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Journal of the International Association of Physicians in AIDS Care - Vol. 1, No. 2, April/June 2002
Syed Ali Zaidi, MD, and Joseph S. Cervia, MD, FACP, FAAP
Division of Infectious Diseases, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, New York 11040, USA
Journal of the International Association of Physician's in AIDS Care - Vol. 1, No. 1, Spring 2002
Esophageal disease is a common complication and cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Opportunistic infections are the leading cause of esophageal complaints and may be a predictor of poor long-term prognosis, presumably as a reflection of severe underlying HIV immunodeficiency. The esophagus may be the site of the first acquired immunodeficiency syndrome (AIDS)-defining opportunistic illness in a large number of patients. Barium esophagography and upper gastrointestinal endoscopy are diagnostic modalities, commonly used to evaluate esophageal complaints in patients with AIDS. Treatment for most etiologies of esophagitis generally has a high degree of success, with a resultant improvement in quality of life. In addition to optimizing antiretroviral therapy, a thorough diagnostic assessment of every HIV infected patient with esophageal complaints is warranted, followed by timely and appropriate treatment.
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Esophageal symptoms occur in 40 percent to 50 percent of patients with AIDS at some point in the course of their disease, and may have a significant impact on their nutritional status and morbidity.1 Infections are the most common cause of esophageal disease, and the incidence of opportunistic disorders increases as immunodeficiency worsens. In the present era of highly active antiretroviral therapy (HAART), the clinical spectrum of esophageal disease is changing and the incidence of many opportunistic diseases appears to be decreasing. Although no controlled trials are available, extensive clinical studies have shown that effective HAART (with consequent CD4 cell count recovery greater than 200/mm3) does result in prolonged remission of symptoms without a need for long-term secondary prophylaxis. Because almost all esophageal infections in HIV-infected patients are treatable, a thorough evaluation is recommended. However, diagnostic modalities, such as barium esophagography and endoscopy, may not be widely available in developing countries where this complication of HIV disease is most prevalent, and where management and treatment may frequently be syndromic or empiric. Treatment is usually rewarding, although the long-term prognosis is primarily dependent on the severity of HIV infection and the accompanying degree of immunodeficiency.
This article reviews the various infectious etiologies of esophagitis in HIV-infected patients, their clinical manifestations, diagnostic modalities involved, and provides an algorithmic approach for empiric and specific therapy, as well as prophylaxis.
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Opportunistic infections represent the most common etiology of symptomatic esophageal disease in HIV infected individuals. Candidiasis is the most common infectious cause of esophagitis, occurring in 50 percent to 79 percent of symptomatic patients.1,2 Besides Candida albicans, several other species, including C. tropicalis, C. krusei, C. dublinensis,3 C. parapsilosis, and C. glabrata, have been associated with oral and esophageal disease in HIV-infected individuals. Esophageal candidiasis often occurs concurrently with other infectious esophageal disorders. In a review of 57 patients with AIDS and Candida esophagitis, 22 patients had coexistent cytomegalovirus (CMV) while 2 patients had Candida with CMV and herpes simplex virus (HSV).1 Fungi other than Candida involve the esophagus rarely, and include Histoplasma capsulatum,4 Exophiala jeanselmei,5 and Penicillium chrysogenum.6
The most common viral pathogen that causes esophageal disease in patients with AIDS is cytomegalovirus, seen in 10 percent to 40 percent of endoscopic biopsies of esophageal lesions.7 CMV and Candida may coexist in up to 20 percent of the patients. Although a frequent cause of esophagitis in immunosuppressed transplant patients and commonly causing oral disease, herpes simplex virus type I (HSV I) appears to be an uncommon primary esophageal pathogen. In a prospective study of 100 HIV-infected patients with ulcerative esophagitis, HSV I esophagitis was only identified in 5 percent, in contrast to a 50 percent prevalence of CMV disease.8 Less commonly occurring viral pathogens include Epstein-Barr virus,9 papovavirus,10 and human herpes virus 6.11 To date, varicella zoster virus (VZV) esophagitis has only been reported in patients without AIDS, although patients with AIDS do develop recurrent VZV infection and are certainly at risk for esophageal manifestations.12
