Medication-Induced Esophagitis

Drug-induced injury of the esophagus is a common cause of esophageal complaints. When potentially caustic medications fail to rapidly transit into the stomach and remain in the esophagus, dissolving and releasing their noxious contents and damaging the esophageal wall, the resulting injury is called medication-induced esophagitis. Most patients experience only self-limited pain, but esophageal hemorrhage, stricture, and perforation may occur, and, in some cases, death has been reported. “Pill-induced” esophagitis is associated with the ingestion of certain drugs ( Box 23-1 ) and accounts for many cases of erosive esophagitis. To date, close to 100 different medications have been reported to induce esophageal disorders. Anti-bacterials such as doxycycline, tetracycline, and clindamycin are the offending agents in more than 50% of cases. Other commonly prescribed drugs that cause esophageal injury include naproxen, aspirin (acetylsalicylic acid), potassium chloride, ferrous sulfate, quinidine, alprenolol, alendronate, and various steroidal and nonsteroidal anti-inflammatory agents. Drug-induced esophagitis remains an underdiagnosed entity, as many physicians and even more patients are not aware of this problem. Pill esophagitis has been reported in all age groups and in both male and female patients. However, patients with pathologic disorders such as esophageal rings, webs, compression from an enlarged left atrium, motility disorders, hiatal hernia, gastroesophageal reflux, or prolonged supine position are more susceptible.

Symptoms are usually acute and can occur immediately after ingestion of medication to as long as several hours later. Most patients present with retrosternal chest pain, odynophagia, and dysphagia, although hematemesis and melena have been reported from drug-induced esophageal damage. The sudden onset of severe retrosternal pain clearly exacerbated by swallowing should raise the possibility of pill esophagitis, even if medication has been taken correctly. In uncomplicated cases with typical symptoms, diagnostic testing may be avoided if the history of taking a potentially noxious medication is elicited. A careful history and physical examination are required to rule out complications and to permit planning of an alternative to the implicated oral medication. Hemorrhage can be the presenting symptom, particularly with use of nonsteroidal anti-inflammatory medications. Deep esophageal ulcers may lead to esophageal perforation and penetration into the adjacent major vessels or the left atrium, resulting in life-threatening or fatal hemorrhage.

When no clear offending medication can be identified by history, or when symptoms progress or persist, and in cases of hemorrhage as the presenting complaint, endoscopy is indicated for further evaluation. Endoscopy is superior to barium esophagography in identifying subtle mucosal lesions, and in establishing alternative diagnoses such as gastroesophageal reflux disease and infectious esophagitis, and findings are usually abnormal in drug-induced esophagitis. The higher yield and accuracy make endoscopy the diagnostic procedure of choice.

The junction of the proximal and middle thirds of the esophagus is a common site of injury, presumably because of lower peristaltic amplitude in this region, but any area of the esophagus may be affected. Discrete ulcers with normal surrounding mucosa are the most common endoscopic findings and can vary from a few millimeters to several centimeters in diameter. Particularly if diffuse inflammation surrounds the ulcers or is the only finding on endoscopy, biopsies help to exclude other pathology such as infection. Larger and more diffuse areas of injury, deep ulcerations, circumferential lesions, or repetitive injury may lead to fibrotic strictures requiring future dilation or even surgery.

Treatment

In most cases, withdrawal of the offending agent is sufficient to allow for healing and resolution of symptoms within several days to a few weeks. No treatment has been proven to speed recovery; however, acid suppression, sucralfate, and topical anesthetics are often used to lessen symptoms and improve oral intake. On rare occasions, prolonged severe odynophagia can lead to anorexia and the need for temporary parenteral nutrition. Complications such as strictures, perforation, mediastinitis, or hemorrhage require specific therapy.

Candida Esophagitis

While fungal species may cause life-threatening infections in some people, most individuals carry them asymptomatically. In fact, in the case of Candida albicans , such fungi are considered to be part of the benign commensal microflora that inhabits the skin, the mucosal surfaces, and the gastrointestinal tract of many healthy individuals. In the immunocompetent host, the frequency of oral yeast carriage varies from 24% in children 5 to 7 years of age to 59% in adults 60 years of age and older. The maintenance of a healthy host-fungal interaction is sustained by a complex equilibrium of several interconnected factors. Theses interactions between fungi and their hosts begin at the cell–cell interface. Fungal cells differ from animal cells primarily in the cell wall that includes numerous molecules that act as pathogen-associated molecular patterns (PAMPs). These PAMPs are recognized by the host through an array of pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), which are able to sense the different molecular moieties that comprise the fungal cell wall. Instead of a simple one-to-one interaction between each PRR and its cognate PAMP the host–fungal interaction is a complex system with many dynamic features allowing the host to discriminate between pathogenic and nonpathogenic fungi.

