Introduction
Abdominal pain and chest pain represent the two most prevalent pain complaints to the US emergency departments each year at 8.6% and 5.2%, respectively. Of those presenting with chest pain, the esophagus is a not uncommon etiology. Fruergaard et al., for example, demonstrated that 42% of patients admitted to a Coronary Care Unit were later found to have esophageal pain or discomfort, not acute coronary syndrome. Accordingly, it is prudent for the modern pain clinician to be well versed in esophageal pain syndromes and their corresponding treatments. What follows is a generalized discussion of esophagitis, highlighting varied common pathophysiologies.
Etiologies and Pathogenesis
Some of the more prevalent etiologies of esophagitis and esophageal injury include eosinophilia, infection, radiation, malignancy, motility disorders, alcohol, and traumatic/surgical. Gastroesophageal reflux disease (GERD) as a cause of esophagitis is a larger topic, and we will, therefore, do justice by discussing it elsewhere in this textbook.
Eosinophilic esophagitis (EoE) is an immune/antigen-mediated disorder characterized by esophageal dysfunction due to a pathologic eosinophilic infiltration. Intramucosal eosinophils are hypothesized to be recruited via a chain reaction, which is initiated by antigenic proteins (most frequently food, less often inhaled particles) that trigger helper T-cells to release inflammatory cytokines (e.g., interleukin 5). ,
Infectious esophagitis (IE) is more prevalent in immunocompromised hosts, for example, human immunodeficiency virus (HIV) and transplant patients (bone marrow > solid organ) but has also been described in patients on chronically inhaled fluticasone for COPD. Although there are others, certainly the most frequented pathogens in IE are the herpes simplex virus (HSV), cytomegalovirus (CMV), and candida species. CMV specifically is most often seen in HIV patients with CD4 counts <50.
Medication or “pill” induced esophagitis is thought to occur secondary to direct mucosal injury of the offending pill at a tight juncture within the esophagus. The most common site of esophageal anatomical narrowing is near the aortic arch. Frequent offenders include antibiotics, bisphosphonates, nonsteroidal antiinflammatory drugs (NSAIDS), aspirin, emepronium, alprenolol, pinaverium, potassium chloride, quinidine, and iron-containing compounds. The mechanism of injury is hypothesized to include caustic injury due to the acidity of the dissolving medications leading to hyperosmolar tissue destruction and vascular injury. Additionally, NSAIDs or aspirin may disturb the protective mucosal lining of the stomach and esophagus normally mediated by prostaglandins. Risk factors for pill esophagitis include old age, large pill size, swallowing the pill with minimal or no fluid, patient positioning during pill swallowing, and abnormal esophageal anatomy.
Radiation therapy directed toward or near the esophagus may disrupt the normal process of cell turnover within the esophagus that can lead to mucosal thinning and denudation. Predictors of the likelihood that a patient might develop radiation esophagitis (RE) include the dose and technique used for radiation therapy, concurrent treatment with chemotherapy, and preexisting esophageal disease.
Esophageal malignancy generally comes in the form of adenocarcinoma or squamous cell carcinoma (SCC). Obesity, GERD, smoking, and diets low in fruits and vegetables are all risk factors for esophageal adenocarcinoma. Barrett’s esophagus, a form of metaplasia where chronic gastric acid exposure causes columnar to squamous metaplasia of the lower esophageal epithelium, is considered a complication of GERD. This metaplasia is then a risk factor for further damage, dysplasia, and thereby adenocarcinoma. Hereditary conditions such as Peutz–Jeghers syndrome along with others associated with mutations in the PTEN gene meanwhile pose an increased risk of esophageal SCC. Smoking and alcohol use, however, are the largest modifiable risk factors and account for nearly 90% of esophageal SCC in the United States.
Esophageal motility disorders are classified by the Chicago classification based on relaxation at the esophago-gastric junction (EGJ) and pattern of peristalsis. Dysfunction of peristalsis accompanied by impairment of relaxation at the EGJ is characteristic of achalasia. When relaxation at the EGJ is not impaired, diagnosis is based on the peristaltic pattern within the esophagus. The complete absence of peristalsis is usually a feature of scleroderma. Contrarily hyper-peristalsis suggests either a hypercontractile “jackhammer” (formerly “nutcracker”) esophagus (possibly due to a hyper-cholinergic state) or distal esophageal spasm.
Alcohol consumption has been linked to GERD, although somewhat controversial. Conflicting data have been published over the years regarding the association between alcohol and reflux. More recently, Pan et al. have published a meta-analysis demonstrating a clear link between the two; however, other large-scale studies have failed to demonstrate an association. This has led some investigators to consider alcohol an intermittent trigger of reflux events in the short term, rather than a causative agent of longer-term persistent reflux or esophagitis. Alcohol is hypothesized to cause reflux by decreasing lower esophageal sphincter (LES) tone or by reducing peristalsis within the lower esophagus. Alternatively, animal studies have suggested that alcohol might have the ability to cause direct noxious injury to esophageal mucosa.