Bacterial and mycobacterial (Mycobacterium tuberculosis, MTB13 and Mycobacterium avium complex, MAC14) esophageal involvement are uncommon in HIV-infected patients. MTB can complicate HIV disease at all stages of immunodeficiency, while MAC infection is generally limited to those with CD4 cell counts below 100/mm3. Esophageal involvement by Nocardia15 and Bartonella henselae16 (bacillary angiomatosis) has also been reported. Actinomyces can cause superinfection of esophageal ulcers or primary esophageal infection.17 Extremely rare protozoal causes of esophagitis include Cryptosporidium parvum,18 Pneumocystis carinii,19 and Leishmania.20
Idiopathic esophageal ulceration (IEU) is a significant problem in HIV-infected patients. These ulcers are almost as frequent as CMV esophagitis, comprising about 40 percent of ulcers in these patients.2 The pathogenic role of HIV in IEU is unclear. Studies have shown that, although HIV viral particles and genome can be shown in the esophagus of these patients, HIV is unlikely to be playing a causal role in every esophageal ulcer. The presence of HIV in esophagitis or esophageal ulcers is incidental to the underlying opportunistic pathogens causing the esophagitis or ulcers.21
Lymphoma and Kaposi's sarcoma are the most common HIV-related neoplastic lesions found in the esophagus. Most patients with AIDS take a variety of common medications, any one of which can cause esophagitis. Among the antiretroviral medications, zidovudine (AZT)22 and zalcitabine (ddC)23 have been reported to cause esophageal ulceration. Patients should be advised to take oral medications in the upright position with water to ensure complete ingestion.
Finally, gastroesophageal reflux disease (GERD) is uncommon in HIV-infected patients. The reason for this low prevalence is not fully known. It may partly be related to hypochlorhydria, which has been described as occurring in about 25 percent of patients with late-stage disease.24 However, several later reports have found acid production to be normal in HIV-infected patients.25,26
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The most common esophageal symptoms described by patients with HIV infection are dysphagia (sensation of food "sticking" in the retrosternal area), and/or odynophagia (painful swallowing). The absence of these symptoms should not be used as evidence against esophageal infection.12 Uncommonly, esophageal involvement may present with singultus (hiccups), chest pain, and gastrointestinal bleeding.21 Table 1 shows the presenting signs and symptoms of HIV-infected patients with different esophageal infections.
The chief presenting characteristics of esophageal candidiasis are dysphagia and odynophagia, with heartburn or retrosternal pain less commonly reported. However, the infection can be completely asymptomatic. In a prospective study by Porro et al, 10 out of 25 patients (40 percent) with AIDS and Candida esophagitis were found to be asymptomatic. When persistent nausea and vomiting, abdominal pain, gastrointestinal bleeding, fever, cough, or diarrhea are present, Candida is unlikely to be the only infecting organism27 (see Table 1). Physical examination may reveal lesions of thrush (oropharyngeal candidasis), which according to one large series, has a positive predictive value of 90 percent for esophageal candidiasis. However, thrush may be absent in onethird of patients with endoscopically documented candidiasis. Oropharyngeal candidiasis is consequently considered to be a moderately useful diagnostic marker for Candida esophagitis.28 Although the infection may occur at any stage of HIV infection, it is usually seen in patients with a CD4 count less than 200/mm3, with approximately 90 percent of patients having a CD4 count less than 100/mm3. Esophageal candidiasis has been reported during primary HIV infection (HIV seroconversion syndrome).29-31 It is associated with a transient but severe decrease in the percentage and absolute number of CD4+ cells, and with an increase in the absolute number of CD8+ cells. Spontaneous resolution of the esophagitis has also been reported in patients seroconverting for HIV antibodies.32