At least five different forms of Candida albicans can be identified (i.e., white and opaque yeast cells, pseudo-hyphae, hyphae, and chlamydospore). Although yeast forms ensure the dissemination of C. albicans , hyphae facilitate tissue invasion or biofilm formation and chlamydospores are predicted to allow survival in hostile environments. Furthermore, C. albicans can induce these different morphologic switches, such as the yeast-to-hyphae transition, in response to several stimuli encountered in the host (such as CO ₂ ), masking certain cell-wall components and unmasking others, thereby qualitatively changing the PAMPs that it exposes to the host.

The control of the fungal population by the human host is not limited to the interaction between the fungi and the immune system. It also involves an estimated 500 to 1000 microbial species that together represent the human microbiome. Several specific synergistic and antagonistic interactions have been identified that take place between bacteria and fungi in the gastrointestinal tract. For example, fluconazole resistance and virulence of C. albicans are enhanced by Pseudomonas aeruginosa, Escherichia coli , and Staphylococcus epidermis, whereas Lactobacilli species produce reactive oxygen, organic acids, and biosurfactants, all of which can inhibit C. albicans growth. Disruption of this equilibrium of the host-bacterial-fungal interaction through primary or acquired immunodeficiency can lead to severe fungal infections.

Oropharyngeal candidiasis (OPC) and esophageal candidiasis (EC) are the most common fungal infections of the gastrointestinal tract and have been well described in adults and children with underlying HIV infection. In a large pediatric study of HIV-positive patients, low CD4 counts (fewer than 200 cells per microliter) and antibiotic exposure were the most prominent risk factors for development of esophageal candidiasis. Indwelling catheters, chemotherapy, use of broad-spectrum antibiotics, and organ transplantation are additional risk factors. However, even in the immune-competent host change of the mucosal balance due to inhaled steroids for asthma therapy, swallowed steroids for treatment of eosinophilic esophagitis, or acid suppression can predispose to candidal esophagitis. Oral thrush may be an indicator of an underlying pathologic esophageal process. In a large pediatric study of esophageal candidiasis, oral thrush was the single most common presentation (94%), followed by odynophagia (80%), retrosternal chest pain (57%), fever (29%), nausea/vomiting (24%), dehydration (12%), and gastrointestinal bleeding (6%). In adults, however, oral thrush was absent in 25% of Candida esophagitis cases.

Endoscopy with brushings and biopsy is the gold standard for diagnosis and assessment of severity of Candida esophagitis. Raised, white candidal plaques in the esophagus cannot be washed away with water. Brushing of the plaques usually leads to bleeding at the site of attachment. The plaque represents desquamated epithelial cells with debris of fungal organisms, inflammatory cells, and bacteria. Esophagitis is graded based on the size of the plaques as well as severity of mucosal injury ( Table 23-1 ). Endoscopic appearance alone is insufficient for diagnosis of Candida esophagitis. Plaque-like material mimicking Candida may be found in severe reflux esophagitis, herpes simplex infection, cytomegalovirus (CMV) infection, pill esophagitis, eosinophilic esophagitis, and swallowed oropharyngeal debris. Cytologic examination of brushings is more sensitive than histologic examination of biopsy specimens to confirm diagnosis of esophagitis. Budding yeast cells, hyphae, and pseudo-hyphae are best seen by silver stain, periodic acid–Schiff (PAS) stain, or Gram stain. Brushings showing mycelial forms and budding yeast should be interpreted as confirming invasive Candida infection ( Figures 23-1 and 23-2 ). Culture of the mucosa is usually not indicated, but should be undertaken if azole-resistant Candida species are suspected or if unusual pathogens (e.g., bacterial, Mycobacterium tuberculosis , or viral esophagitis) are being entertained in the differential diagnosis of the clinical presentation. Rarely adherent plaques may not be present. An inflammatory stricture with no gross hint of a fungal cause may prove to have invasive fungal elements on biopsy.

Invasive Candida esophagitis. The mucosa is necrotic, and the yeasts are within the mucosa (Hematoxylin & Eosin [H&E], ×132). ( See plate section for color. )

(Courtesy David R. Kelly, MD, Children’s Hospital of Alabama and University of Alabama.)

