HIV患者相关吞咽困难与吞咽痛

Klaus E. Mönkemüller, M.D.

and

C. Mel Wilcox, M.D.

Department of Medicine, Division of Gastroenterology and Hepatology; University of Alabama at Birmingham

633 ZRB, UAB STATION

Division of Gastroenterology & Hepatology,

University of Alabama at Birmingham

Birmingham, AL 35294-0007.

(205) 934-6110; Fax: (205) 934-8493;

E-Mail: mel_wilcox@gasmac.dom.uab.edu

译  者： 赵一鸣 博士

             中国协和医科大学

                Email: milan_zym@hotmail.com

校对者： 李玥 博士

                 北京协和医院 消化科

                 北京市东城区帅府园1号

                 100730

INTRODUCTION

简介

               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.

        食管疾病是HIV感染患者的常见并发症，且对于很多患者食管可能是AIDS机会感染的首发部位。AIDS食管疾病最常见的病因是念珠菌和巨细胞病毒等感染。除非CD4淋巴细胞计数低于100/µl，否则机会性感染例如巨细胞病毒（CMV）和特发性食管溃疡很少出现。几乎所有AIDS患者的食管感染都是可治愈的，因此全面检查很有必要。对于有症状的患者，明确诊断之后的治疗通常可以使患者进食功能改善、体重增加从而拥有更高的生活质量。內镜是评估AIDS食管并发症最有效的手段。大部分食管疾病的长期预后主要取决于根本的免疫缺陷程度。随着更加有效的包括蛋白酶抑制剂在内的抗逆转录病毒治疗的广泛应用，很多机会性感染的发生率正在下降。不幸的是现在有不少关于耐多种抗逆转录病毒药物的HIV-1的报道，意味着我们有可能会看到多种机会性感染的发病率再度升高。这一章的主要目的是总结引起AIDS食管炎病原谱的现有资料，为食管炎的临床表现（例如吞咽困难或吞咽痛）提供切实可行的处理方法，讨论合理的诊断策略以及提供经验性及特异性治疗原理。

EPIDEMIOLOGY

流行病学

               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).

        食管疾病是获得性免疫缺陷综合征（AIDS）的重要并发症，至少30%的患者在感染人免疫缺陷病毒1型过程中的某一时间点会出现食管症状（表1）（7,46）。食管疾病的发病率随免疫缺陷的加重而升高，且对于很多患者，食管可能是AIDS机会感染的首发部位（图1）（35）。一项前瞻性内镜研究评估了未接受抗真菌治疗的HIV患者的食管并发症，显示50-79%的患者患有食管念珠菌病（7,46）。食管念珠菌病常见于CD4淋巴细胞计数<200/mm3的患者，其中大约90%的患者CD4计数<100/mm3 (46)。念珠菌食管炎伴发其他食管疾病在HIV患者中可达25%（7,46）。念珠菌食管炎也见于急性HIV感染（HIV血清转化综合征）（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).

        虽然一些关于有症状患者在治疗前的内镜检查的小型前瞻性研究显示CMV和HSV食管炎患病率相当（12），但是在一项大型前瞻性研究中，100名有溃疡性食管炎的HIV患者，HSV食管炎仅占5%，而CMV患病率几乎达到50%（50）。特发性食管溃疡患病率和CMV食管炎差不多，约占食管溃疡患者的40%(46, 28, 22)。自从引入了高效抗逆转录病毒治疗（HAART），机会性感染的发病率正逐步下降（32）。

DIFFERENTIAL DIAGNOSIS

鉴别诊断

               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).

        念珠菌感染是HIV患者食管病变最常见的病因(7, 11)。除了白色念珠菌，其他引起口咽和食管病变的念珠菌包括克柔念珠菌、热带念珠菌、近平滑念珠菌、光滑念珠菌、高里念珠菌及杜氏念珠菌(11, 44)。念珠菌外的其他真菌累及食管十分少见。这些真菌包括荚膜组织胞浆菌、青霉菌及 甄氏外瓶霉（24）（表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).