CMV esophagitis differs in its clinical presentation from other infections. Along with idiopathic esophageal ulceration, it is the most common cause of esophageal ulcerations in HIV-infected patients. Odynophagia is the principal manifestation, while dysphagia is distinctly uncommon, in contrast to Candida esophagitis. Nausea, vomiting, fever, epigastric pain, diarrhea, and weight loss have commonly been reported, reflecting the systemic nature of CMV infection.33,34 The incidence of CMV disease increases with CD4 cell count less than 100/mm3. Concurrent oropharyngeal ulcerations are uncommon, but thrush is often present. CMV may coexist with Candida and/or HSV infections, but the mere presence of CMV cannot be equated with clinical CMV esophagitis, although it may be a predictor of serious extraesophageal infection. In one study, it has been demonstrated that patients with esophagitis and evidence of concomitant Candida and CMV infections (by culture or histology), improved with antifungal therapy alone, regardless of treatment with antiviral agents.35
HSV esophagitis usually presents with an acute onset of severely painful and difficult swallowing. Nausea, vomiting, hematemesis, and fever may be present, although systemic and intra-abdominal symptoms are uncommon. Oral, labial, or cutaneous HSV is evident in only 19 percent to 38 percent of patients.36 The absence of mucocutaneous herpes does not in any way rule out the diagnosis of herpetic esophagitis. As with CMV, HSV esophagitis becomes increasingly common with CD4 cell count less than 100/mm3, and the incidence rises sharply with counts less than 50/mm3. Complications of herpetic esophagitis, including fatal hemorrhage,37 esophageal perforation with tracheoesophageal fistula formation,38 and diffuse visceral dissemination,39 have been reported.
Idiopathic esophageal ulceration generally occurs with severe immunodeficiency, with the median CD4 count less than 50/mm3 in most patients.3,40 As with other causes of ulcerative esophagitis, severe odynophagia is the predominant symptom, often accompanied by chest pain, dehydration, and weight loss. Painful, self-limited IEUs have been reported during acute HIV seroconversion syndrome.41 A macular erythematous lesion is frequently seen in this setting. The diagnosis of IEU should essentially be one of exclusion, and is made after more common infectious etiologies have been ruled out.
Mycobacterium tuberculosis usually causes esophageal symptoms due to erosion of a contiguous mediastinal lymph node into the esophagus.42 Reported complications have been fistulae between the esophagus and the tracheobronchial tree,13 and esophageal perforation.43 Although Mycobacterium avium complex is often widely disseminated in patients with AIDS and also colonizes the gastrointestinal tract, clinical esophageal disease caused by mucosal invasion is unusual. Clinical features of MAC esophagitis can include fever, weight loss, dysphagia and/or odynophagia. Esophageal ulcerations and esophagomediastinal and bronchial fistulae have been described with MAC esophagitis.12,14
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Radiographic evaluation: Radiographic studies are relatively insensitive in establishing an etiologic diagnosis of esophageal infection. Although some features may be unique to these infectious processes, barium esophagography is too often non-specific, necessitating endoscopic evaluation in symptomatic patients. Candida esophagitis usually presents with focal or confluent plaques or a diffuse "shaggy" appearance. Esophagograms may appear normal or, alternatively, have non-specific abnormalities such as stricture, ulceration, polyps, or fistula formation.44 HSV esophagitis is usually associated with multiple, stellate ulcerations in mid-esophagus (less than 1.5 cm in diameter), whereas CMV esophageal ulcers are characteristically quite large and may be single or multiple.19 Ulcers within plaques should suggest herpetic infection or concomitant herpes and Candida esophagitis.45 As with CMV, IEU can result in one or multiple, wellcircumscribed ulcers of variable depth.42 Esophagitis secondary to Mycobacterium tuberculosis may be suggested by the presence of fistulas to the mediastinum with or without esophageal ulcerations.13 Fistulization is not unique to Mycobacterium tuberculosis, and may result from MAC, CMV, or rarely Candida infection.2
Endoscopic evaluation and microbiologic diagnosis: Endoscopy is the most valuable technique in the evaluation of esophageal symptoms in HIV-infected patients. Table 2 summarizes the endoscopic findings seen in various esophageal infections. Multiple biopsies of any lesion (of both the base and margins in case of an ulcer) should be obtained. Various studies have suggested that at least ten biopsy specimens of an esophageal ulcer should be obtained in order to exclude a viral etiology in HIV-infected patients.8,42 The exact number of biopsies required from an esophageal ulcer is not well established. The standard practice is to obtain at least six biopsy specimens, although the sensitivity of diagnostic biopsy is dependent on the number of biopsies.
