Esophagitis is usually caused by gastroesophageal reflux and other noninfectious processes. Infectious esophagitis is distinct from other gastrointestinal infections in that it generally occurs in immunocompromised children and adults and is most often caused by Candida species, either alone or in combination with viral pathogens. When infectious esophagitis occurs in nonimmunocompromised children, it is usually associated with conditions that compromise the esophageal defense mechanisms.
In view of the numerous predisposing conditions, the incidence of infectious esophagitis in children is difficult to quantify. Candida and herpes simplex virus (HSV) esophagitis has been reported in 2% to 4% in immunocompromised patients. Before the availability of combination antiretroviral therapy (cART), 8% to 10% of children infected with human immunodeficiency virus (HIV) developed Candida esophagitis. Candida esophagitis remains one of the most common opportunistic infections in HIV-infected children and generally is associated with low CD4 + T-cell count (<100/µL), prior episodes of oropharyngeal candidiasis, high HIV-1 plasma viral load, and neutropenia (<500/µL). Candida esophagitis is also reported frequently in those who have undergone chemotherapy or radiation therapy for hematologic malignancies; after solid organ and hematopoietic stem cell transplantation; in those with chronic exposure to inhaled, oral, or parenteral corticosteroid medications; and in the setting of poorly controlled diabetes mellitus.
Pathophysiology and Causative Organisms
The defense mechanisms of the esophagus against infection include motility (the continuous flow of luminal contents discourages colonization by microbes), a mucosal lining of stratified squamous epithelium that is resistant to microbial invasion, and local and systemic immune responses. Disruption of any of these protective factors may lead to esophageal infections. Immunosuppression (as seen with HIV infection or after organ transplantation), chronic mucocutaneous candidiasis, ataxia-telangiectasia, malignancy, chemotherapy, and prolonged corticosteroid treatment are the most common predisposing factors for fungal and viral infection of the esophagus. In immunocompetent children, dysmotility of the esophagus or mucosal injury secondary to gastroesophageal reflux can render the esophagus vulnerable to infections.
Most esophageal infections are caused by fungi and viruses. Candida spp. (especially Candida albicans ), herpes simplex virus (HSV), and cytomegalovirus (CMV) are the major pathogens and may be present at the same time in immunocompromised individuals. The esophagus can be infected by local invasion ( Candida, HSV, bacteria), as a result of systemic infection (CMV, Candida, Pneumocystis ), or by contiguous spread from the mediastinum or neck (tuberculosis, retropharyngeal abscess). Infections with fungi such as Pneumocystis, Aspergillus, and Histoplasma spp.; viruses such as varicella-zoster virus (VZV), human papillomaviruses, Epstein-Barr virus (EBV), and HIV; and protozoa such as Cryptosporidium and Leishmania donovani are less frequent yet well-documented causes of esophagitis.
Bacterial infections of the esophagus are probably underreported. Ten percent to 16% of esophageal infections can have a bacterial etiology, mostly in granulocytopenic patients and as a secondary infection in fungal or viral esophagitis. Mycobacterium tuberculosis and gram-positive and gram-negative organisms that are part of the oropharyngeal microbiome are most commonly identified.
Clinical Features
Patients with infectious esophagitis can present with systemic, esophageal, or abdominal signs and symptoms ( Box 43.1 ). Fever is generally found in the setting of systemic or secondary infection, such as tuberculosis or disseminated CMV infection, or complications that occur after esophageal perforation. In HSV-associated esophagitis, retrosternal pain and fevers are commonly found (all cases in one series of children). Fever does not occur commonly in bacterial esophagitis. Cough is characteristic of tuberculosis, tracheobronchial fistulas, or high-grade esophageal obstruction. A maculopapular truncal rash and fever may be present in patients with idiopathic esophageal ulceration during acute HIV infection.