        病毒中，巨细胞病毒（CMV）是AIDS患者食管炎最常见的病因(35, 20, 47)。和其他免疫抑制状态的患者（肾和肝移植患者）相比，单纯疱疹病毒（HSV）在HIV患者中并不是常见的食管感染病原体。其它引起HIV患者食管感染的不太常见的病毒有EB病毒（27），乳头瘤病毒（41），HSV Ⅱ型和人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.

        特发性食管溃疡是AIDS患者食管溃疡的常见及重要原因。特发性食管溃疡的发病机制还不清楚，且尚未发现特发性食管溃疡和某种特殊感染有明确关系（35）。尽管通过免疫组化染色在特发性食管溃疡患者的溃疡组织里发现了HIV（22），但在其他原因如CMV引起的食管病变里也存在相似的HIV发现率（43）。因此，HIV本身作为病原体在特发性食管溃疡发病机制中的作用还不明确。

               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).

        细菌是HIV患者食管炎的少见病因。有报道鸟分枝杆菌复合体直接引起食管感染（18）。HIV患者在免疫缺陷的任何时期均可并发结核分枝杆菌感染，免疫缺陷严重时临床表现常不典型。结核分枝杆菌感染食管受累多不常见，尤其是在发达国家更为少见。曾有报道HIV感染患者出现亨氏巴尔通体（杆菌性血管瘤病或猫抓病）感染导致的弥漫性食管受累（9）。也有过奴卡氏菌食管炎引起吞咽困难的报道（26）。放线菌既可致食管溃疡基础上双重感染也可致原发性食管感染（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).

        AIDS患者食管溃疡性病变的鉴别诊断应常规考虑到药物性食管炎。包括齐多夫定（AZT、ZDV、Retrovir®）（17）和扎西他滨（ddC）（25）在内的许多HIV患者特殊用药可导致药物性食管炎。

               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).

        胃食管反流病（GERD）在HIV患者中并不常见。在一组共100名HIV食管溃疡患者中，仅有4人的病因是GERD相关（50）。GERD在HIV感染人群中患病率较低的原因还不清楚，可能是因为这些患者年纪较轻或因为约有25%的疾病晚期患者胃酸分泌过少（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).

危险因素

        HIV患者发生食管机会性感染最重要的危险因素是患者的免疫状态，通常可通过CD4细胞绝对计数反映出来。举例来说， CMV食管炎通常发生在严重免疫缺陷时（CD4淋巴细胞计数<100/mm³）。和CMV一样，HSV发病率随免疫缺陷的加重而升高，当CD4计数<100/mm³发病率达到最高(2, 21, 52)。特发性食管溃疡是食管溃疡的常见病因，在免疫缺陷严重时发生，大部分患者CD4中位计数<50/ml (28, 50)

CLINICAL MANIFESTATIONS

临床表现

Signs And Symptoms

症状及体征            

               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.

        AIDS食管病变主要表现为两个主要症状：吞咽困难（感觉食物或药片“粘在胸部”或食物团通过很慢）或吞咽痛（吞咽后胸骨下疼痛）。HIV感染患者食管病变的少见表现包括呃逆（“打嗝”），胸痛和出血。

               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).

        吞咽困难是食管念珠菌病患者最常见的主诉（46），吞咽痛、烧心或胸骨后疼痛次之。发热、恶心、呕吐和上腹痛做则提示念珠菌感染之外的病因。  几乎所有CMV食管炎患者都具有吞咽痛的表现（16，36，46）。自发性胸骨后疼痛（食管痉挛）也是常见主诉。和念珠菌食管炎相比，吞咽困难较为少见。CMV食管炎很少出现烧心，而恶心、呕吐和低热都有报道。并发口咽溃疡也较为少见（＜10%），但常出现鹅口疮。HSV食管炎最常见的表现是吞咽痛和吞咽困难（82%）、胸痛（68%）和发热（44%）（36）。消化道出血少见，血小板减少的患者可并发消化道出血。特发性食管溃疡的症状和任何一种病因的溃疡性食管炎类似，通常均出现严重的吞咽痛（28，16，50）。也可出现胸骨后疼痛、脱水和体重减轻。口咽溃疡不常见。尽管也有周围组织窦道和瘘管形成的报道，但没有直接穿孔的纪录，出血也较罕见（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).

