The diagnosis of infectious esophagitis usually is established by endoscopy with esophageal biopsy. Candida esophagitis has a characteristic endoscopic appearance with raised, white plaques that resemble cottage cheese clinging to the esophageal mucosa. This material cannot be washed away readily, and the friable underlying mucosa frequently bleeds when the adherent plaques are dislodged by contact with the endoscope or biopsy forceps. Confirmation of the diagnosis of candida esophagitis requires the demonstration of budding yeast cells, hyphae, or pseudohyphae in esophageal biopsy specimens.

The endoscopic findings in HSV esophagitis vary with the interval between esophageal infection and endoscopic examination. The earliest lesions, which are seldom observed, are small (1-3 mm) rounded vesicles, often in the mid- to distal esophagus. When the vesicles slough, the lesions become small ulcers that have raised margins and a yellowish base. The mucosa between the ulcerations usually appears normal. In some cases, the small ulcers coalesce to form larger ulcers that can be covered with dense exudates.

HSV infects the esophageal squamous epithelial cells and, therefore, histologic confirmation of HSV esophagitis is accomplished by obtaining biopsy specimens from the squamous epithelium at the edges of ulcerations. Typical histologic changes of HSV infection include multinucleated giant cells and intranuclear (Cowdry type A) inclusion bodies.

CMV typically causes discrete, large esophageal ulcerations (up to 15 cm in length) that are surrounded by normal-appearing esophageal mucosa. The virus infects fibroblasts and endothelial cells and, therefore, biopsy specimens should be obtained from the granulation tissue in the base of the esophageal ulcer rather than from the squamous epithelial cells (that do not harbor the virus) at the edges of the ulcer. Cells infected with CMV have distinctive histological abnormalities that include cellular enlargement (cytomegaly) and inclusion bodies within the nucleus. Unlike the inclusion bodies of HSV infection that are found only within the nucleus, CMV-infected cells exhibit granular inclusion bodies in the cytoplasm as well.