20
Esophagitis

Mário C. Vieira, Luciana B. Mendez Ribeiro, and Sabine Krüger Truppel

Introduction

The term esophagitis has many clinical and pathological connotations and may describe different chemical, immunological, infectious, and ischemic disorders. Gastroesophageal reflux disease (GERD) and eosinophilic esophagitis, which are the major causes of esophagitis in children, as well as chemical injuries of the esophagus, are topics covered in other chapters of this book. In this chapter, less common causes, such as infectious disorders, epidermolysis bullosa, inflammatory bowel disease, chemotherapy and radiation‐induced inflammation, which are also part of the injury panel of esophageal mucosa, will be reviewed [1,2].

Infectious esophagitis

Infectious esophagitis is a disease observed, in most cases, in immunocompromised patients. It may occur in patients infected by the human immunodeficiency virus (HIV), undergoing chemotherapy, receiving treatment with immunosuppressive drugs and those under prolonged therapy with antibiotics or corticosteroids [2].

The most common symptoms of esophageal infections are odynophagia, dysphagia, retrosternal chest pain, nausea, vomiting, and fever. Symptoms may lead to worsening of nutritional status and increased mortality of associated diseases. Infectious esophagitis, under special conditions, may present with serious complications such as gastrointestinal bleeding, strictures, fistulae or perforation [2].

Upper gastrointestinal (GI) endoscopy is the gold standard for the diagnosis of esophageal lesions. It is the most sensitive and specific method, since it allows macroscopic evaluation of the mucosa and collection of samples for analysis through biopsies and cytology brushings. There is increased sensitivity if polymerase chain reaction (PCR), viral tissue culture, and immunohistochemistry tests are performed on the samples obtained through endoscopy [1,2].

Esophagitis associated with HIV

Infections of the digestive tract affect most HIV‐infected patients. The most common pathogens involved are yeasts (Candida sp.), viruses (cytomegalovirus [CMV], herpes simplex virus [HSV], Epstein–Barr virus [EBV], human papillomavirus [HPV]), bacteria and protozoa (Cryptosporidium sp. and Pneumocystis carinii), which are usually associated with systemic disease. Infections may be isolated or co‐existent [2]. Antiretroviral therapy has enabled viral load control and improvement of the immune function, with a significant reduction in the incidence of these opportunistic complications, decreasing morbidity and mortality from HIV infection [3].

Infectious esophagitis is the second most common gastrointestinal manifestation in HIV‐infected patients [4]. The most common agent is Candida albicans co‐existing often with other pathogens, particularly CMV.

The presence of symptoms of esophageal disfunction in these patients is an indication for endoscopic evaluation for the detection of lesions in the esophageal mucosa and biopsies and/or brushing for differential diagnosis [5].

Erosive or ulcerated esophagitis is, in general, assigned to CMV infection [4,5].

Esophagitis caused by Candida

Candida albicans is a normal commensal agent in the GI tract. Esophageal candidiasis is a common fungal infection in immunocompromised patients and is rare in immunocompetent patients. There are several Candida species that may be involved, but C. albicans is the main etiological agent of infectious esophagitis and can occur with or without concomitant oropharyngeal infection [6].

The most common symptoms of esophageal candidiasis are sialorrhea, odynophagia, and retrosternal chest pain, and most patients present with concomitant oropharyngeal candidiasis. Rare complications include bleeding, stricture, and perforation [7].

Upper GI endoscopy reveals whitish pseudomembranous plaques adhered to the esophageal wall, extending from the proximal to the distal part of the esophagus. Friability, edema, and erythema of varying degrees eventually associated with ulcerations may be observed (Figure 20.1) [8]. The endoscopic aspect can be classified in grades from I to IV (Table 20.1) [9].

Histopathological analysis with routine stains confirms the diagnosis through the identification of spores, hyphae, and pseudohyphae compatible with Candida sp. Culture is not useful unless susceptibility testing is required for suspected resistant agents [6,10].

