The technique for performing endoscopy with videoendoscopes miniaturized to a diameter of 4.8 mm has made the procedure far more tolerable in immunocompromised patients, requiring less sedation and anesthesia and allowing the procedure to be performed even in newborns. These new instruments have biopsy capabilities comparable to older, wider endoscopes [2].

Characteristic macroscopic lesions are associated with some infectious agents. Macroscopic appearances overlap considerably, however, and histopathologic or immunohistochemical analysis (or both) of endoscopic and brush biopsy specimens is essential for diagnosis.

Endoscopic biopsy specimens should be obtained from the edge and the base of the lesions. In cytomegalovirus (CMV) infection, specimens from the edge do not yield diagnostic information [12]. The pathologist should be alerted to the possibility of fungal, viral, and polymicrobial infection. Appropriate fixatives should be used for routine hematoxylin and eosin stain, Gram stain, and special stains for fungi and bacteria such as Mycobacterium. Immunohistochemical studies and DNA hybridization techniques often are required to establish the diagnosis [1].

Candida is the most common cause of infective esophagitis [13] and immunosuppressed patients are prone to this infection . Candida esophagitis is common in human immunodeficiency virus (HIV)-infected patients, in whom it tends to occur when CD4 counts fall below 200 μl. Treatments with broad-spectrum antibiotics, acid-suppressive therapy and inhaled corticosteroids are also risk factors [14–16]. In apparently immunocompetent individuals, predisposing medical conditions or risk factors are often identified [17, 18]. The causative organism is almost always Candida albicans, although other species are occasionally found [19].

Patients present with dysphagia , odynophagia, and⁄or retrosternal chest pain. Esophageal candidiasis may be the initial presentation of disseminated disease in an immunocompromised patient. The majority of patients, particularly those who are immunocompromised, also have concomitant oropharyngeal candidiasis [19, 20]. Nearly all patients with AIDS and oral candidiasis and odynophagia have endoscopic evidence of esophageal candidiasis [5, 21, 22] . However, some of these patients ultimately proven to have esophagitis have no signs or symptoms at presentation. Children who develop esophageal candidiasis, despite being treated with HAART, are less likely to have typical symptoms (e.g., odynophagia and retrosternal pain) or to have concomitant oropharyngeal candidiasis [11].

A specific etiological diagnosis is established by endoscopy with or without biopsy or brushings. Endoscopy reveals the presence of characteristic confluent yellow-white plaques overlying and adherent to an erythematous mucosa. Remarkably, the presence of ulceration is unusual and should prompt further evaluation for an alternative etiology. Endoscopic findings without biopsy have been reported to have a sensitivity and specificity of 100 and 83 %, respectively, for a diagnosis of candida esophagitis [23] .

The histological examination shows active esophagitis with budding spores and pseudohyphae within squamous debris, ulcer slough, and fibrino-purulent exudate. Invasion of mucosal and submucosal blood vessels is sometimes a prominent feature of invasive candidiasis [24]. Candida species are commensal organisms of the gastrointestinal tract, and colonize the esophagus in about one-fifth of healthy adults, making histological evidence of fungal invasion into tissue or ulcer slough important [15]. Parakeratosis with neutrophils may call attention to the presence of Candida.

Brushings may be obtained and stained with Gomori silver or periodic acid-Schiff stains. Fungal culture is not performed routinely as it is generally not useful except in defining the species and drug sensitivities, especially in treatment resistant cases [24].

Candida can colonize preexisting ulcers or damaged mucosa of any etiology, and the pathologist should consider the possibility of dual pathology .

Expert consensus guidelines recommend systemic therapy with newer azole medications (fluconazole, itraconazole solution, or voriconazole) for esophageal candidiasis. Topical therapy may produce an initial response, but early treatment failures are common. Oral fluconazole 200–400 mg (3–6 mg/kg) daily for 14–21 days is recommended. If oral therapy cannot be tolerated, intravenous fluconazole 400 mg daily, amphotericin B, or an echinocandin, such as caspofungin, micafungin, or anidulafungin may be used [25–27]. Oral fluconazole and itraconazole suspension seem comparable in efficacy for initial therapy, and some patients whose disease fails to respond to fluconazole may see improvement with subsequent itraconazole therapy [28]. Although voriconazole has efficacy similar to that of fluconazole, it is associated with a higher rate of adverse events [29] .

Cases of esophagitis caused by Aspergillus, Blastomyces, Cryptococcus, and Histoplasma spp. have been described. Unlike Candida, these are not commensals and are acquired by significantly immunocompromised individuals from the environment . Primary infection of the esophagus is very unusual and has been described in immunocompromised patients. Aspergillus infection occurs as a result of contiguous spread from mediastinal infection [30, 31]. Blastomyces and Histoplasma infect the esophagus from a concomitant pulmonary infection or from disseminated infection [1]. Mediastinal fibrosis with esophageal obstruction and esophageal fistula may occur with histoplasmosis [31].

