Dysphagia and Odynophagia

in HIV Patients

Chinese Version

Klaus E. Mönkemüller, M.D., C. Mel Wilcox, M.D.

 

INTRODUCTION

               Esophageal disorders are a common complication of HIV-infected patients and in a significant number of patients the esophagus may be the site of the first AIDS-defining opportunistic illness. The most common causes of esophageal disease in AIDS are infections such as Candida and Cytomegalovirus. Opportunistic disorders such as cytomegalovirus (CMV) and idiopathic esophageal ulceration rarely present until the CD4 lymphocyte count falls below 100/µl. Almost all esophageal infections in patients with AIDS are treatable; therefore, a thorough work-up is indicated. In the symptomatic patient, a definite diagnosis followed by treatment usually results in an improved ability to eat, weight gain and consequently a better quality of life. The most valuable tool for evaluating esophageal complaints in AIDS is endoscopy. The long-term prognosis for most esophageal disorders is dictated primarily by the degree of underlying immunodeficiency. With the widespread use of more effective antiretroviral therapy including the protease inhibitors, the incidence of many opportunistic diseases is decreasing. Unfortunately, there are several reports of resistance of HIV-1 to multiple antiretroviral agents, and thus it is possible that we will observe a rise in various opportunistic disorders again. The aims of this chapter are to summarize the available data on the spectrum of pathogens causing esophagitis in AIDS, to provide a practical approach to the clinical presentation of esophagitis (e.g. dysphagia or odynophagia), discuss the appropriate diagnostic strategies, and to provide the rationale for empirical and specific therapy.

EPIDEMIOLOGY

               Diseases of the esophagus are an important complication of the acquired immunodeficiency syndrome (AIDS) with at least 30% of patients experiencing esophageal symptoms at some point during the course of human immunodeficiency virus-type 1 (HIV) infection (Table 1) (7, 46). The incidence of these esophageal disorders increases as immunodeficiency worsens, and in a significant number of patients, the esophagus may be the site of the first AIDS-defining opportunistic infection (Figure 1) (35). Prospective endoscopic studies evaluating esophageal complaints in HIV-infected patients who are not receiving antifungal therapy have shown that 50-79% of patients have esophageal candidiasis (7, 46). Esophageal candidiasis is usually seen in patients with CD4 lymphocyte count <200/mm3, with approximately 90% of patients having a CD4 count <100/mm3 (46). Candida esophagitis co-exists with other esophageal disorders in up to 25% of HIV-infected patients (7, 46). Candida esophagitis has also been found to complicate acute HIV-infection (HIV seroconversion syndrome) (10).

               Although small prospective studies of symptomatic patients undergoing endoscopy prior to any therapy have documented an equivalent prevalence of CMV and HSV esophagitis (12), in a large prospective study of 100 HIV-infected patients with ulcerative esophagitis, HSV esophagitis was only identified in 5%, whereas the prevalence of CMV disease was almost 50% (50). Idiopathic esophageal ulcer is almost as frequent as CMV esophagitis, comprising approximately 40% of esophageal ulcers in these patients (46, 28, 22). Since the introduction of highly active antiretroviral therapy (HAART) the incidence of opportunistic disorders is declining (32).

DIFFERENTIAL DIAGNOSIS

               Candidiasis is the most common cause of esophageal disease in HIV-infected patients (7, 11). Besides Candida albicans, other candidal species which cause oropharyngeal and esophageal disease include C. krusei, C. tropicalis, C. parapsilosis, C. glabrata, C. guillermondi and C. dublinensis (11, 44). Esophageal involvement by fungi other than Candida sp. is very rare. These fungi include Histoplasma capsulatum (5), Penicillium chrysogenum and Exophiala jeanselmei (24) (Table 1).

               Among the viruses, cytomegalovirus (CMV) is the most common cause of esophagitis in patients with AIDS (35, 20, 47). In contrast to other immunocompromised states (renal and liver transplant patients), herpes simplex virus (HSV) is an uncommon esophageal pathogen in HIV-infected patients. Less commonly occurring viral pathogens which infect the esophagus in HIV-infected patients include Epstein-Barr virus (27), papovavirus (41), HSV type II and human HSV-6 (14).