The treatment for esophageal candidiasis is fluconazole for 14–21 days, orally or intravenously, in cases of significant dysphagia. Amphotericin B may be an alternative for cases refractory to fluconazole [6].

Photos depict friability, edema, and erythema of varying degrees eventually associated with ulceration. — **Figure 20.1** Friability, edema, and erythema of varying degrees eventually associated with ulceration.

Table 20.1 Endoscopic classification of esophageal candida

Source: Reproduced with permission from Kodsi et al. [9].

Grade	Description
I	A few small candida plaques up to 2 mm in size, with mucosal hyperemia but without edema or ulcerations
II	Multiple bigger white candida plaques with mucosal hyperemia and edema but without ulcerations
III	Confluent linear candida plaques with mucosal hyperemia and ulcerations
IV	As grade III but with constriction of the esophageal lumen

Esophagitis caused by CMV

Primary infection by CMV in immunocompetent patients is very frequent, occurring mainly in preschool children and young adults, and may be asymptomatic in most cases. In situ hybridization studies may show that CMV DNA may persist in a latent form in most organs. In the immunocompromised host, the latent virus may become reactivated and cause several diseases [11,12].

Cytomegalovirus esophagitis is rarely documented in immunocompetent patients [13,14]. It usually affects patients after organ or bone marrow transplantation, patients undergoing long‐term dialysis, patients infected by HIV or those with acquired immunodeficiency syndrome (AIDS), patients with other debilitating diseases and those treated with immunosuppressive drugs [2,11,12]. The average time for the development of CMV esophagitis after solid organ transplantation is 5–7 months and after bone marrow transplantation is 2–3 months [11,12].

Nonspecific symptoms including nausea, vomiting, and fever are characteristic of the viral infection; however, odynophagia, dysphagia, chest pain, and bleeding may occur when there is esophageal involvement [2,12].

On upper GI endoscopy, diffuse erythema associated with small, shallow ulcers or multiple linear and deep ulcers with elevated margins may be observe,d especially involving the middle and distal portions of the esophagus [12].

Biopsies should be performed in the central area of the lesion, as the cytopathic effects of the virus are not found in the squamous epithelium. Histological diagnosis is performed with the detection of large cells, mainly fibroblasts and endothelial cells, presenting, typically, bulky nuclei with viral inclusions and peripheral light halo (“owl’s eye”). In addition to histological analysis, the specimens should be subjected to antigen detection and viral culture [15].

The first‐line treatment is intravenous ganciclovir 10 mg/kg/day for 14–21 days.

Esophagitis caused by HSV

Primary infection by the herpes simplex virus is common in childhood, and there are positive antibody titers for HSV in 90% of adolescents. The most common presentation of the infection is gingivostomatitis, and some patients with severe involvement of the oropharyngeal wall may present with esophagitis. In immunocompetent children, herpes esophagitis is rare but should be considered in patients with odynophagia, even in those without skin or oropharyngeal lesions. Esophagitis is mainly caused by HSV type 1, by direct propagation of oral infection [16,17].

The typical clinical picture of herpetic esophagitis includes the triad of acute odynophagia, retrosternal pain, and fever. Hematemesis may occur in approximately 5% of patients. Esophageal perforation, systemic infection, food impaction, and tracheoesophageal fistula formation rarely occur. There are descriptions of herpetic esophagitis associated with eosinophilic esophagitis but the relationship between these two disorders has not yet been elucidated [18,19].

The endoscopic characteristics of herpes esophagitis are mucosal friability and small rounded vesicles or well‐delimited shallow ulcers, typically affecting the middle and distal esophagus (Figures 20.2 and 20.3). Biopsies should be collected from the ulcer’s edge as the agent is present in squamous epithelium [17,20].

Differential diagnosis of the lesions includes other infections (CMV, HIV, Candida sp. and bacteria); caustic ingestion; Behçet’s disease, Crohn’s disease and lesions due to pill ingestion [16].