The endoscopic appearance of candidiasis resembles cheesy friable plaques that may involve the entire esophagus, occasionally causing luminal obstruction. It rarely causes ulcers. Biopsy of an ulcer in the patient with Candida esophagitis is necessary to identify coexisting pathogens like CMV, or to suggest an idiopathic cause.42 A definitive diagnosis is established by esophageal brushings with subsequent fungal staining or by mucosal biopsy. Budding yeast cells, and pseudohyphae are best seen by silver stain, periodic acid-shiff (PAS) stain, or gram stain and are diagnostic of Candida infection.12 Balloon cytology is another useful tool for the evaluation of Candida esophagitis.46 The use of this technique is becoming increasingly widespread due to potential diagnostic and therapeutic implications to either identify or exclude coexistent processes. It should be remembered that detection of Candida does not exclude concurrent infectious etiologies, which should specifically be looked for in patients.
CMV esophagitis most commonly results in one or more, large (greater than 10 cm2), shallow or deep, "punchedout" ulcers, located in the middle to distal half of the esophagus.42 In contrast to HSV infection, complete esophageal denudation is unusual. Histopathologic examination is the most reliable diagnostic method. Characteristic histologic features include large cells in the subepithelial layer with intranuclear inclusions, a peri-nuclear halo, and cytoplasmic inclusions.12 Viral culture of biopsy material is not useful in diagnosis since cultures are frequently positive when there is no histologic evidence of CMV and vice versa. This is likely due to contamination of esophageal specimens by virus harbored in blood or saliva. Immunohistochemical staining (for early, intermediate, and late antigens), and direct fluorescent staining techniques are highly specific for the diagnosis of CMV and HSV infections. According to a study by Goodgame et al, CMV was identified by immunoperoxidase stain in only 50 percent of lesions with cytomegalic cells.47
HSV lesions appear endoscopically as multiple, small, superficial ulcers in the distal third of the esophagus, which may have raised margins around a central crater ("volcano ulcers").42,45 Alternatively, a diffuse and erosive esophagitis may be seen. Although the presence of small vesicles is commonly seen in immunocompetent hosts, this finding is unusual in HIV-infected patients.5 HSV is usually readily identified on biopsy, cytology, or culture. Overall, viral culture is more sensitive than microscopic examination for the diagnosis of HSV infection.36 Diagnostic histologic features include multinucleated giant cells and intranuclear Cowdrey type A inclusion bodies, but cytoplasmic inclusions are typically absent.12 As with CMV, immunohistochemical staining may increase diagnostic specificity.
Idiopathic esophageal ulceration appears endoscopically as one or multiple well-circumscribed ulcers of variable depth, with normal intervening mucosa.40 A diffuse superficial esophagitis has not been described. Histopathologically, the ulcer tissue resembles that of CMV and HSV except viral cytopathic effect is absent. IEU and CMV esophagitis are indistinguishable clinically, radiographically, and endoscopically. Multiple biopsies of an ulcer are necessary to exclude infectious etiologies.
Tuberculous lesions usually appear as shallow ulcers with a necrotic base, ranging in size from small mucosal defects to large linear ulcerations. Probing the ulcer base may reveal a fistulous tract. Alternatively, the only endoscopic feature may be an extrinsic compression of the lumen, with no mucosal lesions.48 Specimens from biopsied lesions should be sent for acid-fast stain and mycobacterial culture, in addition to routine histologic studies.