        结核引起的食管病变最常见的原因是纵隔淋巴结感染播散到了相邻的食管，常导致食管纵隔瘘或支气管瘘；因此通常以肺部症状为主（40）。HIV患者GERD和药物性食管炎的临床表现和非免疫抑制患者相似，例如烧心、非特异性胸痛等，吞咽困难不太常见（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).

        具有食管相关主诉的HIV患者查体方面最重要的是评价是否存在全身系统性疾病，例如结核、淋巴瘤、卡波西肉瘤等的证据。有必要行眼底镜检查以除外CMV视网膜炎。检查口咽部明确是否存在鹅口疮、卡波西肉瘤和溃疡也很重要（20）。但鹅口疮的存在并不一定说明是食管念珠菌病导致患者的症状（7），约有1/3内镜证实的食管念珠菌病患者并没有鹅口疮（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).

        食管念珠菌病患者查体最常见的发现是鹅口疮（口咽念珠菌病），表现为多发黄白色斑片，局灶分布或完全覆盖于颊粘膜上，通过这一特征性表现很容易即可做出诊断(7, 16, 45, 53)。但是鹅口疮不能证明是念珠菌引起或促成了食管症状（52，16）。此外，在有症状的HIV患者中，高达50%的患者在发生念珠菌食管炎的同时合并了其它食管病变（如CMV、特发性食管溃疡）（7，46）。

DIAGNOSIS

诊断

Laboratory

实验室检查  

               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.

        对于有食管症状的HIV患者，最重要的实验室检查是CD4细胞计数。CD4细胞计数> 200/mm³的患者很少出现机会性感染，而CD4细胞计数< 100/mm³的患者机会感染的可能性显著提高。CMV、特发性食管溃疡和HSV食管炎主要发生在严重免疫缺陷（CD4细胞计数<50/mm³）的情况下(2, 21, 50)。如果存在上消化道出血，则应查红细胞压积、血小板计数和出凝血检查如凝血酶原时间和部分凝血活酶时间。

Radiographic Manifestations

影像学表现 

               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).

        对于评价AIDS患者食管炎，食管钡餐造影是一个相对既不敏感也不特异的检查。但对于某些感染性病变可具有特殊的影像学特点。念珠菌食管炎最常见的影像学表现是多发斑块影或弥漫粘膜不规则引起类似于溃疡的表面“毛糙”表现。疱疹性食管炎通常表现为多发小溃疡（31）。食管钡剂造影不能准确地区分CMV和特发性食管溃疡，因为它们都会引起单个或多发的深浅不一、边缘完整的溃疡(7,50,16)。结核、MAC或CMV可引起食管纵隔瘘(40, 8)。

Invasive Diagnostic Tests

有创检查 

               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.

        内镜是评价AIDS食管病变的最有意义的检查。除内镜外还需配备完备的诊断所需设备，包括各种尺寸的活检钳、细胞刷、福尔马林、电镜检查保存试剂、转送病毒的培养基以及培养真菌和结核的无菌盐水容器。为了更好地呈现出消化道淋巴瘤的特点，可应用流式细胞仪进行细胞分类，对于判断预后和治疗意义重大。要求将新鲜的组织标本置于湿润的纸上并立即送至实验室。

               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).

        典型的食管念珠菌病表现为多发的“酸奶酪”样的黄白色斑块，病变可以是孤立的，也可融合并覆盖全部食管（表2）。明确诊断依靠内镜下粘膜活检、毛刷或球囊细胞学检查鉴定出典型的酵母体（52）。即使通过上述方法发现了念珠菌，也不能除外其他病变，因为25%的有症状患者念珠菌感染同时合并其他食管病变（52，52）。

               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.