               Idiopathic esophageal ulcer is a common and important cause of esophageal ulceration in patients with AIDS. The pathogenesis of idiopathic esophageal ulceration is unknown, and idiopathic esophageal ulceration has not been clearly linked to a specific infection (35). Although HIV has been identified by immunohistochemical stains in ulcer tissue from patients with idiopathic esophageal ulcer (22), a similar prevalence of HIV has been observed in other causes of esophageal disease, such as CMV (43). Thus, the pathogenic role of HIV in idiopathic esophageal ulcer remains unclear.

               Bacteria are infrequent etiologic agents of esophagitis in HIV-infected patients. Direct esophageal infection has been described with Mycobacterium avium complex (18). M. tuberculosis complicates HIV disease at all stages of immunodeficiency, and the clinical presentation is often atypical when immunodeficiency is severe. Nevertheless, esophageal involvement remains rare, especially in developed countries. Diffuse esophageal involvement by Bartonella henselae (bacillary angiomatosis or cat-scratch disease) was described in an HIV-infected patient (9). Dysphagia due to Nocardia esophagitis has also been reported (26). Actinomyces can cause superinfection of esophageal ulcers or primary esophageal infection (38).

               Pill-induced esophagitis should always be considered in the differential diagnosis of ulcerative esophagitis in patients with AIDS. A number of medications unique to HIV-infected patients that have been linked to pill-induced esophagitis include zidovudine (AZT, ZDV, Retrovir®) (17) and zalcitabine (ddC) (25).

               Gastroesophageal reflux disease (GERD) is uncommon in HIV-infected persons. In a series of 100 HIV-infected patients with esophageal ulcer, reflux was etiologic in four (50). The reason(s) for this low prevalence is not known, but may be due to the young age of these patients, or perhaps to hypochlorhydria which has been documented in approximately 25% of patients with late-stage disease (30).

RISK FACTORS

               The most important risk factor for opportunistic esophageal disorders in HIV is the patient's immune status, as reflected by the absolute CD-4 count. For example, CMV-esophagitis occurs when immunodeficiency is severe (CD4 lymphocyte count <100/mm3). Like CMV, the incidence of HSV disease increases as immunodeficiency worsens, with the greatest frequency occurring when the CD4 count is <100/mm3 (2, 21, 52). Idiopathic esophageal ulcer, a common cause of esophageal ulcer, occurs in the setting of severe immunodeficiency, with the median CD4 count in most series of <50/ml (28, 50).

CLINICAL MANIFESTATIONS

Signs And Symptoms

               Esophageal disease in AIDS is mainly manifested by two main symptoms: dysphagia (sensation of food or pills "sticking in the chest" or slow transit of a food bolus) or odynophagia (substernal pain after swallowing). Uncommon manifestations of esophageal disease in HIV-infected patients include singultus ("hiccups"), chest pain and bleeding.

               Dysphagia is the most common complaint in patients with esophageal candidiasis (46), with odynophagia, heartburn or retrosternal pain being less commonly reported. The presence of fever, nausea, vomiting and epigastric pain suggests an etiology other than Candida. Patients with CMV esophagitis almost uniformly present with odynophagia (16, 36, 46). Spontaneous retrosternal pain (esophagospasm) is also a frequent complaint. In contrast to Candida esophagitis, dysphagia is distinctly uncommon. Heartburn is rare in CMV esophagitis, whereas nausea, vomiting and low-grade fever may be reported. Concurrent oropharyngeal ulcerations are also rare (<10%), but thrush is often present (50). The most common manifestations of HSV esophagitis are odynophagia and dysphagia (82%), chest pain (68%) and fever (44%) (36). Gastrointestinal bleeding is rare (21) and is usually observed in patients with thrombocytopenia. Symptoms of idiopathic esophageal ulcer are similar to those associated with ulcerative esophagitis from any cause; severe odynophagia is almost uniformly present (28, 16, 50). Substernal chest pain, dehydration, and weight loss may also be noted. Concurrent oropharyngeal ulcerations are infrequent. Although sinus tract formation and fistulization to surrounding tissues has been reported, frank perforation has not been described, and bleeding is rare (50).