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Candidiasis: Unlike oropharyngeal disease, non-systemic therapy (eg, nystatin and clotrimazole troches) is mostly ineffective in the treatment of Candida esophagitis. Of the antifungal agents, three drugs have been extensively investigated and used: ketoconazole, fluconazole, and itraconazole (see Table 3). Randomized trials have have shown fluconazole to be superior to capsules of ketoconazole49 and itraconazole50 for esophageal candidiasis, making it the antifungal agent of choice. The stated superior efficacy of fluconazole and itraconazole over ketoconazole might be qualified by the greater speed of response, or apparent potency of the former over the latter, while their relative difference in effectiveness may not be so great. As the absorption of ketoconazole and itraconazole is pH-dependent, these agents should be avoided in patients requiring anti-acid therapy, especially in view of some degree of hypochlorhydria seen in patients with AIDS. Ketoconazole and itraconazole are known to have interactions with commonly prescribed drugs like terfenadine, cisapride, ritonavir, indinavir, saquinavir, carbamazepime, phenytoin, phenobarbital, and the rifamycins.42 The response rate with fluconazole tends to be very rapid, with most patients experiencing significant clinical improvement within five days. An important therapeutic issue is the optimal duration of therapy before considering the patient a non-responder. Wilcox et al have suggested that assessment as early as one week may be accurate in predicting those patients who are likely to have underlying ulcerative esophagitis.51 Oral solution forms of both fluconazole and itraconazole are available. Greater efficacy has been inferred for the itraconazole oral solution over the capsules. Oral solution has been shown to be equivalent to fluconazole in the management of esophageal candidiasis.52 The same equivalence has not been demonstrated for itraconazole capsules. Similarly, for fluconazole refractory oral candidiasis, itraconazole solution appears to have greater efficacy. The oral solution formulations also have an additional topical antifungal effect.53
Azole-resistant strains of Candida are an emerging problem. Risk factors for acquiring resistance include advanced immunosuppression, relapsing oropharyngeal candidiasis with repeated courses of treatment, and chronic (maintenance) suppressive therapy with azole drugs.53 Resistance may in some cases be overcome by increasing the dose of the azole, but switching to amphotericin B (either topically or as a last resort intravenously) may be required in some cases.42 Some of the investigational azoles hold promise for the management of fluconazole-refractory oral candidiasis, including posaconazole and voriconazole. Optimal antiretroviral therapy, possibly by increasing the CD4 cell count and immune function, may also lead to clearance of refractory candidiasis.
Amphotericin B is effective against all strains of Candida. Due to its toxicity profile, it is generally reserved for oropharyngeal and/or esophageal candidiasis that has shown clinical or microbiologic resistance to one of the azole agents.54
Cytomegalovirus: Antiviral agents available for CMV esophagitis include intravenous ganciclovir, foscarnet, and more recently, cidofovir. Due to its efficacy, tolerability, and cost, ganciclovir is usually the first-line therapy. Oral ganciclovir has been evaluated mainly in the setting of maintenance therapy of AIDS-related CMV retinitis. Its efficacy for induction therapy for any of the forms of CMV disease is unknown but doubtful, given its low bioavailability and sub-optimal blood levels compared to intravenous ganciclovir. Ganciclovir has been shown to cause significant neutropenia in 25 percent to 68 percent of patients, and thrombocytopenia in 5 percent, necessitating discontinuation of therapy, especially in patients who are also on AZT.55 This problem can be treated with addition of granulocyte colonystimulating factor or by substituting ganciclovir with foscarnet. Valganciclovir, an oral pro-drug of ganciclovir, is a newer agent that has a much higher bioavailability than oral ganciclovir. It is presently being used for the treatment of CMV retinitis in patients with AIDS and will likely prove to be effective in the treatment of CMV esophagitis in the future. Foscarnet also represents an effective treatment for cases that are refractory to ganciclovir. Due to its ability to inhibit the reverse transcriptase of HIV-1, the effect of AZT and foscarnet on HIV may be additive.55 This possible additive antiviral effect of foscarnet appeared to be encouraging in the pre-HAART era, but it is outweighed by the current available array of antiretrovirals that have considerably greater potency and much less toxicity. The principal side effects of foscarnet include renal toxicity and electrolyte disturbances such as hypocalcemia and hypophosphatemia. Adequate hydration with saline prior to drug administration can be helpful in preventing renal dysfunction. Seizures and genital ulcers are less commonly reported side effects.56 Cidofovir is effective for CMV retinitis and recent case reports have documented its efficacy for esophageal disease.57
A commonly used policy is to administer intravenous ganciclovir, assuming there are no major contraindications such as pancytopenia. Most patients respond clinically within first week of therapy, and the relapse rate of 30 percent to 60 percent is similar for esophageal and colonic CMV disease.58 This relapse rate was identified in the pre-HAART era, and may have declined considerably with the effective use of HAART. Ophthalmologic examination is mandatory at the time of diagnosis of CMV infection to exclude retinal disease. If retinal disease is absent and a complete symptomatic and endoscopic response is documented after induction, therapy is stopped and the patient observed. Endoscopic reexamination with biopsy of any mucosal abnormality is indicated in those patients who continue to have persistent symptoms following therapy. For patients with major contraindications or failure to respond to ganciclovir, foscarnet is usually effective. Combination therapy with ganciclovir and foscarnet may be as effective as induction therapy and maintenance therapy with a single drug, and is also efficacious for ganciclovir failures.59,60 For patients with the first episode of CMV esophagitis and relapses of it, anti-CMV therapy and an emphasis on initiating or revising HAART is recommended to attempt partial immune reconstitution, rather than considering poorly tolerated and aggressive combination therapy with ganciclovir and foscarnet.
