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微孢子虫病 Updated March, 2008
译者：李娅 住院医师 北京协和医院 内科 Email：liya_de@hotmail.com 审阅者：杨德彦 总住院医师 北京协和医院 内科
GENERAL DESCRIPTION 概述 Parasitology Guided Medline Search 寄生虫学 生活史 Microsporidia are obligate intracellular spore-forming protists belonging to the phylum Microsporidia. More than 140 microsporidial genera and 1,200 species have been identified that are parasitic in every major animal group (68). To date, seven genera (Enterocytozoon, Encephalitozoon, Nosema, Pleistophora, Vittaforma, Trachipleistophora, and Brachiola) and unclassified Microsporidia, assigned to the collective group Microsporidium, have been implicated in human infections. 微孢子虫，属微孢子门，是专性细胞内寄生并可形成芽孢的原虫。已证实有超过140属和1200种的微孢子虫广泛寄生于所有主要动物群体中（68）。迄今为止，共发现7属微孢子虫（肠上皮细胞微孢子虫属、脑炎微孢子虫属、小孢子虫属、匹里虫属、条纹微孢子虫属、粗糙多孢微孢子虫属和Brachiola）和未分类微孢子虫，和人类感染有关。 Microsporidia are considered to be true eukaryotes because they have a membrane bound nucleus, an intracytoplasmic membrane system, and chromosome separation on mitotic spindles, but are unusual eukaryotes in that they have 70S ribosomes, no mitochondria, and have simple vesicular Golgi membranes. A unique life cycle involving a proliferative merogonic stage followed by a sporogonic stage results in distinct and environmentally resistant spores. Mature spores contain an exceptional tubular extrusion apparatus for injecting infective spore contents into the host cell (12). 由于微孢子虫有核膜包绕的细胞核，有一套胞浆内膜系统，并且染色体以形成纺锤体的形式进行有丝分裂，故属于真核生物，但其同时又具有70S核糖体，缺乏线粒体，并有简单的囊状高尔基体，故并非典型的真核生物。历经一个独特的包括裂体增殖期及随后的孢子增殖期的发育周期后，可形成特有的能抵抗环境因素的孢子。成熟孢子内含一套特殊的小管射出装置，可将感染性孢子内容物注入宿主细胞内（12）。 Berger S. Emergence of Infectious Diseases into the 21st Century, 2008. Epidemiology Guided Medline Search 流行病学 Human microsporidiosis appears to occur most frequently in persons infected with HIV but it is emerging as an infection in other immunocompromised hosts as well as in otherwise healthy immunocompetent individuals. Human microsporidial infections have been documented globally. The sources of Microsporidia infecting humans and their modes of transmission are uncertain. Zoonotic transmission of microsporidial species has not been verified but appears likely because many Microsporidia species can infect both man and animals. Ingestion of the environmentally highly resistant spores is probably the normal mode of transmission. A possible transmission by the aerosol route has also been considered because Microsporidia have also been found in respiratory specimens. 人类微孢子虫病最常见于HIV感染者，但其他免疫功能低下和免疫功能正常患者的感染也日渐增多。人类微孢子虫感染全球均有报道，但其传染源及传播方式还不清楚。尽管动物源性传播尚未被确证，但由于许多微孢子虫是人畜共患的，故此类传播是可能的。吞入具有高度环境抵抗力的孢子很可能是其主要的传播方式，但由于呼吸道标本中也发现过微孢子虫，气溶胶也是可能的传播方式之一。 Clinical Manifestations Guided Medline Search 临床表现 Human disease due to microsporidial infection appears to manifest primarily in immunocompromised persons (Table 1). The clinical manifestations of microsporidiosis are diverse and include intestinal, pulmonary, ocular, muscular, renal, cerebral, and disseminated infections affecting almost every organ system (68). The most frequent microsporidial infection is due to Enterocytozoon bieneusi causing chronic diarrhea among HIV-infected persons (71). 