               Esophageal disease caused by tuberculosis most commonly results from contiguous spread from infected mediastinal lymph nodes to the esophagus, often resulting in an esophagomediastinal or bronchial fistula; therefore, pulmonary symptoms usually predominate (40). The clinical presentation of GERD and pill-induced esophagitis in HIV-infected patients is similar to that of the non-immunocompromised host, i.e. heartburn, non-specific chest pain and less commonly, dysphagia (17, 25).

               The most important aspects of the physical exam in the HIV-infected patient with esophageal complaints is the evaluation for any evidence of a generalized systemic disorder such as tuberculosis, lymphoma, Kaposi's sarcoma, etc. A fundoscopic exam to rule out CMV-retinitis is essential. Inspection of the oropharynx to evaluate for thrush, Kaposi's sarcoma and ulcerations is also very important (20). However, the presence of thrush does not prove that Candida causes or contributes to the esophageal symptoms (7), and thrush may be absent in one-third of patients with endoscopy-documented esophageal candidiasis (13, 9).

               The most common physical finding in patients with esophageal candidiasis is thrush (oropharyngeal candidiasis), which is readily diagnosed by the characteristic appearing multiple white-yellow plaques which may be focal or completely coat the buccal mucosa (7, 16, 45, 53). However, the presence of thrush does not prove that Candida causes or contributes to the esophageal symptoms (52, 16). In addition, Candida esophagitis co-exists with other esophageal disorders (e.g. CMV, idiopathic esophageal ulcer) in up to 50% of symptomatic HIV-infected patients (7, 46).

DIAGNOSIS

Laboratory

               The most important laboratory information in HIV-infected patients with esophageal symptoms is the CD4-cell count. Patients with a CD4-cell count > 200/mm3 rarely have an opportunistic disorder, whereas in patients with CD4 cell counts < 100/mm3 the likelihood of an opportunistic process increases significantly. CMV, idiopathic esophageal ulcer and HSV-esophagitis occur mainly when immunodeficiency is severe (CD4 lymphocyte count <50/mm3) (2, 21, 50). In the presence of upper gastrointestinal bleeding it is mandatory to obtain a hematocrit, platelet count and bleeding studies such as prothrombin time and partial thromboplastin time.

Radiographic Manifestations

               Barium esophagogram is a relatively insensitive and non-specific test for the evaluation of esophagitis in patients with AIDS. There are, however, some radiographic features unique to these infectious processes. The most common radiographic findings for Candida esophagitis are multiple plaques or a diffuse mucosal irregularity resulting in a "shaggy" appearance which may mimic ulceration. Herpetic esophagitis is usually associated with multiple small ulcerations (31). Barium esophagograms can not reliably distinguish CMV from idiopathic esophageal ulcer since both disorders result in one or multiple well-circumscribed ulcers of variable depth (7,50,16). Fistulas to the mediastinum may result from tuberculosis, MAC or CMV (40, 8).

Invasive Diagnostic Tests

               The most valuable tool for evaluating esophageal complaints in AIDS is endoscopy. All diagnostic equipment should be readily available in the endoscopy suite, including biopsy forceps of variable sizes, cytology brush(es), formalin, media for electron microscopy, transport media for viruses, as well as sterile saline containers for fungal and mycobacterial cultures. To best characterize gastrointestinal lymphoma, flow cytometry should also be performed to categorize the cell population, which has both prognostic and therapeutic implications. This requires placing a fresh sample of the tissue on damp paper with immediate transportation to the laboratory.

               Esophageal candidiasis classically results in multiple yellow-white plaques with the appearance of  "cottage cheese", which may be isolated or confluent and coat the entire esophagus (Table 2). A definitive diagnosis rests on the identification of typical yeast forms in endoscopic mucosal biopsies, esophageal brushings or balloon cytology (52). The detection of Candida by these methods does not exclude other disorders as Candida has been found to coexist with additional esophageal processes in up to 25% of symptomatic patients (52,53).

               The most common endoscopic manifestation of CMV is one or more large, well circumscribed shallow or deep esophageal ulcer(s) that may be circumferential (52). The diagnosis is best established by the identification of CMV viral cytopathic effect (intranuclear inclusions) in esophageal mucosal biopsies by routine hematoxylin-eosin stains (34). Immunohistochemical stains of mucosal biopsies may be required to confirm the infection; serologic tests and viral culture of biopsy specimens are not reliable to identify CMV in patients with gastrointestinal AIDS (34). Whereas cytology is helpful in the diagnosis of esophageal infections such as Candida and HSV, its usefulness in the diagnosis of CMV has not been proven consistently.