Herpes simplex virus: HSV esophagitis should be initially treated with intravenous acyclovir. Therapy with oral acyclovir may then be continued for a total of two weeks.61 Famciclovir and valacyclovir are equally effective oral agents. Complete resolution is reported in 70 percent of patients treated with acyclovir, but relapse occurs in 15 percent within four months.36 Due to its side effects, foscarnet is generally reserved for patients with acyclovir resistance. Although ganciclovir may not have proven efficacy in this setting, this does not necessarily imply inefficacy.
Idiopathic esophageal ulcer: HIV-infected patients with IEUs have improved on systemic steroid therapy in more than 90 percent of cases.62 Because oropharyngeal and/or esophageal candidiasis may complicate steroid use and confuse the therapeutic response, short courses of concomitant azole therapy are recommended.5 Steroids may also increase the risk of clinical CMV disease in patients with AIDS.42 Before contemplating steroid therapy, a thorough search for treatable infectious etiologies must be undertaken. Recently, thalidomide, which has immunomodulatory activity, has been reported to improve IEUs in HIVinfected patients.63 However, the drug has not been approved for this indication. Common side effects of thalidomide include somnolence, peripheral neuropathy, and a skin rash. Use in pregnancy is contraindicated because of a strong association with birth defects. Regardless of the initial therapy, the relapse rate of IEU is approximately 40 percent to 50 percent.58 It is quite likely that this figure has declined considerably in the present HAART era, but this is not well described.
Mycobacteria: In the absence of drug resistance, a ninemonth course of multi-drug therapy generally cures esophageal tuberculosis and often closes fistulas. If fistulas do not close with medical therapy, surgical intervention is required.54 MAC is difficult to treat and requires long-term therapy. Commonly used agents include clarithromycin, ethambutol, amikacin, ciprofloxacin, and rifabutin. Current recommended therapy for MAC is a combination of clarithromycin plus ethambutol. Amikacin and ciprofloxacin are second-line agents, which seldom need to be considered except in the setting of claritromycin-resistant MAC disease. It has been shown that a macrolide (clarithromycin)-containing multi-drug regimen is superior to a non-macrolide containing regimen in the treatment of MAC disease.64
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Despite the frequency of oropharyngeal and esophageal candidiasis in HIV-infected patients, primary prophylaxis is not widely administered. These disorders are not lifethreatening, therapy is usually very effective, and there is concern that widespread use of primary prophylaxis will exacerbate the problem of drug resistance.5 Secondary prophylaxis (with fluconazole 50 to 100 mg/day or 150 mg once weekly) is commonly given for patients with multiple recurrences of oropharyngeal and/or esophageal candidiasis. For CMV disease, primary prophylaxis with oral ganciclovir has been recommended with severe immunodeficiency (CD4 cell count less than 50/mm3). Although efficacious in the prophylaxis of CMV retinitis, no definite data exist on the effectiveness of primary prophyaxis for decreasing gastrointestinal CMV disease in HIV-infected patients.65 Secondary prophylaxis with intravenous ganciclovir or foscarnet did not affect disease progression among HIV-infected patients with gastrointestinal CMV disease.66 Primary prophylaxis against HSV disease is not currently recommended. Patients with frequent relapses of genital, oropharyngeal, or esophageal disease usually benefit from secondary prophylaxis with acyclovir (400 to 600 mg daily).61
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In the HIV-infected patient presenting with new onset esophageal symptoms, history and physical examination may help in formulating a rational approach toward management (Figure 1). Patients should be questioned about the use of any medications linked to drug-induced esophagitis, such as AZT, ddC, aspirin, NSAIDS, particularly at bedtime or prior to assuming the supine position for prolonged periods. Discontinuation of the drug or a change in its administration may benefit the patient. Physical examination may reveal oropharyngeal candidiasis or CMV retinitis, suggesting esophageal involvement by these pathogens.