微孢子虫感染引起的人类疾患主要体现于免疫力低下者（表1）。微孢子虫病的临床表现多种多样，可累及肠道、肺、眼、肌肉、肾和脑，播散型感染则可波及几乎全身各个器官（68）。最常见的则是由比氏肠微孢子虫感染引起的HIV感染者的慢性腹泻（71）。 Among immunocompetent persons, particularly among person who reside or have traveled in tropical countries, self-limited diarrhea due to Enterocytozoon bieneusi and Encephalitozoon sp. have been documented. Furthermore, case reports of deep stromal infections of the cornea due to different microsporidial species have been described (Table 1). 已发现比氏肠微孢子虫和兔脑炎微孢子虫可引起免疫力正常者，尤其是热带地区居住或旅行者的自限性腹泻。也有多篇有关不同种类微孢子虫引起角膜深部间质感染的病例报道（表1）。 Laboratory Diagnosis Guided Medline Search 实验室诊断 The most robust technique for diagnosis of microsporidiosis is light microscopical detection of the parasites' spores in tissue or body fluids. Spores of different microsporidial species are of different size, ranging from 1 to 4 ”m. In stool specimens, spores can be visualized using a chromotrope (67) or a chemofluorescent stain (62); in urine using gram or chromotrope stain, and in tissue specimens using gram, chromotrope, giemsa or silver stains. Sufficient magnification, i.e. x630 or x1,000, is required for light microscopical detection of Microsporidia. The spores of Enterocytozoon bieneusi can be detected in stool specimens; spores of Encephalitozoon are excreted in stool, urine or respiratory secretions. Definitive species identification of Microsporidia is made by electron microscopy of tissue sections, or molecular or antigenic analyses of tissue or body fluids. 诊断微孢子虫病最有用的技术是光镜检测组织或体液中的寄生虫孢子。不同种类微孢子虫孢子大小不一，约1-4”m。采用变色酸（67）或chemofluorescent（62）染色可观察到粪便标本中的孢子；尿液标本采用革兰染色或变色酸染色；组织标本则可采用革兰染色、变色酸染色、吉姆萨染色或银染。光镜检测微孢子虫需有足够的放大倍数，如x630或x1000。可于粪便标本中检测到比氏肠微孢子虫孢子；脑炎微孢子虫孢子则可随粪便、尿液或呼吸道分泌物外排。最终的微孢子虫种类鉴定有赖于组织切片电子显微镜检测，或者组织、体液标本的分子或抗原分析。 Pathogenesis Guided Medline Search 致病机制 Microsporidiosis has been associated with abnormalities in structure and function of infected organs, but the mechanisms of pathogenicity are not understood. Patients with severe cellular immunodeficiency are at the highest risk for developing microsporidial disease. 微孢子虫病可引起受累器官结构和功能的异常，但致病机制还不清楚。严重细胞免疫缺陷的患者患微孢子虫病的风险最大。 SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo 体外、体内药物易感性 In vitro evaluation of antimicrosporidial drugs and treatment studies in humans and animals are limited. In vitro susceptibility testing is hampered because Microsporidia do not grow on axenic medium. Propagation of some pathogenic species (including Encephalitozoon spp., Vittaforma corneae, Trachipleistophora hominis, and Brachiola spp.) and drug susceptibility testing have been accomplished in cell culture using several different cell lines (55, 58). Despite many attempts to culture the most frequent species found in humans, Enterocytozoon bieneusi, only short-term propagation has been achieved (63). 体外评价抗微孢子虫药物和治疗效果的人体和动物实验均较少。微孢子虫不能在无寄生物的培养基中生长，故难以进行体外药敏试验。一些致病种类（包括兔脑炎微孢子虫、Vittaforma corneae, Trachipleistophora hominis, and Brachiola spp.）的繁殖和药物感敏试验是采用数种不同细胞系进行细胞培养的方式完成的（55，58）。尽管已多次尝试培养比氏肠微孢子虫，这一人体内最常见的微孢子虫，但仅获得短期繁殖（63）。 