Yeasts, germ tubes (chlamydospores), and pseudo-hyphae of Candida in esophageal brushing specimen (GMS, ×330). ( See plate section for color. )

(Courtesy David R. Kelly, MD, Children’s Hospital of Alabama and University of Alabama.)

Treatment

Systemic antifungal therapy using oral or parenteral fluconazole has been the mainstay in the management of esophageal candidiasis for over two decades. Topical antifungals such as nystatin, clotrimazole, and miconazole are of minimal value in EC and are now reserved to treat candidal colonization in patients with normal immune function. The initial step in the management of EC should minimize, to the extent possible, predisposing factors, such as corticosteroids, chemotherapeutic agents, and antimicrobials.

Fluconazole, like all triazole agents, inhibits the fungal cytochrome system required for fungal sterol synthesis to maintain cell-wall integrity. The triazoles affect the fungal cell membrane permeability, leading to injury and cell death. They have excellent oral bioavailability, with levels after oral administration greater than 90% of the levels achieved with intravenous dosing. Intravenous therapy is indicated only in patients who are unable to swallow. Absorption is facilitated by gastric acid; thus, it is important to avoid simultaneous acid reduction therapy if possible. Because triazole agents are much less potent inducers of the cytochrome P450 system compared to earlier azole agents (ketoconazole), there is less potential for significant drug–drug interactions. Moreover, fluconazole demonstrated a more rapid onset of action and quicker resolution of symptoms. Fluconazole is now the drug of choice for both treatment and prophylaxis of candidal esophagitis in patients with either granulocyte or lymphocyte dysfunction. Toxicities are uncommon and can include nausea, headache, and rash; significant hepatotoxicity is rare.

Itraconazole has also been shown to be effective in the treatment of EC. Patients treated with itraconazole oral solution had clinical response rates comparable to those of patients treated with fluconazole of 94% and 91%, respectively, without significant adverse effects in either group. The mycologic cure rates were also similar at 92% and 78%, respectively.

The echinocandin class of antifungals, which includes caspofungin, micafungin, and anidulafungin, works by a different mechanism. These antifungal agents inhibit the 1,3-beta- d -glucan synthase. The resulting reduced formation of 1,3-beta- d -glucan, an essential polysaccharide comprising 30% to 60% of Candida cell walls, leads to osmotic instability and cellular lysis. All three agents have demonstrated excellent in vitro activity against a broad array of Candida species, including those that are resistant to fluconazole, itraconazole, or voriconazole. In a direct comparison of fluconazole 200 mg/day and caspofungin 50 mg/day in 177 adult patients, caspofungin was found to have response and relapse rates similar to those of fluconazole. In another clinical trial, the treatment of EC among HIV-positive patients was also found to be similar for micafungin 150 mg/day when compared to fluconazole 200 mg/day. A separate multicenter clinical study in HIV-positive adult patients (n = 601, 75% with acquired immunodeficiency syndrome [AIDS]) showed comparable clinical response for anidulafungin versus fluconazole in patients with EC, in terms of both efficacy and safety. Although the echinocandins are not considered first-line therapy for candidal esophagitis, they are effective antifungals for the treatment of EC in HIV-positive patients. Their use, however, is limited because of the lack of an oral formulation. Several large adult studies have shown the benefit of oral fluconazole in the prevention of serious candidal infections in patients undergoing bone marrow or solid organ transplantation, acute leukemia patients undergoing intensive cytotoxic chemotherapy, and critically ill patients in intensive care units who are taking broad-spectrum antibiotics. Many treatment protocols now incorporate triazole agents as part of their standard prophylaxis regimen. The risk of emergence of acquired fluconazole resistance appears to be low in these settings. More controversial is the role of prophylaxis in HIV-infected patients. The main rationale for use of antifungal prophylaxis in these patients has been prevention of cryptococcal infections, which are associated with significant morbidity and mortality. Cyclical therapeutic protocols have been reported in small populations. Because of concern of development of antifungal resistance, current U.S. Public Health Service/Infectious Diseases Society of America (IDSA) guidelines do not recommend routine use of primary antifungal prophylaxis with triazole agents. Chronic secondary prophylaxis with fluconazole may be appropriate for patients with multiple or severe recurrences of Candida esophagitis.