Because candidiasis is the most common cause of esophageal disease in AIDS, an empiric trial of fluconazole is commonly used for new onset esophageal complaints in these patients.2,5,51,53 This approach may not be appropriate for patients with severe odynophagia, since such individuals are more likely to have ulcerative lesions present. A loading dose of 200 mg/day followed by 100 mg/day for a 14- to 21-day period is usually given. A prospective study comparing empirical fluconazole with endoscopy has shown the former to be the best initial management, documenting safety and effectiveness.51 If symptoms abate, the diagnosis of candidiasis can be established empirically. The failure of symptoms to respond by day seven of empirical therapy necessitates further diagnostic testing, preferably endoscopy with mucosal biopsy. Most patients who do not respond to antifungal therapy have esophageal ulceration, rather than evidence of persistent esophageal candidiasis. If Candida is the only pathogen identified during endoscopy, then fluconazole is usually continued. If symptomatic improvement does not follow fluconazole therapy within a few weeks, the patient should undergo another endoscopy, and amphotericin B should be given if Candida is again the only pathogen identified.67 Antifungal drug susceptibility testing may be useful at this point, in view of possible azole-resistant candidiasis, although the technique is not available in all microbiology laboratories. The predictive value of susceptibility data for individual patients can be influenced by various host and pharmacokinetic factors, and in vitro susceptibility does not always predict successful therapy. Overall, clinical usefulness of antifungal susceptibility studies is limited.53
Endoscopy is recommended for all HIV-infected patients with symptoms refractory to antifungal therapy or with upper gastrointestinal bleeding. According to a study by Bashir et al, symptom-specific use of endoscopy, particularly in patients with refractory symptoms such as odynophagia and upper gastrointestinal bleeding, had the highest diagnostic yield with a corresponding response to therapy.68 Endoscopy was found to be less useful for the evaluation of abdominal pain or nausea and vomiting. Overall, pathologic findings were identified in refractory esophageal symptoms (82 percent), upper gastrointestinal bleeding (92 percent), abdominal pain (39 percent), and nausea and vomiting (27 percent). In addition, a CD4 cell count less than 100/mm3 was found to be an independent predictor of opportunistic disorders diagnosed by endoscopy, with a sensitivity of 98 percent and a positive predictive value of 83 percent.68
The use of empirical antiviral therapy, such as acyclovir and ganciclovir, has not proven to be safe and effective and should be discouraged.69 Treatment regimens for CMV and HSV esophagitis have been discussed earlier. As a general rule, lesions that do not respond to appropriate therapy should be re-evaluated by endoscopy with biopsy and culture to confirm the diagnosis, and if indicated, to perform drug susceptibility testing. Additional diagnostic procedures are usually not required, but may be useful in special circumstances when there is a clinical suspicion of esophageal dysmotility.
In patients who present with symptoms suggestive of gastroesophageal reflux, an empirical trial of H2-receptor blockers or proton pump inhibitors is warranted. If no pathogen is found on multiple adequate biopsies of an esophageal ulcer, and after thorough review by an experienced pathologist, the patient could be treated with oral prednisone 40 mg/day which can be tapered to 10 mg/week after symptoms improve.42 Treatment of underlying HIV disease remains an important adjunct to therapy for any esophageal disorder.
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