Esofagitis

01Pathophysiology

Esophagitis refers to inflammation of the esophageal mucosa, and the mechanism differs based on the underlying cause. Understanding what drives each subtype is essential because the pathophysiology directly predicts the clinical presentation, endoscopic appearance, and treatment approach.

Reflux esophagitis results from prolonged exposure of the esophageal squamous epithelium to gastric acid and pepsin. The lower esophageal sphincter (LES) is either transiently relaxed or chronically hypotonic, allowing retrograde flow of acidic contents. The distal esophagus bears the brunt of the injury, leading to erosions that start at the gastroesophageal junction and extend proximally. Chronic reflux can trigger Barrett metaplasia, where the normal stratified squamous epithelium undergoes intestinal metaplasia to columnar epithelium with goblet cells, a precancerous change.

Eosinophilic esophagitis (EoE) is an immune-mediated, antigen-driven process. In genetically predisposed individuals (often with a strong atopic background), food or aeroallergens trigger a Th2-mediated inflammatory cascade. Interleukin-5 and interleukin-13 recruit eosinophils into the esophageal mucosa, where they degranulate and release cytotoxic proteins. Over time, this causes subepithelial fibrosis and stricture formation, which explains why patients present with solid-food dysphagia and episodes of food impaction rather than heartburn.

Infectious esophagitis occurs almost exclusively in patients with impaired cell-mediated immunity, most classically in HIV/AIDS with a CD4 count below 100 cells/mm${}^3^3$. The three major pathogens are:

• Candida albicans: The most common cause. The organism adheres to damaged squamous epithelium and forms pseudomembranes (white plaques). Because Candida also colonizes the oropharynx, concurrent oral thrush is a strong clinical clue.

• Herpes simplex virus (HSV): The virus infects squamous epithelial cells, causing cell lysis at the ulcer margins. This produces well-circumscribed, shallow, "punched-out" or volcano-like ulcers, often in the mid to distal esophagus. Histology reveals multinucleated giant cells with Cowdry type A inclusions (intranuclear eosinophilic inclusions with a surrounding halo).

• Cytomegalovirus (CMV): Unlike HSV, CMV infects endothelial cells and fibroblasts in the ulcer base, not the squamous epithelium at the margins. This produces fewer but larger, deeper, and more linear ulcers. Biopsy must be taken from the base of the ulcer (not the edges), and histology shows large cells with intranuclear "owl-eye" inclusions.

Pill esophagitis results from direct chemical injury to the mucosa when a tablet lodges in the esophagus, usually at points of anatomic narrowing (aortic arch, left atrium, LES). The medication dissolves locally and creates a caustic environment. Common culprits include bisphosphonates (alendronate), doxycycline, potassium chloride, NSAIDs, and iron supplements. Patients characteristically report sudden-onset odynophagia and can often pinpoint exactly when it started. The injury is typically a discrete ulcer at the mid-esophagus level.

Radiation esophagitis develops in patients receiving thoracic radiation therapy (commonly for lung, esophageal, or mediastinal cancers). Ionizing radiation damages rapidly dividing basal epithelial cells, leading to mucosal atrophy, ulceration, and in chronic cases, fibrosis and stricture.

02Classification and Clinical Manifestation

03Diagnostic Workup

The diagnostic approach depends heavily on the clinical context.

In an immunocompromised patient presenting with odynophagia, the best initial step is to look for oral thrush. If thrush is present, the most likely diagnosis is Candida esophagitis, and the correct next step is an empiric trial of oral fluconazole without endoscopy. This is a commonly tested principle. Endoscopy is reserved for patients who fail empiric antifungal therapy (no improvement in 5-7 days) or who present without oral thrush, because the absence of thrush raises the likelihood of HSV or CMV, which require biopsy for diagnosis.

When endoscopy is performed, the appearance of the ulcers and the location of biopsy are both high-yield concepts. For HSV, the characteristic finding is multiple small, shallow, well-circumscribed ulcers, and biopsies must be taken from the edges of the ulcers because HSV infects squamous epithelial cells at the ulcer margin. For CMV, the ulcers are large and deep, and biopsies must be obtained from the base of the ulcer because CMV infects the granulation tissue (endothelial cells and fibroblasts) at the ulcer floor. Getting the biopsy location wrong leads to a false-negative result, and this distinction is frequently tested.