Lastly, depending on size and location, penetrating esophageal injury has the potential to be catastrophic, and should be considered a surgical emergency until proven otherwise. Esophageal injury is most often (>50%) iatrogenic, being caused by proceduralists intervention. Most frequently this occurs during endoscopy, but can also be a complication of transesophageal echocardiogram or pneumatic dilation. Other causes of esophageal perforation include (in decreasing frequency): Boerhaave’s syndrome (full-thickness tear of the esophageal wall often caused by severe retching/emesis), foreign body ingestion, trauma (e.g., penetrating stab injuries), intraoperative injury, and malignancy. , This condition can have mortality rates upwards of 20%, largely in part due to the esophagus’s real estate with adjacent proximity to other high acuity organs (trachea, heart, lungs).
Clinical Features
Clinical features of esophagitis generally present as some combination of heartburn, dysphagia, odynophagia, regurgitation, feelings of food impaction, and rarely hematemesis. , The pain is typically described as retrosternal, chest or upper abdominal, and may or may not radiate to the back. , , Herpes labialis and oral vesicles are specifically more suspicious of HSV IE. In HSV, the vesicles eventually coalesce to form well-circumscribed ulcers but usually smaller than those identified in CMV.
Harmful clinical features of radiation on esophageal tissue may be seen as early as 2–3 weeks from commencing therapy and as late as 3 months after completion of therapy. Early/acute effects will be similar to those seen in other causes of esophagitis while later effects of RE usually relate to strictures, motility alterations, perforation, and/or fistula. A small percentage of esophageal cancer is detected early via routine surveillance. For a majority of patients, however, oncologic symptoms prompt clinician visits and evaluation. As malignancy progresses, it may present with signs of esophageal lumen obstruction (dysphagia to solids) due to frank mass plus the red flag of unwarranted weight loss. Contrarily, insidious dysphagia of both solids and liquids is more suggestive of an esophageal motility disorder (e.g., achalasia). Sudden acute chest pain that radiates to the back or left shoulder is often the cardinal symptom of the dreaded esophageal rupture. A triad of chest pain emesis and subcutaneous emphysema is known as Mackler’s triad and should be very suspicious for an esophageal perforation. , Along the lines of emphysema, any penetrating esophageal injury may also demonstrate Hamman’s sign on mediastinal auscultation that is a crunching sound felt to result from the heart beating against air-filled tissues. Finally, other ominous indications of esophageal penetration may involve rapid development of a systemic inflammatory response (tachycardia, fever) or bacterial-related sepsis.
Diagnosis
Diagnostic evaluation of esophagitis begins with a thorough history and physical examination primarily of the oral/labial region. Further assessment may consist of lab work, endoscopy, biopsy, and occasionally barium esophagram or other imaging (CT, MRI).
Eosinophilic esophagitis is histologically defined by an eosinophilic predominance and is primarily a diagnosis of exclusion. , , , Characteristic EoE endoscopic findings include linear furrows (longitudinal creases), esophageal trachealization (mucosal stacked rings), changes to vascular patterns in the subepithelium, small caliber esophagus, white papules/exudates (eosinophil microabscesses), and strictures. , , Barium studies for assessment of anatomical changes and esophageal dysfunction may be helpful as well. , In 2018, the international consensus for EoE diagnostic criteria was updated to include the following: symptoms of esophageal dysfunction, biopsy demonstrating ≥15 eosinophils per high power field (~60 eosinophils/mm 2 ), and rule out of alternative causes of esophageal eosinophilia. ,
Biopsies in HSV IE should reveal multinucleated giant cells with ground glass nuclei and eosinophilic inclusions. CMV lesions meanwhile appear as shallow lower esophageal erosions/ulcerations on endoscopic exam. Histological analysis of CMV uncovers cytomegalic cells and intracytoplasmic or intranuclear inclusions. White oral thrush is suspicious of candida esophagitis and similarly Candida appears as white plaques on endoscopy. Biopsies show yeasts with pseudohyphae while cultures should grow out the Candida species (usually albicans, but glabrata, krusei, and tropicalis are occasionally seen).
Regarding pill esophagitis, diagnosis is frequently made by history and clinical suspicion alone. Invasive diagnostic studies are rarely warranted except in patients with severe or rare findings (e.g., hematemesis). Upper endoscopy and biopsy may help rule out other causes. If esophageal compression is suspected based on exam, a barium esophagram may be clinically useful to further delineate patients’ anatomy.