Histology reveals signs of acute inflammation, ulceration and abnormalities of epithelial cells suggestive of viral infection, including ballooning degeneration and necrosis. The nuclei present a “ground‐glass” aspect, with multinucleated cells and nuclear molding. To increase the sensitivity of the histological findings, it is ideal to perform immunohistochemistry, in situ hybridization or tissue culture [20,21].

Photos depict endoscopic characteristics of herpes esophagitis including mucosal friability and small rounded vesicles or well-delimited shallow ulcers, typically affecting the middle and distal esophagus. — **Figure 20.2** Endoscopic characteristics of herpes esophagitis including mucosal friability and small rounded vesicles or well‐delimited shallow ulcers, typically affecting the middle and distal esophagus.

Photos depict similar characteristics that are shown in this figure. — **Figure 20.3** Similar characteristics are shown in this figure.

Treatment is based on maintaining hydration, nutrition and adequate analgesia, including acid suppression therapy. The use of intravenous aciclovir in immunocompetent patients is controversial but may be considered in patients with severe odynophagia [22].

Esophagitis caused by tuberculosis

The GI tract is the sixth site of extrapulmonary tuberculosis infection. Esophageal involvement is an extremely rare form of infection, accounting for only 0.2–1% of the GI manifestations of the disease. Primary esophageal tuberculosis is uncommon and rarely affects immunocompetent patients [23]. The most frequent symptoms are odynophagia, retrosternal pain, and weight loss followed by dysphagia and hematemesis [24].

The typical lesion of esophageal tuberculosis is a solitary ulcer, with irregular margins, in the middle third of the esophagus. Complications such as bleeding, fistulae, and perforation are more frequent in tuberculosis esophagitis than in other infectious esophagitis. Histology confirms the diagnosis when Mycobacterium tuberculosis or evidence of classic caseous granuloma is identified [25].

Other esophageal infections

Other viral infections rarely affect the esophagus in immunocompetent children. Among them, herpes zoster and EBV infections are reported as causes of ulcerative esophagitis in isolated cases [6]. The involvement of the esophagus by other fungal infections such as blastomycosis and histoplasmosis is reported sporadically in immunocompetent patients [2].

Epidermolysis bullosa

Epidermolysis bullosa (EB) is a hereditary rare disease, characterized by the development of blisters on the skin or mucous membranes with minimal trauma. The onset of the lesions usually occurs in early childhood [26,27].

The disease is classified into three major groups according to the form of genetic inheritance, specific clinical features and distribution of lesions, mucosal involvement and morbidity associated with the disease: EB simplex, junctional EB, and dystrophic EB [26,27].

The involvement of the GI tract is more frequent in patients with the recessive dystrophic form than other subtypes of EB. The intraluminal blisters, as they heal, can lead to single or multiple, short or long esophageal strictures, resulting in dysphagia, odynophagia, severe nutritional impairment, refractory anemia, hypoalbuminemia, malabsorption, and failure to thrive [26–28].

The onset of symptoms occurs up to the age of 10 in more than half of cases. Narrowing of the esophagus is more pronounced in the upper third, related to the intake of food that causes direct damage to the esophageal mucosa (Figure 20.4). The more distal strictures may be precipitated or exacerbated by gastroesophageal reflux. Radiological contrast studies provide additional information for planning the therapeutic strategy [26,28].

Photos depict epidermolysis bullosa, narrowing of the esophagus is more pronounced in the upper third, related to the intake of food that causes direct damage to the esophageal mucosa. — **Figure 20.4** In epidermolysis bullosa, narrowing of the esophagus is more pronounced in the upper third, related to the intake of food that causes direct damage to the esophageal mucosa.

The goal of treatment is to facilitate swallowing and improve the nutritional status of the patient. Initial measures include dietary changes and nutritional supplementation associated with corticosteroid therapy, but only a few cases respond satisfactorily. When these measures are not sufficient to ensure adequate nutritional intake, esophageal dilation is necessary [26,28,29].