For eosinophilic esophagitis, endoscopy reveals a constellation of findings: concentric rings (trachealization or "ringed esophagus"), linear furrows, white exudates (eosinophilic microabscesses), and mucosal fragility (crepe-paper mucosa). However, the diagnosis is confirmed only by biopsy showing >=15 eosinophils per high-power field in the esophageal mucosa, taken from both the proximal and distal esophagus. A critical step before making this diagnosis is ensuring the patient has had an adequate PPI trial (8 weeks of high-dose PPI), because PPI-responsive esophageal eosinophilia can mimic EoE. Current guidelines have evolved on this point, with newer consensus statements recognizing that PPI responsiveness does not exclude EoE, but exam questions may still frame PPI trial as a prerequisite.

For reflux esophagitis, the diagnosis is usually clinical. Endoscopy is indicated for alarm features (dysphagia, weight loss, anemia, age >60 with new symptoms) and reveals erosions in the distal esophagus classified by the Los Angeles grading system (A through D based on erosion length and circumferential extent). Barrett esophagus is identified by salmon-colored mucosa extending above the GEJ, confirmed on biopsy by intestinal metaplasia with goblet cells.

04Management and Treatment

Acute stabilization differs by subtype. For infectious esophagitis in a severely immunocompromised patient who cannot swallow, the priority is IV therapy (IV fluconazole for Candida, IV acyclovir for HSV, IV ganciclovir for CMV) along with IV fluid support. For food impaction in EoE, emergent endoscopic disimpaction is the immediate step, followed by initiation of maintenance therapy to prevent recurrence.

Long-term management of EoE centers on maintaining remission with either ongoing swallowed topical steroids or dietary elimination. Unlike reflux esophagitis, PPI monotherapy is typically insufficient. Esophageal dilation is reserved for patients with established strictures causing persistent dysphagia, and it should be performed carefully because the esophageal mucosa in EoE is notably fragile.

For reflux esophagitis, the standard course is 8 weeks of PPI therapy followed by reassessment. Patients with erosive esophagitis (Los Angeles grade C or D) or Barrett esophagus generally require long-term PPI maintenance. When stepping down, switching to an H2 blocker or on-demand PPI use is appropriate for patients with mild disease.

A commonly tested contraindication: ganciclovir is myelosuppressive. In patients already pancytopenic from HIV or chemotherapy, ganciclovir may worsen the neutropenia. In this scenario, foscarnet is the preferred alternative, though it carries its own toxicity profile (nephrotoxicity, electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia).

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on esophagitis questions is by jumping to endoscopy in every immunocompromised patient with odynophagia. The tested principle is that if an HIV patient has odynophagia AND oral thrush, the next best step is empiric fluconazole, not endoscopy. Endoscopy becomes the answer only when empiric therapy fails or when thrush is absent.

The second major trap involves biopsy technique in infectious esophagitis. Students frequently forget that HSV and CMV require biopsies from different locations. HSV infects squamous cells at the ulcer margin (biopsy the edge), while CMV infects stromal cells at the ulcer floor (biopsy the base). If a question describes endoscopic findings and asks about the best biopsy approach, this distinction is what they are testing.

For eosinophilic esophagitis, the trap is confusing it with GERD because both may show partial PPI response and both involve the esophagus. The discriminators are the patient profile (young, male, atopic), the symptom pattern (solid-food dysphagia with food impaction rather than heartburn), and the biopsy threshold (>=15 eos/HPF). Another subtle trap is the treatment: students sometimes choose inhaled fluticasone, but the correct answer for EoE is swallowed fluticasone (the patient is instructed to puff the inhaler into the mouth and swallow, not inhale).

For pill esophagitis, the classic vignette describes a patient who took a medication (often doxycycline or alendronate) with minimal water just before going to bed, then woke up with acute retrosternal pain and odynophagia. The key teaching point is that the ulcer is typically at the mid-esophagus (level of the aortic arch), and management is supportive with medication discontinuation, not antifungals or antivirals.

The overarching competency being tested across all esophagitis subtypes is the ability to integrate the patient's immune status, symptom pattern, and endoscopic appearance to arrive at the correct diagnosis and then select the appropriate next step in management without over-testing or under-treating.