Optimal therapy has not been established, but systemic therapy, as for other manifestations of invasive infection with these organisms, has been successful. Currently, this approach would involve intravenous or oral azole agents or an amphotericin B preparation. Echinocandins (micafungin, caspofungin, or anidulafungin) may be useful for Aspergillus or Histoplasma infections, but they have no activity against cryptococci .

Herpes Simplex Virus (HSV) esophagitis is primarily a disease of immunocompromised patients and occurs most commonly in patients with solid organ and bone marrow transplants [32–34] . These patients may have life-threatening disseminated infection at the time of diagnosis [32]. It has also been reported in the setting of acute rejection [34]. In contrast to transplant recipients, it accounts for only 3–5 % of esophagitis in HIV patients [35–37]. Most infections in immunocompromised patients probably represent viral reactivation as these patients have higher baseline seroprevalence rates. HSV esophagitis can occasionally occur in subjects with normal immune function, who usually have a self-limiting infection that resolves spontaneously within 1–2 weeks [38, 39].

Although the esophagus is the most frequent site of gastrointestinal involvement, HSV esophagitis is uncommon. The vast majority of documented cases are due to HSV-1, though HSV-2 esophagitis from heterosexual orogenital contact in an immunocompetent patient has been described [40] .

Symptoms are similar in both immunocompetent and immunocompromised patients. HSV in the immunocompetent is characterized by the acute onset of odynophagia, while 60–76 % of patients exhibit retrosternal chest pain or heartburn [38, 41]. This may be associated with fever and systemic manifestations. Unlike in Candida, where oral disease is present in the majority of patients, coexisting herpes labialis and oropharyngeal ulcers are only seen in about one-fourth of patients [4, 38]. Symptoms may be more severe in immunocompromised patients with bleeding, perforation, tracheoesophageal fistula, and necrotizing esophagitis having been reported [42–46] .

Endoscopic findings include nonspecific erosive esophagitis and discrete or coalescent superficial ulcers with an exudate. Vesicles that are the earliest manifestations are rarely seen. They coalesce to form ulcers often with normal intervening mucosa. Multiple esophageal ulcers are the commonest endoscopic finding seen in 59–86 % of HSV patients, but these are nonspecific [38, 41]. The ulcers are usually small and discrete or occasionally confluent. The ulcers are “volcano-like” in appearance, in contrast to CMV ulcers which are linear or longitudinal and deeper. In addition to ulcers, friable mucosa and white exudates are commonly seen on endoscopy in HSV esophagitis. The distal esophagus is the commonest site of involvement; the entire esophagus may be involved in 15 % of patients [38].

The diagnosis is usually based on a combination of histological findings and viral isolation from culture. Biopsies from the edge of the ulcers provide the highest diagnostic yield as the base of the ulcers often lack epithelial cells. Ulceration with neutrophils and an inflammatory exudate may be seen. Squamous cells may show viral cytopathic effects, including multinucleation, groundglass nuclei, and dense eosinophilic inclusions with a thickened nuclear membrane and a clear halo (Cowdry type A inclusion bodies). However, viral inclusions and multinucleated cells are not always identifiable in endoscopic biopsies [32] and may also be seen in other viral infections such as those caused by CMV and Varicella-zoster Virus (VZV). Aggregates of macrophages with convoluted nuclei have been identified adjacent to infected epithelium and may make the pathologist suspect herpes virus infection and prompt further investigation [47]. HSV isolation in the absence of histological findings is of questionable significance as it may represent asymptomatic viral shedding .

Acyclovir for 14–21 days has been advocated in the treatment of immunocompromised individuals with the use of intravenous preparations in those unable to swallow. In contrast to immunocompromised patients, HSV esophagitis in the immunocompetent is an indolent but usually self-limiting disease. The value of treatment with acyclovir is uncertain [41]. While case reports suggest therapeutic benefit in hastening illness resolution [39], the relative rarity of the condition precludes any randomized controlled trials, and spontaneous resolution usually occurs within 1–2 weeks. A search should be made for any underlying immunosuppressive illness in patients presenting with HSV esophagitis .

CMV is a significant pathogen in the immunocompromised subject, usually occurring in patients with AIDS [23], transplant recipients, malignancies, and those receiving immunosuppressive medications . These patients frequently have multiorgan involvement, while CMV infection is usually subclinical and asymptomatic in immunocompetent patients [48]. Indeed, serious symptomatic CMV esophagitis in immunocompetent patients is rare [49].

Patients with CMV esophagitis clinically present with dysphagia , odynophagia, or nonspecific symptoms such as nausea , vomiting, abdominal pain , anorexia, and fever that reflect multiorgan or systemic involvement. Thrombocytopenia and leucopenia may be present but are not invariable.

Endoscopy may reveal variable findings from esophageal erosions to deep ulcers, located in the mid or distal esophagus with a halo of edema. In the setting of hematopoietic stem cell transplantation , they may be macroscopically confused with graft-versus-host disease. Stricture formation is relatively uncommon despite the occurrence of deep CMV ulceration [50, 51] .