Gastrointestinal complaints are the most common complaints. In adults, 59% to 79% of patients with documented esophageal infection have dysphagia and odynophagia, These may not be apparent in small children who may instead describe a sensation of food “sticking” behind the sternum or a feeling of a food or liquid bolus passing through the chest. Nausea and vomiting are associated more commonly with CMV esophagitis. The abdominal pain in esophagitis may be caused by referred pain from inflammation of the distal one-third of the esophagus, associated gastritis (as in CMV infection), or concomitant intraabdominal infections in immunocompromised hosts. Diarrhea may also be present in CMV infection (due to diffuse involvement of the gastrointestinal tract) or HIV infection (either opportunistic enteral infections or HIV enteropathy). In one report of fungal esophagitis in children, hematemesis was the most common initial symptom. Drooling is an unusual manifestation in esophagitis per se (except perhaps in HSV esophagitis ) but may be present when there is concomitant pharyngeal involvement by the infectious agent.
Thrush (oropharyngeal candidiasis) and ulcers suggestive of HSV or acute HIV infection may serve as a clue that esophageal involvement is also present. Indeed nearly all patients with untreated HIV infection and oral candidiasis and odynophagia have endoscopic evidence of esophageal candidiasis. Similarly recurrent cold sores, vesicular lesions on the nasolabial folds, and esophageal symptoms sometimes may also be seen as initial features of HSV esophagitis in immunocompetent adults and children, but their absence does not exclude HSV infection. By contrast, oral lesions are usually absent in cases of esophagitis with CMV infection and tuberculosis, and the absence of oral thrush does not rule out Candida esophagitis. HIV-infected children who develop esophageal candidiasis despite cART are less likely to have typical symptoms (e.g., odynophagia and retrosternal pain) or to have concomitant oropharyngeal candidiasis.
Finally it is important to note that some cases of infectious esophagitis are asymptomatic and identified incidentally. For example, asymptomatic Candida esophagitis has been identified during follow-up endoscopy after topical corticosteroid therapy has been given for eosinophilic esophagitis. Moreover because physicians seldom seek evidence of esophagitis in the absence of dysphagia or odynophagia, infectious esophagitis may be underdiagnosed in infants and children. Consequently the true incidence of Candida esophagitis in infants with thrush is unknown.
Differential Diagnosis
Noninfectious esophagitis can be caused by a variety of mechanisms. Pathologic gastroesophageal reflux is the most common cause of esophageal symptoms. Other causes include chemical irritation (including medications or caustic ingestions), immunologic factors (e.g., cow’s milk protein allergy), trauma (e.g., presence of nasogastric tube), radiation therapy, cancer chemotherapy, systemic disease (e.g., Crohn disease or chronic granulomatous disease), eosinophilic esophagitis, and motility disorders.
“Pill” esophagitis may be identified by history; nonsteroidal antiinflammatory drugs, potassium chloride supplements, and tetracyclines are the most commonly implicated medications. Secondary bacterial or fungal infections can be present in reflux esophagitis and Chagas disease, especially when severe inflammation and obstruction are present. Absence of reflux symptoms (long-standing heartburn, a water brash taste in the mouth, vomiting, spitting up [in infants], pillow wetting, or coughing) tends to exclude reflux esophagitis. Achalasia, diffuse esophageal spasm, foreign body impaction, and mediastinal or retropharyngeal abscesses can cause esophageal symptoms and may result in secondary infection. In addition to imaging and endoscopy (see later discussion), other available tools include 24-hour intraesophageal pH probe, esophageal impedance, and manometry.
Diagnosis
Establishing a specific diagnosis is essential for management of infectious esophagitis, particularly because fungal and bacterial superinfections occur commonly in the setting of viral esophagitis. Although the clinical profile, barium esophagogram, and endoscopic appearance can provide some clue to the etiology of esophagitis, histopathology, immunohistochemistry, and culture of endoscopic and brush biopsy specimens are essential for confirmation of specific pathogens. Serology for HSV, CMV, or EBV may help establish the diagnosis in some cases by providing evidence of acute infection. DNA detection methods also may provide evidence of viremia with these herpesviruses. Detection of fungal or viral esophagitis in an ostensibly healthy host should prompt an evaluation for the presence of primary or secondary immunodeficiency states, including HIV infection.
