retrosternal pain)
• Nausea and vomiting
• Abdominal pain
• Fever
• Diarrhea
• Weight loss
• Chest pain
• Hemoptysis

Physical examination findings may include the following:

• Adenopathy
• Ulcerated oropharynx (uncommon)
• Erythematous oropharynx

Specimens can be stained by specific immunofluorescent antibodies to detect viral antigens or viral DNA.

The most commonly used culture technique is the shell viral assay of cultured cells, in which immediate early antigens are detected by the use of monoclonal antibodies. This reduces the time to positivity to 24-72 hours, whereas other cultures take days to weeks.

Wilcox et al reported that viral culture and brushings add little to the evaluation of esophageal ulcers in patients with AIDS over multiple biopsy specimens with routine histology.^[4]

Findings from imaging studies are nonspecific.

The study of choice is EGD, which allows direct visualization and allows for biopsies that aid in diagnosis.

A definitive diagnosis is established in more than 70% of cases.

Not uncommonly, large, solitary, shallow ulcers or multiple discrete lesions appear, especially in the distal esophagus. However, ulceration is not necessary. For example, esophageal necrosis has also been reported in 1 kidney transplant patient,^[5] and shallow erosions have been found in a liver transplant patient.^[6]

The biopsy specimen should be taken from the base of the ulcer. Studies have shown that at least 10 biopsy specimens should be obtained to yield a significant result. Specimens should be submitted for histologic examination, antigen detection, and viral culture studies.

Histology of affected specimens may show acute and chronic inflammation, vasculitis, and/or mucosal ulceration. Deep biopsy specimens are preferred. Histologic staining with Papanicolaou or hematoxylin and eosin stains may reveal classic findings that include giant cells (typically 25-35 µm) (as shown in the image below) with cytomegaly and large, ovoid, or pleomorphic nuclei with basophilic inclusions. These inclusions are known as owl's eyes because of their separation from the nuclear membrane by a halo. Immunochemistry is more specific than standard staining techniques.

Other studies, such as antibody tests, qualitative or quantitative polymerase chain reaction (PCR) tests, or studies of blood or other body fluids, yield less diagnostic information for CMV esophagitis and may not indicate current active infection.

Borges et al reported that although PCR may have a role in diagnosing CMV and other infective causes of esophagitis, the presence of multiple infections in immune-compromised hosts occasionally limits the utility of PCR.^[7]

Patients with HIV infection

Studies have documented the profound effect of potent antiretroviral therapy on the natural history of HIV infection. Because most patients affected by CMV esophagitis have HIV infection, the increased use of these newer therapies has helped in the prevention and treatment of CMV disease.

Patients receiving antiretroviral therapy have shown a decrease in HIV viral load, increased CD4⁺ lymphocyte counts, decreased hospitalization, and a decreased incidence of opportunistic infections, including CMV esophagitis. For these patients, therefore, aggressive treatment of HIV infection is key to treating and preventing CMV infection.

Intravenous ganciclovir is the treatment of choice for patients with HIV infection who are also infected with CMV. If ganciclovir is contraindicated or cannot be used, intravenous foscarnet is the second-line therapy.

Combination therapy with ganciclovir and foscarnet may be effective if monotherapy fails, but this is associated with significant toxicity.

The use of oral ganciclovir is increasing in patients who require long-term suppressive treatment.^[8] Long-term prophylaxis with peroral ganciclovir is considered in patients with HIV infection who have CD4⁺ lymphocyte counts of less than 50 cells/µL.

Patients with immunosuppressive factors other than HIV infection

Potent antiviral agents, such as ganciclovir, are also essential in the treatment of patients with non-HIV causes of immunosuppression, such as transplantation, long-term steroid use, renal dialysis, or an iatrogenic source.

Evidence suggests that patients with invasive disease may benefit from combined ganciclovir and IgG-CMV (Cytotec), although conclusive evidence is lacking.^[9] Data also indicate that oral valganciclovir is comparable in safety and efficacy to intravenous ganciclovir in liver transplant recipients.^[10]

Discontinuation of steroid or immunosuppressive agents in these patients is discouraged if this will further compromise the patient's health.^[11] However, tapering immunosuppression may allow the patient to develop immunity.

CMV esophagitis does not require surgical intervention.

Prognosis

With rapid diagnosis and proper antiviral therapy, the prognosis of patients with CMV disease has dramatically improved.

Multiple consultations should be obtained for patients with CMV esophagitis.

An ophthalmologist should be consulted to evaluate the patient for CMV retinitis. Patients should self-monitor their vision and report any changes in acuity or the presence of floaters.

A gastroenterologist should be asked to aid in diagnosis and treatment.

Infectious disease experts can offer advice on the treatment of CMV infection and, possibly, HIV infection, if the patient is found to be HIV-positive.

Drug-resistant strains may develop, which would require alternate therapies.

Maintenance therapy may be considered, especially in patients requiring reinduction drug therapy for relapse.

Discontinuation of long-term maintenance therapy can be considered in patients with HIV infection in whom CD4⁺ T-lymphocyte counts have increased to more than 100-150 cells/µL and whose HIV plasma ribonucleic acid (RNA) levels have been suppressed.

Unless the patient is unable to take food by mouth secondary to odynophagia, no special nutritional requirements are needed. However, if a patient is not able to take food by mouth, temporary peripheral nutrition may be necessary.

No limitations on patient activity are necessary.

CMV vaccines are under development. Prophylactic esophageal screening has not been beneficial.

Patients should be educated about the nature of their disease and the possibility of recurrence.

Patients with HIV infection or AIDS, in particular, should be aware of the possibility of recurrence.

For patient education information, see eMedicine's Immune System Center, as well as HIV/AIDS and HIV Testing.