Endoscopic hydrostatic balloon dilation under direct visualization under fluoroscopic guidance is the preferred method. Balloon dilation produces radial force in the areas of stenosis and the localized lacerations are significantly smaller and therefore less likely to cause additional damage to the mucosa and esophageal perforation [26,29–31].

In situations where dilation of the esophagus is not available or in cases that do not respond satisfactorily to the procedure, a variety of surgical procedures may be used, but these procedures are complex and have high morbidity and mortality rates. Therefore, these procedures should be reserved for situations where the most conservative approach was ineffective [31].

Esophagitis in Crohn’s disease

Crohn’s disease can affect the entire GI tract. The esophagus is affected in approximately 3% of patients with ileocolonic disease, but isolated esophageal involvement is rare [32].

Esophageal symptoms range from odynophagia, heartburn, and chest pain to mild to severe dysphagia. In severe cases, bronchoesophageal or esophagogastric fistulae may develop [32].

Upper GI endoscopy reveals aphthous ulcerations and erosions usually located in the proximal esophagus, which helps in differentiating from peptic esophagitis (Figure 20.5). The typical histological finding is the presence of noncaseating granulomas, but this feature occurs in only 10% of patients [33].

Chemotherapy and radiotherapy‐induced esophagitis

Esophageal disease is present in most patients undergoing chemotherapy and has been reported as the most troubling symptoms experienced by these patients [34,35]. Different chemotherapeutic agents (5‐fluorouracil, methotrexate, vincristine, dactinomycin, bleomycin, daunorubicin, cytarabine) may induce esophageal damage, usually associated with severe oropharyngeal mucositis [36].

Photos depict Crohn’s esophageal involvement is usually with aphthoid ulceration and erosions can be seen throughout the esophagus, often located in the proximal esophagus, which helps in differentiating from peptic esophagitis. — **Figure 20.5** Crohn’s esophageal involvement is usually with aphthoid ulceration and erosions can be seen throughout the esophagus, often located in the proximal esophagus, which helps in differentiating from peptic esophagitis.

Thoracic irradiation‐induced esophageal injury may also occur either by direct toxicity or by the radiosensitizing action of agents previously used for chemotherapy [37].

Patients receiving chemotherapy or radiation therapy are also at risk of presenting concomitant infectious (viral or fungal) esophagitis which must be considered in the differential diagnosis.

Symptoms of dysphagia and odynophagia that impair proper oral feeding should raise the suspicion of esophageal inflammation in these patients.

Endoscopy plays a role in the diagnosis, allowing sampling of the mucosa for identification of co‐existing infections (e.g., cytological brushings, biopsy). However, a risk–benefit analysis for performing the procedure must consider patient factors (e.g., thrombocytopenia, neutropenia). Friability, edema, and erosions or ulcers are often found, with stricture formation as a further complication. The effectiveness of different treatment regimens for chemotherapy or radiation‐induced esophagitis has not been properly evaluated. Acid suppression, topical anesthetics (e.g., viscous lidocaine), steroids or narcotic analgesics have been routinely utilized to alleviate symptoms [38]. When identified, strictures are managed with endoscopic dilation (Figure 20.6).

Photos depict radiation- or chemotherapy-induced esophagitis can be significant and can be treated with balloon dilation if strictures are identified. — **Figure 20.6** Radiation‐ or chemotherapy‐induced esophagitis can be significant and can be treated with balloon dilation if strictures are identified.

Final considerations

Injury to the esophagus may result from a variety of causes including infection, medical treatment (chemotherapy and radiation therapy), or systemic illness. Endoscopy can be useful for diagnosing esophagitis, although a specific pattern is not identified in all cases and sampling of the mucosa may be useful in identifying the etiology of the injury.

Although other etiologies of esophageal injury occur less frequently than GERD in the pediatric population, pediatricians should be aware that esophageal symptoms may be the presenting feature of one of these conditions.