A major obstacle of treatment appears to be the thick wall of mature spores which resists penetration of drugs so that, even if the developing stages of Microsporidia are destroyed or sporogony is perturbed, the mature spores may lead to persistent infection (11, 14, 31). 治疗微孢子虫病的主要困难在于成熟孢子具有可抵御药物渗透的厚细胞壁。即使消灭了发育阶段的微孢子虫或干扰了孢子生殖，成熟孢子仍可导致持续性感染（11，14，31）。 In Vitro Studies 体外实验 Albendazole as well as other benzimidazole derivatives have been found to cause growth deformities of Encephalitozoon spp. and to reduce or eradicate the parasites propagated in cell cultures (3, 31, 36, 55). Other in vitro studies, however, have indicated that albendazole does not destroy mature microsporidial spores such that these spores may lead to persistent infection (14, 31). The microtubule protein b-tubulin has been identified as the benzimidazole target in helminths and fungi. Correlations between benzimidazole activity and partial b-tubulin sequences of Encephalitozoon hellem and Encephalitozoon cuniculi were analyzed using molecular techniques; these analyses predicted that Encephalitozoon spp. would be benzimidazole susceptible (37, 43). In vitro studies indicated that host cells expressing a P-glycoprotein pump protect intracellular stages of Encephalitozoon from agents such as albendazole, probably by limiting the intracellular concentration of the drug (41). A P-glycoprotein pump was also demonstrated in developing stages of the parasite which may further contribute to protecting the parasite from albendazole. Chemosensitizing agents such as verapamil and cyclosporin inhibiting these pumps may therefore increase the efficacy of antiparasitic agents in these microsporidia (41). 已发现阿苯达唑和其他苯丙咪唑类衍生物可致兔脑炎微孢子虫生长畸形，并可减少或根除寄生虫在培养细胞中的繁殖(3, 31, 36, 55)。然而，其它体外实验发现阿苯哒唑并不能破坏成熟微孢子虫的孢子，这些孢子仍可能会引起持续性感染（14，31）。已证实微管蛋白b-tubulin是苯丙咪唑类药物作用于寄生虫和真菌的靶位点。已采用分子技术对苯丙咪唑活性和Encephalitozoon hellem and Encephalitozoon cuniculi中部分b-tubulin 序列间的关系进行了研究；这些研究预测兔脑炎微孢子虫对苯丙咪唑是敏感的(37, 43)。体外实验指出表达一种P-糖蛋白泵的宿主细胞可保护脑炎微孢子虫的细胞内阶段不受阿苯达唑等药物影响；其机制可能是降低药物在细胞内的浓度 (41)。 已证实P-糖蛋白泵也存在于这种寄生虫的发育阶段，可能会进一步影响阿苯达唑的作用。维拉帕米、环孢菌素等化学增敏剂对这些泵有抑制作用，可能会提高抗寄生虫药物在这些微孢子虫中的作用（41）。 Fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus, has been shown to reduce Microsporidia (Nosema apis) in infected honey-bees (38) and to inhibit replication of Encephalitozoon cuniculi in infected cell cultures in vitro (3, 21, 31, 55), but lasting eradication of the parasites has not been achieved. The semisynthetic fumagillin analog TNP-470 appears to have similar in vitro activity against Encephalitozoon intestinalis and Vittaforma corneae (17, 21). 烟曲霉素，由烟曲霉分泌的天然抗生素，可以减少受感染蜜蜂中的微孢子虫数量(Nosema apis)（38），还可以抑制体外感染细胞培养中兔脑炎微孢子虫的复制（3,21,31,55），但不能长期根除微孢子虫感染。半合成烟曲霉素类似物TNP-470，有着相似的体外抗肠脑炎微孢子虫和Vittaforma corneae的活性（17，21）。 Nikkomycin Z has been described to inhibit the replication of Encephalitozoon hellem (6). Different compounds including 5-fluorouracil, sparfloxacin (3), propamidine isethionate, thiabendazole and oxibendazole (31), sinefungin (11), the calcium-channel blocker nifedipine, two nitric oxide (NO) donors (S-nitroso-N-acetylpenicillamine and sodium nitroprusside (33)), and some polyamine analogues (16, 73), have been shown to inhibit replication or spore germination of Encephalitozoon spp. in vitro. Furthermore, chloroquine (3, 64), pefloxacin, azithromycin and rifabutin were partially effective, at high concentrations (3). Cytochalasin D, demecolcine, nifedipine and itraconazole were found to inhibit spontaneous and H2O2-stimulated polar filament extrusion (42). Most of these drugs, however, are either not licensed for human use or inactive in vivo. 