        CMV食管炎内镜下最常见的表现是单个或多个深浅不一边缘完整的大溃疡，溃疡可为环形（52）。食管粘膜活检苏木精-伊红染色发现CMV病毒细胞病变作用（细胞核内包涵体）可明确诊断（34）。可能需要粘膜活检组织的免疫组化染色来明确感染；对于鉴定消化道AIDS患者的CMV感染来说，血清学检查和活检标本的病毒培养结果并不可靠（34）。虽然细胞学有助于诊断念珠菌和HSV导致的食管感染，但在诊断CMV方面的作用尚未得到证实。

               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.

        HSV食管炎内镜下表现为弥漫的糜烂性食管炎或小的离散的浅表性溃疡，有的可凸出表面，呈锥型，中心有溃疡（“火山口样溃疡”）（13）。免疫健全的宿主感染HSV常可见到小的囊泡，但HIV患者却少见。单纯疱疹病毒通常可通过活检、细胞学或培养得到鉴定（33）。和CMV一样，免疫组化染色可提高诊断的准确性。

               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).

        特发性食管溃疡是一个除外性诊断，需要通过全面的内镜和组织学检查以除外其他病因如HSV和CMV（28，52）。特发性食管溃疡内镜下表现为单个或多个深浅不一边缘完整的溃疡。和CMV相关溃疡一样，溃疡间粘膜是正常的。需行溃疡底部和边缘的多点活检以除外其它病变(28, 52, 50)。

MANAGEMENT

治疗

Empiric Therapy

经验性治疗

               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.

        考虑到食管念珠菌病是最常见的AIDS食管病变，许多医生常规给有食管症状和鹅口疮的HIV患者经验性抗真菌治疗并根据治疗反应决定进一步的诊断检查。事实也是如此，一项前瞻性研究比较了经验性氟康唑治疗和内镜检查，安全性和成本效益分析结果均支持氟康唑是初始治疗的最佳方案（54）。氟康唑首剂200mg，继之100mg/天，疗程10-14天（表3）。氟康唑治疗念珠菌性食管炎临床起效非常快，很多患者在3天内症状即有所好转（49）。经验性治疗超过7天如无明显疗效，推荐进行进一步的诊断性检查（首选内镜）（54）。经验性抗病毒治疗（如阿昔洛韦、更昔洛韦）的安全性和有效性还没得到证实，不推荐使用。对具有典型GERD症状的患者应给予经验性H2受体拮抗剂或质子泵抑制剂治疗。

Antimicrobial Therapy

抗微生物治疗

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).

念珠菌病：制霉菌素和克霉唑片剂对于治疗AIDS食管念珠菌病很大程度上是无效的。一些全身性抗真菌药，如酮康唑、氟康唑和伊曲康唑经广泛研究证实可用于治疗食管念珠菌病（55）。进行抗酸治疗的患者应避免使用酮康唑和伊曲康唑，因为碱性pH值会限制着上述两种药物的生物利用度。此外，酮康唑与这类患者的一些常用药如利托那韦、茚地那韦、西沙必利及特非那定发生交叉反应的机率更较高（55）。随机临床试验显示氟康唑治疗食管念珠菌病优于酮康唑和伊曲康唑，因此将其作为抗真菌药的首选（55）。氟康唑和伊曲康唑口服混悬剂的疗效和片剂相当，但这一剂型具有额外的局部抗真菌效果，这一点上可能优于片剂（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).

        两性霉素B具有高效的抗所有念珠菌和组织胞浆菌作用。由于毒性很强，两性霉素B仅用于临床或微生物学证实为耐药念珠菌的鹅口疮和/或食管念珠菌病的患者。两性霉素B锭剂和口服混悬剂也可用于治疗食管念珠菌病（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.

        当前，对唑类耐药的念珠菌属的产生成为一个严重的问题。耐药的危险因素包括既往念珠菌病或其他机会感染病史，既往使用唑类药物的疗程以及严重的免疫抑制（39）。在假定由于耐药菌产生导致治疗失败之前，应仔细注意用药的依从性和药物之间相互作用等可能降低药物吸收度的因素以及存在其他食管病变的可能性。耐药的问题通常可以通过提高唑类药物剂量来解决，但有的病例需要应用静脉两性霉素。通过三联抗逆转录病毒治疗使CD4细胞计数增长，宿主免疫功能得到改善，也有助于耐药念珠菌的清楚。

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).