In radiation esophagitis, endoscopic exam may reveal ulcers, mucositis, and/or strictures while biopsy should show evidence of fibrotic tissue with chronic inflammation and epithelial thickening.
Early endoscopic findings of esophageal malignancies often appear as plaque or ulcers while later stages may show circumferential masses causing strictures and increased luminal obstruction. Diagnosis is typically confirmed via direct endoscopic biopsy or histological examination of metastases.
Diagnostic workup of suspected motility disorders begins with upper endoscopy that may demonstrate retained food products and increased resistance to passing the endoscope at the EGJ. Endoscopy is often followed by manometry which, in achalasia, may show absent peristalsis in the lower two-thirds of the esophagus and above average integrated relaxation pressure at the LES. Manometry in the jackhammer esophagus would show sequential abnormally elevated esophageal contraction pressure in the setting of normal LES relaxation. When the manometric findings are equivocal, barium swallow is suggested, which on patients with achalasia would demonstrate delayed emptying, aperistalsis, narrowing at the EGJ, and abnormal esophageal dilation.
Radiographic evidence is instrumental to the diagnosis of esophageal traumatic perforation. Plain chest radiographs, for example, may demonstrate pneumomediastinum, subcutaneous emphysema, pneumothorax, lung collapse, and pleural effusion. Meanwhile, a water-soluble contrast swallow study (plain films or computed tomography) should reveal obvious leak often in need of urgent or emergent repair. , ,
Physical Exam
There are no pathognomonic findings for esophagitis and most patients will have unremarkable findings. As previously mentioned, the examination of the oral cavity may reveal thrush, suggesting the presence of candidiasis, which is commonly associated with esophageal candidiasis. The presence of oral herpetic lesions may also indicate herpetic esophagitis. Patients with EoE may present with signs of atopy, such as wheezing on lung auscultation and atopic dermatitis. Abdominal exam is typically benign without positive findings.
Treatment
Esophagitis treatment is often divided into curing the underlying etiology (e.g., antivirals in HSV) and treating the symptomatology (e.g., esophageal dilation, stents, Heller myotomy/fundoplication). , As the supportive options apply to most etiologies, what follows will touch on the more directed curative therapies.
The prevalence of food allergies is higher in patients diagnosed with eosinophilic esophagitis. Accordingly, prevention via avoiding the known triggering allergen is the first line, as it is effective and inexpensive. Next line therapy, is generally suggested as an 8-week course with a proton pump inhibitor (PPI). For EoE suffering patients still refractory, topical steroids are the therapy standard as they have been found to improve 95% of cases and systemic corticosteroids are reserved for the most extreme cases given their undesirable adverse effects. , Specifically, fluticasone and nebulized budesonide are the topical agents of choice, where patients are instructed to swallow as opposed to inhale the medication. , , It is often suggested to continue corticosteroid therapy as maintenance in the hope of avoiding relapse. There are experimental agents being studied for the treatment of EoE, such as monoclonal antibodies targeting various interleukins, prostaglandin antagonists, and montelukast.
Oral acyclovir (7–10 days) is the mainstay in HSV treatment with immunocompromised patients oftentimes necessitating longer treatments (14–21 days). Intravenous (IV) acyclovir is traditionally reserved for HSV in-patients with severe odynophagia. In patients with high clinical suspicion of CMV esophagitis, empiric treatment with ganciclovir > foscarnet should commence immediately, rather than wait for pathologic confirmation. IV induction is often recommended given patients’ moderate-to-severe odynophagia but with symptomatic improvement may be transitioned to oral. The induction phase generally lasts 3–6 weeks. Furthermore, as perhaps alluded to, the patient population that tends to develop CMV esophagitis is frequently not on or not compliant with HIV antiretroviral therapy (ART). Therefore, it is a first-rate recommendation to commence treatment (the exception being if there is concomitant CMV retinitis in which case ART risks immune reconstitution inflammatory syndrome). Maintenance therapy with oral valganciclovir is typically reserved for patients with recurrences or those with concurrent CMV retinitis. Candida esophagitis is treated with typical antifungals such as fluconazole (alternatively voriconazole, posaconazole, or itraconazole) for a 14–21-day course. Due to their increased cost and IV preparation, Echinocandins (capsofungin, micafungin, anidulafungin) are generally considered the second line. Amphotericin is a known toxic drug and such is reserved for drug-resistant cases and during pregnancy (azoles are known teratogens and echinocandins have not been studied in pregnancy). ,
Prevention is the best treatment for “stuck pill” esophagitis. In patients with known difficulty swallowing, liquid formulations may be preferred to tablets or capsules. Patients should be guided to take their medication with at least 8oz of water and remain upright for at least 30 min after ingestion.