据报道，尼柯霉素Z可以抑制Encephalitozoon hellem的复制（6）。许多化合物，包括5-氟尿嘧啶、司帕沙星（3）、羟乙磺酸丙氧苯脒、噻苯咪唑和奥苯哒唑（31）、西奈芬净（11）、钙通道阻滞剂硝苯地平、两种一氧化氮（NO）供体（S-亚硝基-N-乙酰青霉胺和硝普钠（33））、和某些多胺类似物（16，73）也被证实可在体外抑制兔脑炎微孢子虫复制和孢子出芽。此外，氯喹（6，34）、培氟沙星、阿奇霉素和利福布汀在高浓度时有部分活性（3）。细胞松弛素D、秋水仙碱、硝苯地平和伊曲康唑可抑制自发或H2O2-激活的极丝弹出（42）。但是，这些药物中的绝大部分要么未批准应用于人体，要么在体内无活性。 Compounds that were found to be inactive in vitro included pyrimethamine, piritrexim, sulfonamides, paromomycin, roxithromycin, atovaquone, flucytosine (3), itraconazole, toltrazuril, metronidazole, ronidazole, ganciclovir (31) as well as thalidomide (53) which was proposed to have some efficacy in preliminary clinical studies in HIV-infected patients suffering from microsporidiosis. 已发现体外无抗寄生虫活性的化合物包括乙胺嘧啶、吡曲克辛、磺胺类药物、巴龙霉素、罗红霉素、阿托伐琨、氟胞嘧啶（3）、依曲康唑、托曲珠利、甲硝唑、罗硝唑、更昔洛韦（31）和反应停（53），这一曾在初步临床试验中认为对患微孢子虫病的HIV感染者有一定疗效的化合物。 In vitro evaluation of drugs to treat Enterocytozoon bieneusi has not been done. 体外评价治疗比氏肠微孢子虫药物疗效的试验尚未开展。 In Vivo Studies 体内试验 Enterocytozoon bieneusi has mainly been found in humans but also detected in healthy pigs and in Rhesus monkeys experimentally infected with simian immunodeficiency virus. Treatment trials, however, have not yet been conducted in these animals. Natural microsporidial infections due to another microsporidian of the family Enterocytozoonidae, Nucleospora (formerly Enterocytozoon salmonis), occurs in salmonid fish. Experimental N. salmonis infection in salmonid fish has successfully been treated with fumagillin as well as TNP-470, a semisynthetic analogue of fumagillin (17). 比氏肠微孢子虫主要发现于人类，但也见于健康的猪类和人工感染了猿类免疫缺陷病毒的恒河猴。然而，尚未在这些动物中进行治疗试验。鲑鱼中存在Enterocytozoonidae, Nucleospora (formerly Enterocytozoon salmonis)的天然感染。烟曲霉素和TNP-470这一烟曲霉素半合成类似物已成功用于治疗人工感染了N. salmonis的鲑鱼（17）。 Effects of benzimidazole derivatives (albendazole, mebendazole, fenbendazole) were investigated in fish naturally infected with Glugea anomala parasitizing connective tissue (54). All developmental stages of the Microsporidia were irreversibly damaged by either drug as documented by ultrastructural studies. Fenbendazole was found to be effective in preventing the establishment of experimental infection of Encephalitozoon cuniculi in rabbits, as well as for eliminating the parasite from the central nervous system of naturally infected rabbits (61). 已研究了苯丙咪唑类衍生物（阿苯达唑、甲苯咪唑、芬苯哒唑）对天然感染结缔组织寄生Glugea anomala的鱼类的治疗效果（54）。超微结构研究证实这些药物均可引起该种微孢子虫各个发育阶段的不可逆性损害。还发现芬苯哒唑可有效预防家兔人工感染兔脑炎微孢子虫，并可将天然感染的兔脑炎微孢子虫从兔类中枢神经系统中清除（61）。 In the athymic nude mouse model of disseminated Encephalitozoon cuniculi infection, treatment studies with TNP-470 resulted in prolonged survival and the prevention of the development of ascites in infected animals (17). CD8 knockout mice infected with Encephalitozoon cuniculi showed improved survival when treated with alkylpolyamine analogues (73). 