Barium Esophagography
The usefulness of an esophagogram in diagnosing infectious esophagitis is limited because it does not generally aid in differentiating among infectious etiologies; normal or nonspecific findings also can be found in some cases of esophagitis. Barium esophagograms are useful for assessing dysmotility, which can be a predisposing factor for esophagitis and for excluding obstruction, perforation, and fistulas of the esophagus. However, barium studies are generally not needed if endoscopy is planned.
Candida esophagitis generally is found throughout the esophagus, whereas HSV or CMV lesions are found more frequently in its mid to distal portions. Discrete longitudinal plaques, a grossly irregular or “shaggy” appearance, or tiny nodular lesions with a granular radiographic appearance are characteristic of Candida esophagitis ( Fig. 43.1 ). The presence of discrete superficial stellate ulcers in the mid esophagus with normal-appearing surrounding mucosa is characteristic of HSV esophagitis, whereas CMV lesions may mimic HSV lesions in barium esophagograms. Oval or elongated large ulcers are found mostly in CMV infection. Idiopathic esophageal ulceration is found in HIV infection. Esophagograms of patients with tuberculosis can show intramural pseudodiverticula, extrinsic compression, or esophageal displacement by mediastinal lymph nodes and sinus tracts.
Esophagoscopy
The diagnosis of esophagitis can be made by upper endoscopy with biopsies, although esophageal brushings often are of greater diagnostic yield. The technique for performing endoscopy with videoendoscope miniaturized to a diameter of 4.8 mm has made the procedure far more tolerable in immunocompromised patients, infants, and small children, and these instruments have biopsy capabilities.
Characteristic macroscopic lesions are associated with some infectious agents, but the features of these lesions overlap considerably, and histopathologic or immunohistochemical analysis (or both) of endoscopic and brush biopsy specimens is essential for specific diagnosis. A diffuse esophageal lesion is characteristic of Candida infection, whereas CMV and HSV infections mainly involve the distal part of the esophagus. White, longitudinal plaques that resemble cottage cheese and adhere to the esophageal mucosa are characteristic of Candida infection ( Fig. 43.2 ). The endoscopic severity of fungal esophagitis, which ranges from a few small raised lesions to large plaques, mucosal friability, and luminal narrowing, can be staged using Kodsi’s classification. Plaques from oral thrush, common findings in infants and immunocompromised children, can be washed away to reveal a nonulcerated underlying mucosa. Similar-appearing plaques also may be seen in CMV, HSV, bacterial, and “pill” esophagitis and after sucralfate ingestion.
Small, 1- to 3-mm vesicles are characteristic of HSV esophagitis, but by the time endoscopy is done these vesicles usually slough off and reveal sharply demarcated “volcano-like” ulcers in the distal esophagus with a raised edge, necrotic base, and normal-appearing surrounding mucosa. In progressive disease, these ulcers may coalesce to resemble Candida esophagitis. Multiple superficial ulcers in the distal portion of the esophagus often are seen in CMV esophagitis. Large elongated ulcers also are typical manifestations of CMV infection, but they may occur in idiopathic esophageal ulcerations in HIV infection as well. Complete denudation of the mucosa is an unusual finding with CMV infection. Endoscopy done in patients with VZV esophagitis can show vesicles, discrete ulcers, or necrotizing esophagitis, depending on the stage of the disease. Tubercular ulcers of the esophagus usually are of varying size, distinct, and shallow with a necrotic base.
Endoscopic biopsy specimens should be obtained from the edge and the base of the lesions. 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. Candida and Aspergillus can be shown by silver stain, periodic acid–Schiff stain, or Gram stain ( Fig. 43.3 ). Diagnostic histopathologic changes, such as multinucleated giant cells, ballooning degeneration, intranuclear Cowdry type A inclusion bodies, and margination of chromatin in HSV infection ( Fig. 43.4 ) and amphophilic intranuclear inclusions and small multiple cytoplasmic inclusion bodies in CMV infection ( Fig. 43.5 ), can be diagnostic. Immunohistochemical studies and DNA hybridization techniques often are required to establish the diagnosis, however.