Chronic mucocutaneous candidiasis is a rare clinical syndrome in which patients have persistent or recurrent candidal infections of the skin, nails, and mucous membranes. Invasive or disseminated infection is rare. A common immunologic abnormality is failure of the patient’s T lymphocytes to produce cytokines that are essential for expression of cell-mediated immunity to Candida . Patients with chronic mucocutaneous candidiasis are at increased risk of developing autoimmune disorders (hemolytic anemia, idiopathic thrombocytopenic purpura, chronic active hepatitis, juvenile rheumatoid arthritis), and endocrinopathies (hypoparathyroidism, hypothyroidism, and Addison’s disease). These patients require chronic prophylactic therapy and are at high risk to develop resistant strains.

Herpes Simplex Esophagitis

Herpes simplex virus (HSV) has been well described as a common cause of ulcerative esophagitis in the immunocompromised host. Particularly patients undergoing solid organ transplantation (SOT), bone marrow transplantation, and high-dose chemotherapy regimen are at risk for esophageal involvement and severe disseminated disease. In the immunocompetent host, HSV esophagitis (HSVE) has rarely been reported, despite the high prevalence of primary and recurrent HSV infection in the general pediatric population. Clinical features such as labial and oropharyngeal ulcers are frequently seen in acute infection or reactivation of the disease; however, HSV esophagitis has been reported in immunocompetent children without any evidence of herpetic lesions on the lips or oropharynx. Herpes simplex virus 1 (HSV-1) is almost exclusively the causative infectious agent, although rare cases of HSV-2–induced esophagitis have been reported.

The gold standard for diagnosis is upper endoscopy. The earliest manifestation is vesicles of squamous mucosa in the distal esophagus, although this early stage is rarely seen on upper endoscopy. Lesions coalesce, leading to nonspecific appearing ulcers usually smaller than 1 cm in greatest dimension. These are sharply demarcated superficial ulcers with raised margins and yellow-gray bases (“volcano-like” appearance). Plaque-like lesions with erythematous and friable mucosa that mimics Candida may also be present. Uninvolved mucosa appears normal. The diagnosis of HSV esophagitis is made by histopathologic evaluation, viral culture, and polymerase chain reaction (PCR). Biopsies obtained from the margins of ulcers are more likely to show characteristic changes including multinucleated giant cells, cellular “ballooning,” and the presence of eosinophilic intranuclear inclusions. Immunohistochemical stains for debris obtained from brushing ulcers may be useful in identifying sloughed HSV-infected cells. Culture of HSV from esophageal biopsies is considered diagnostic and has been reported to have a higher yield than histologic techniques.

Treatment

The therapeutic approach for HSV esophagitis is guided by the immune status and disease severity of each patient. In patients with severe odynophagia or dysphagia, hospitalization for hydration, nutrition, and pain management may be required regardless of immune status. Intravenous acyclovir can be used in severely ill patients that are unable to tolerate oral therapy and can be switched as soon as tolerated to an oral regimen to complete the therapeutic course.

Immunocompetent

HSV infection in healthy individuals tends to be self-limited, and generally requires only supportive care. Resolution of symptoms is expected within 1 to 2 weeks after onset of illness and can be gradual. Oral acyclovir has not been studied in a prospective randomized controlled fashion in immunocompetent patients; however, case reports as well as experience with treatment of other herpes infections suggest therapeutic benefit, by improving resolution of lesions and symptoms. Unless symptoms are already decreasing or the disease appears to be abating, a short course of oral acyclovir to hasten recovery is suggested (400 mg every 8 hours for patients older than 2 years of age: max 80 mg/kg/day) for 7 to 10 days.

Immunocompromised

The drug of choice for treatment in the immunocompromised hosts is acyclovir (oral, 80 mg/kg per day, up to 1600 mg/day in three to five doses for 14 to 21 days; IV: 15 to 30 mg/kg per day in three divided doses for 14 to 21 days). The decision to use parenteral therapy is based on the patient’s ability to take oral medication and the severity of disease. Relapse may occur in immunocompromised patients and is reported in up to 15% of HIV-infected individuals. Such patients may require prolonged suppressive therapy. Acyclovir-resistant HSV infections have been described, especially in immunocompromised patients maintained on long-term therapy. Acyclovir resistance results from mutations within the thymidine kinase (TK) or less commonly the DNA polymerase gene of HSV. Viruses with the TK mutation are generally cross-resistant to other medications in the same class, such as valacyclovir and famciclovir, but remain susceptible to antiviral agents that target DNA polymerase such as foscarnet (IV, 80 to 120 mg/kg per day in two to three divided doses).