应用TNP-470治疗播散型兔脑炎微孢子虫感染的无胸腺裸鼠的研究中发现，TNP-40可延长感染动物的生存期，并预防腹水的出现（17）。感染兔脑炎微孢子虫的CD8敲除大鼠的生存率在应用烷基多胺类似物治疗后有所改善（73）。 ANTIPARASITIC THERAPY Guided Medline Search Smart search 抗寄生虫治疗 Little information on clinical experience in the therapy of human microsporidiosis is available, and, with two exceptions, blinded, placebo-controlled comparative treatment trials are lacking. Virtually all published studies to date have involved severely immunocompromised, HIV-infected patients. Case reports of patients infected with different Encephalitozoon species as well as one controlled trial of eight HIV-infected patients with E. intestinalis associated diarrhea (47, 49) have suggested that treatment of Encephalitozoon infections with albendazole may be curative. In contrast, experience in treating intestinal Enterocytozoon bieneusi infection has met with only limited success, and only a few prospective, open label studies and one small randomized controlled trial have been reported. 治疗人类微孢子虫病的临床经验少之又少，亦缺乏双盲、安慰剂对照的治疗研究。事实上迄今为止，所有已发表的研究都是针对重度免疫力低下、HIV感染的患者。一些关于感染不同种类脑炎微孢子虫病人的个案报道和一项在8个感染了肠脑炎微孢子虫伴腹泻的HIV病人中进行的对照试验（47，49）提示阿苯哒唑可能有效。相反，有关肠道比氏肠微孢子虫感染治疗的研究有限，只有几个前瞻、开放标记研究和一项小的随机对照试验见于报道。 Drug of Choice 常用药物 Immunocompetent Persons 免疫力正常患者 Only single case observations of immunocompetent patients with microsporidial infection have been reported (9, 65, 66). In these patients, microsporidiosis presented as a self-limiting disease without any sequelae. Thus, treatment of microsporidiosis in otherwise healthy persons appears not to be indicated. 免疫力正常者感染微孢子虫仅有零星个案报导（9，65，66）。在这些患者中，微孢子虫病是自限、无后遗症的。因此，健康人感染微孢子虫无需治疗。 Immunocompromised Patients 免疫缺陷患者
Encephalitozoon spp. Infection:
Case reports have indicated that a 2- to 4-week course of oral albendazole, 400 mg twice daily, led to clinical improvement in HIV-infected patients with Encephalitozoon intestinalis, E. hellem or E. cuniculi infection (49, 50a, 72); paralleling the clinical improvement was the disappearance of spores from stool, urine, respiratory specimens or conjunctival scrapings. A response to albendazole was found in patients with clinical and radiographic improvement of Encephalitozoon-associated chronic sinusitis or lower respiratory tract infections (20, 40, 62, 69); urethritis (15); reversible renal failure in a patient with serum urea and creatinine peaks of 37.6 mm/L and 487 μmol/L, respectively (1); intermittent clinical and radiologic improvement of cerebral encephalitozoonosis in one patient (69); and clinical and parasitologic improvement of patients with disseminated infection (19, 22, 27). Further studies are needed to determine whether maintenance therapy will be necessary and what dose regimen would be appropriate. Long-term follow-up observations and autopsy studies in some of these patients indicated that Encephalitozoon infections indeed were cured after albendazole treatment (20, 35, 60). In other patients, however, cessation of therapy resulted in clinical relapse that required reinstitution of therapy (27, 49, 62, 72). Complete treatment failures were rare but at least one fatal treatment failure in a patient with cerebral Encephalitozoon cuniculi infection has been reported (69). 