Although cessation of radiation is likely to improve symptoms in radiation caused esophagitis, this approach is likely to interfere with malignancy outcomes.
Surgical resection is the recommended treatment when patients present with early esophageal malignancy as it can be curative. However, once there exist metastases to other organs or lymph nodes, resection may be less advised. Radiation and chemotherapeutics may be used as neoadjuvants (to decrease tumor size preoperatively) or as adjuvant treatment in patients who are poorer surgical candidates.
In suspected achalasia, patients are often treated with 4 weeks of a PPI before any diagnostic workup. For confirmed achalasia, nitroglycerin or isosorbide dinitrate (not available in the US) may be prescribed before meals. Unfortunately, pharmacotherapy is often insufficient for achalasia but may be an attractive option for those that are not surgical candidates. Injected botulinum toxin and pneumatic dilation at the LES may be offered as interventional options in achalasia, where laparoscopic Heller myotomy with fundoplication offer the most invasive options. Recently, peroral endoscopic myotomy has been gaining popularity as an ostensibly less invasive option for patients with achalasia. During this endoscopic procedure, an incision is made through the mucosa of the esophagus and the endoscope is tunneled from the submucosa of the esophagus into the gastric cardia. Once there, the muscularis propria can be severed with endoscopic tools and decreased LES pressures achieved. As this endoscopic myotomy is not accompanied by antireflux measures such as fundoplication, there is potential for resultant GERD postoperatively. In jackhammer esophagus, it is recommended to first control heartburn symptoms with 3 months of PPI ± H2-antagonists. Peppermint oil serves to relax the esophageal smooth muscle that may provide symptomatic relief. The second line for esophageal smooth muscle relaxation is calcium channel blockers such as diltiazem. For scleroderma related disease, a promotility agent (e.g., metoclopramide) may be of more utility. Patients with scleroderma who exhibit esophageal strictures or webs are offered pneumatic dilation treatment. In scleroderma patients exhibiting bad reflux, surgical correction via Nissen fundoplication is the procedure of choice after more conservative options like PPIs, promotility agents, and dilations have been exhausted.
Akin to pill esophagitis, as mentioned earlier for pill esophagitis, alcohol-related reflux is best treated with prevention through abstinence. Alcohol is considered a trigger of symptoms in these cases, and patients are counseled to avoid it.
Esophageal perforation should be regarded with some trepidation as patients may be critically ill. , First recommendation is that all patients be immediately nil per os and transferred to a higher acuity setting with near continuous oxygen monitoring. In instances of contained perforation or limited injury, conservative nonoperative treatment modalities may suffice with broad-spectrum antibiotics, IV hydration, PPIs, and possibly nutritional support. Conversely, in patients that are critically ill or with larger/mal-positioned esophageal perforations, immediate surgical repair may be warranted. When the perforation is due to a more distal stricture, a myotomy ± fundoplication might be indicated. T-tubes (shaped like the letter “T”) is a surgical option that creates an esophagocutaneous fistula that permits drainage, allowing time for the local tissue to heal and is typically removed after 4–6 weeks. , Occasionally, prompt partial or complete esophageal resection may be obligatory, but in this urgent/emergent setting, mortality remains high (15%–40%). ,
Pain Treatment
Esophageal nociception is carried by two varieties of pain fibers. The general somatic afferent myelinated small diameter A∂ fibers transmit fast somatosensory sharp and abrupt pain. The general visceral afferent unmyelinated smaller diameter C-fibers transmit slow visceral dull or burning discomfort that is less well localized and often attributed to heat (gastric acidity) or chemicals. These afferent neurons are carried with the vagal and spinal (C1–L2) nerves. , ,
Coffee, caffeine, alcohol, spicy foods, and foods at extremes of temperature may all exacerbate esophageal pain and should be avoided. Bland pureed soft foods are the ideal. Proton-pump inhibitors and competitive H2 receptor antagonists may be of benefit in decreasing heartburn-type discomfort.
Further pain therapeutics are advised for in-line with the World Health Organization’ (WHO) pain relief ladder, which was originally designed for cancer-related pain, but now is widely applied to all types of pain. In the ladder model, nonopioids are described as first line (e.g., NSAIDs, acetaminophen), mild opioids (e.g., codeine, tramadol) are second line, and stronger opioids (e.g., morphine, hydromorphone) are reserved for severe refractory pain. Along any step of the ladder, adjuvants may be added as appropriate (e.g., gabapentinoids, steroids, antidepressants). This three-step approach has been described as effective in 80%–90% of patients. In patients where this pain ladder proves insufficient, a fourth step ( Fig. 22.1 ) has been proposed that concerns itself with interventional pain approaches, which in our esophageal-related pain discussion may include high thoracic epidurals and intrathecal drug-delivery systems.