巨细胞病毒：巨细胞病毒食管病变的治疗限于静脉更昔洛韦和膦甲酸治疗；这两种药物的临床有效率可达75%（5，50）。鉴于更昔洛韦的疗效、耐受性及花费使其成为治疗AIDS消化道CMV感染的一线用药。在不存在主要禁忌证如全血细胞减少等情况下，即可开始静脉更昔洛韦治疗。大部分患者治疗第一周内可临床见效。所有患者诊断同时应行眼科检查以除外视网膜病变。如果除外了视网膜病变且诱导治疗后症状和内镜检查均提示完全缓解，可停药观察症状是否复发；CMV食管感染的复发率约为30%（5）。治疗后重复内镜检查对于症状持续不缓解的患者非常重要。如果复发，复治在使用和初治相同的药物后理应继续维持治疗。没有研究评估口服更昔洛韦（片剂或口服液）对于维持治疗或治疗急性消化道感染的效果。西多福韦对治疗CMV视网膜炎有效，且数个病例报道证实其对CMV食管病变有效（6）。三联抗逆转录病毒治疗后改善宿主免疫功能，有助于巨细胞病毒食管炎的治愈（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.

        多达32%的CMV消化道感染患者不能耐受更昔洛韦的毒性（如全血细胞减少）或治疗无效。对于这类患者，膦甲酸通常是有效的（15）。膦甲酸常见的副作用包括电解质紊乱（低钙血症、低磷血症）、癫痫、肾功能不全和外生殖器溃疡。用药前充分水化并根据肌酐清除率调整药物剂量可预防肾功能不全的发生。

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).

单纯疱疹：对单纯疱疹食管炎的患者，推荐开始治疗时使用静脉阿昔洛韦，随后过渡为口服，总疗程2周（55）。新型口服抗病毒药物泛昔洛韦和伐昔洛韦治疗同样有效。更昔洛韦治疗HSV感染也很有效。一些研究证实了膦甲酸治疗HSV感染的安全性和有效性，但由于其不良反应如电解质紊乱、癫痫和外生殖器溃疡等，仅在阿昔洛韦耐药时使用（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.

分枝杆菌：在过去的十年，MAC的治疗有了显著的提高。既往使用的多药联合治疗由于显著的副作用难以耐受，疗效也差。目前已经明确对于MAC病变的初始治疗，含有大环内酯（克拉霉素）的多药疗法优于不含大环内酯的多药疗法（42）。MAC消化道感染的治疗和预防与全身播散性感染的治疗相同。结核分枝杆菌多药联合治疗有效，不存在耐药的情况下，疗程9个月可获得微生物学和临床治愈；因此无需长期治疗。

Non-Antimicrobial Agent Therapy

非抗菌治疗

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.

特发性食管溃疡：通常使用口服糖皮质激素（强的松）治疗HIV相关的特发性食管溃疡（48）。病灶内注射皮质激素只作为二线治疗。激素使用后可能并发口咽和/或食管念珠菌病，使得难以准确判断激素的临床疗效，所以我们使用强的松治疗时常短期联用唑类抗真菌药物（氟康唑1-2次每周）。尽管研究还不充分，但沙利度胺治疗特发性食管溃疡似乎非常有效，临床和内镜的完全治愈率超过90%（1，37）。沙利度胺耐受性好，主要副作用为嗜睡；睡前给药往往可以克服这一副作用。也可出现周围神经病变和皮疹（37）。主要担心的是在早孕期无意中使用沙利度胺，常会引起严重婴儿畸形。因此大多数人会避免给育龄期妇女使用该药。目前该药的应用还在研究阶段，尚未得到FDA的批准用于治疗特发性食管溃疡。特发性食管溃疡的复发率约为40-50%（1，37）。对于复发频繁的患者，可能有必要终身使用小剂量皮质激素或沙利度胺治疗以维持缓解。

Tables and Figures

表格和图表

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