               The endoscopic appearance of HSV esophagitis is that of diffuse erosive esophagitis or small, discrete, superficial ulcers, which occasionally may be raised, cone-shaped, with an ulcerated center ("volcano ulcers") (13). Although the presence of small vesicles is commonly seen in immunocompetent hosts, this finding is unusual in HIV-infected patients. Herpes simplex virus is usually readily identified on biopsy, cytology or culture (33). As with CMV, immunohistochemical stains may increase diagnostic accuracy.

               Idiopathic esophageal ulcer is a diagnosis of exclusion and is made after a thorough endoscopic and histologic investigation has ruled out other etiologies such as HSV and CMV (28, 52). Idiopathic esophageal ulcer appears endoscopically as one or more well-circumscribed ulcers of variable depth. As with CMV-associated ulcers, the intervening mucosa is normal. Multiple biopsies of the ulcer base and margins are necessary to exclude other disorders (28, 52, 50).

MANAGEMENT

Empiric Therapy

               Given that esophageal candidiasis is the most common cause of esophageal disease in AIDS, many clinicians routinely give an empirical trial of anti-fungal therapy in HIV-infected patients with esophageal symptoms and thrush and base further diagnostic testing on the clinical response. Indeed, a prospective study comparing empirical fluconazole to endoscopy has shown empirical fluconazole to be the best initial management strategy, documenting both safety and effectiveness (54). We administer fluconazole starting with a loading dose of 200 mg/d followed by 100 mg/d for a 10-14 days treatment course (Table 3). The clinical response of Candida esophagitis to fluconazole is very rapid with many patients experiencing symptomatic improvement within three days (49). When using empirical therapy, if no substantial improvement has occurred by day seven, further diagnostic testing (preferably endoscopy) is recommended (54). The use of empirical antiviral therapy (e.g. acyclovir, ganciclovir) has not been proven to be safe and effective and should be discouraged. An empirical trial of H2-blockers or proton pump inhibitors is warranted in the patient with classic symptoms of GERD.

Antimicrobial Therapy

Candidiasis: Nystatin and clotrimazole troches are largely ineffective in the treatment of esophageal candidiasis in AIDS. A number of systemic antifungal agents have been extensively investigated to treat esophageal candidiasis, including ketoconazole, fluconazole and itraconazole (55). Ketoconazole and itraconazole should be avoided in the patient who requires anti-acid therapy as an alkaline pH limits bioavailability. In addition, ketoconazole has more frequent drug interactions with agents that are frequently prescribed in these patients such as ritonavir, indinavir, cisapride and terfenadine (55). Randomized trials have shown fluconazole to be superior to ketoconazole (4) and itraconazole (56) for esophageal candidiasis, thus establishing it as the antifungal agent of choice (55). The efficacy of oral suspension forms of both fluconazole and itraconazole appear similar to pill forms and these formulations may have superior efficacy over pills due to an additional local antifungal effect (56).

               Amphotericin B is highly effective against all Candida species and histoplasmosis. Because of its toxicity, amphotericin B is used almost exclusively for patients with thrush and/or esophageal candidiasis with clinical or microbiological resistance to Candida. Amphotericin B lozenges and suspension have also been used to treat esophageal candidiasis (55).

               Azole-resistant Candida species are now emerging as a significant problem. Risk factors for drug resistance include prior episodes of candidiasis or other opportunistic infections, duration of prior exposure to azole drugs, and advanced immunosuppression (39). Before assuming that clinical failure is due to a resistant strain, careful attention should be given to drug compliance and interactions (drug-drug) that may potentially reduce absorption, and the possibility of other esophageal disorders. Resistance can often be overcome by increasing the dose of azole, but switching to intravenous amphotericin may be required in some cases. Improvement in the host immune function with triple drug antiretroviral therapy as evidenced by a rise in CD4 T lymphocytes has also been associated with clearance of resistant candidiasis.

Cytomegalovirus: Treatment for esophageal CMV disease is limited to intravenous therapy with ganciclovir and foscarnet; both drugs have demonstrated clinical improvement in ~75% of patients (5, 50). The efficacy, tolerability, and cost of ganciclovir have established it as first line therapy for gastrointestinal CMV disease in AIDS. We start therapy with intravenous ganciclovir assuming there are no major contra-indications to this agent such as pancytopenia. Most patients respond clinically within the first week of therapy. Ophthalmologic examination is mandatory at the time of diagnosis in all patients to exclude retinal disease. If retinal disease is absent and a complete symptomatic and endoscopic response is documented following induction therapy, we stop therapy and observe for recurrent symptoms; the relapse rate for esophageal CMV disease is 30% (5). Endoscopic re-examination following therapy is important for those patients with persistent symptoms. If relapse occurs, retreatment with the same drug as used initially is reasonable followed by maintenance therapy. There are no studies that evaluate the efficacy of oral ganciclovir (pill or liquid formulations) for either maintenance therapy or treatment of acute gastrointestinal disease. Cidofovir is effective for CMV retinitis and several case reports have documented efficacy for esophageal CMV disease (6). Improvement in the host immune function with triple drug antiretroviral therapy has been associated with clearance of cytomegalovirus esophagitis (55).

               As many as 32% of patients with gastrointestinal CMV disease do not tolerate ganciclovir due to toxicities (e.g. pancytopenia) or ineffectiveness. For these patients, foscarnet is usually effective (15). Common side effects of foscarnet include electrolyte disturbances (hypocalcemia, hypophosphatemia), seizures, renal dysfunction and genital ulcers. Renal dysfunction can be prevented by vigorous hydration with saline prior to drug administration and dose adjustments based on creatinine clearance.

Herpes Simplex: For the patient with HSV esophagitis, it is recommended to start therapy with intravenous acyclovir and to complete treatment with oral drug for a total of two weeks (55). New oral agents that appear as effective are famciclovir and valacyclovir. Ganciclovir is also highly effective against HSV. The safety and efficacy of foscarnet for HSV disease has been confirmed in several studies (3), but should be reserved for patients with acyclovir resistance, due to its higher profile of side effects including electrolyte disturbances, seizures and genital ulcers (55).

Mycobacteria: Therapy for MAC has improved substantially over the last decade. Previously used multi-drug regimens were poorly tolerated, associated with significant side effects, and had low efficacy. It has now been clearly established that a macrolide (clarithromycin)-containing multidrug regimen is superior to a non-macrolide containing regimen for initial therapy of MAC-disease (42). Therapy and prophylaxis for gastrointestinal MAC is the same as for disseminated infection. Multidrug regimens are effective for M. tuberculosis with microbiological and clinical cure seen at 9 months provided drug resistance is not present; long-term therapy is thus unnecessary.

Non-Antimicrobial Agent Therapy

Idiopathic Esophageal Ulcer: Treatment of HIV-associated idiopathic esophageal ulcer is usually accomplished with oral corticosteroids (prednisone) (48). Although beneficial, intralesional injection of corticosteroids should be considered as second line therapy. Because oropharyngeal and/or esophageal candidiasis may complicate steroid use and confuse assessment of the clinical response, we combine prednisone with short courses of azole therapy (fluconazole once or twice weekly). Although not as well studied, thalidomide also appears to be highly effective for idiopathic esophageal ulcer with a complete clinical response and endoscopic cure of over 90% (1, 37). Thalidomide is well tolerated with the main side effect being somnolence; administration of the drug at bedtime tends to overcome this side effect. Peripheral neuropathy and skin rash have also been seen (37). The major fear with thalidomide is the inadvertent use in the first trimester of pregnancy, which consistently results in severe birth defects. Thus, most would prohibit its use in women of child bearing age. At present, the use of this drug is investigational and has not been approved by the FDA for the treatment of idiopathic esophageal ulcer. The relapse rate of idiopathic esophageal ulcer is approximately 40-50% (1, 37). Life-long low-dose corticosteroid or thalidomide therapy may be necessary to maintain remission for patients with frequent relapses.

 

Tables and Figures

Table 1. Etiology of Esophagitis in AIDS  [Download PDF]

Table 2. Clinical Presentation and Diagnosis of Esophageal Disease in Patients with HIV-Infection  [Download PDF]

Table 3. Suggested Regimens for the Therapy of Esophageal Infections in HIV-Infected Patients  [Download PDF]

Figure 1. Relative Prevalence of Esophageal Diseases in HIV

 

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