一些个案报道指出，口服阿苯达唑400mg 一天两次2-4周，可改善HIV感染者合并肠脑炎微孢子虫、E. hellem 或E. cuniculi感染的临床症状（49，50a，72）；并有与之相应的粪便、尿液、呼吸道标本或结膜刮除物中孢子的消失。已发现阿苯达唑治疗可分别改善脑炎微孢子虫相关的慢性鼻窦炎、下呼吸道感染（20，40，62，69）、尿道炎（15）、1例血尿素氮和肌酐峰值分别达37.6 mmol/L 和487 μmol/L的可逆性肾功能衰竭患者的临床和影像表现（1）；1例颅内脑炎微孢子虫感染患者的临床和影像表现亦间断改善（69）；亦可改善播散性感染患者的临床症状和寄生虫负荷（19，22，27）。最佳方案的确定及维持治疗是否必要仍有待进一步研究。对上述部分患者的长期随访观察和尸检发现阿苯达唑的确可以治愈脑炎微孢子虫感染（20，35，60）。然而，其他患者中则发现停止治疗后临床症状复发，需要重新治疗（27，49，62，72）。罕见经正规治疗失败者，但至少有1例颅内兔脑炎微孢子虫感染治疗失败死亡者见于报导（69）。 A double-blind placebo-controlled trial including eight patients with AIDS and diarrhea due to Encephalitozoon intestinalis infection has confirmed that treatment with albendazole, 400 mg twice daily for 3 weeks, results in clinical improvement as well as clearance of microsporidia from the intestine in all patients (46). 一项纳入8例艾滋病患者感染肠脑炎微孢子虫引起腹泻的双盲、安慰剂对照试验证实，阿苯达唑400mg 每天两次治疗3周可使所有患者临床症状获得改善，并可将微孢子虫从肠道内清除（46）。 Enterocytozoon Bieneusi Infection: No recommendations regarding a specific antiparasitic treatment of HIV-associated Enterocytozoon bieneusi infection can be made at this time, although clinical studies with oral fumagillin in patients with HIV infection were promising (47, 48). However, the drug had substantial adverse effects and is not approved for clinical use. 比氏肠微孢子虫感染：目前仍无推荐用于治疗HIV相关的比氏肠微孢子虫感染的药物，尽管有临床研究提示口服烟曲霉素治疗很可能有效（47，48），但烟曲霉素存在严重不良反应，故未批准用于临床。 No therapy has been unquestionably proven effective for Enterocytozoon bieneusi infection. Preliminary reports of a clinical response among patients treated with metronidazole (28), azithromycin (34), atovaquone (2), albendazole, and various other antibiotics or antiprotozoal drugs could not be substantiated (47). Preliminary results indicated at least partial efficacy of fumagillin (48,50). 目前尚无充分证实有效的治疗比氏微孢子虫感染的药物。早期有关甲硝唑（28）、阿齐霉素（34）、阿托伐醌（2）、阿苯达唑和其他多种抗生素或抗原虫药物疗效的报道无法获得证实（47）。初期结果指出烟曲霉素至少是有部分疗效的（48，50）。 Some reports have suggested that treatment with albendazole may lead to clinical improvement in some patients, although parasites were still present in intestinal biopsy specimens, and microsporidial spores were still detected in stool specimens obtained after treatment (8). In an open-label prospective trial of HIV-infected patients, conducted before potent antiretroviral therapy was available, 400 mg albendazole (twice daily for 4 weeks or longer) was used. In 13 out of 26 patients, there was a greater than 50% reduction in bowel movements, and in nine there was a partial response. Small-bowel biopsy revealed persistent microsporidial infection in all patients, irrespective of their clinical response to albendazole (24). 有报道指出阿苯达唑治疗可改善某些患者的临床症状，但仍可于肠道活检标本中发现寄生虫，治疗后留取的粪便标本中仍存在微孢子虫孢子（8）。在有效抗逆转录病毒治疗问世之前，于HIV感染者中进行的一项开放、前瞻性研究中使用了阿苯达唑400mg（每天两次达4周或4周以上）。26人中有13人肠道蠕动减轻50%以上，9人部分有效。但不论对阿苯达唑治疗反应如何，小肠活检标本提示所有病人中持续存在微孢子虫感染（24）。 Thalidomide, an anti-Tumor Necrosis Factor-a agent, was studied in 18 severely immunodeficient HIV-infected patients with chronic diarrhea due to Enterocytozoon bieneusi that had not responded to albendazole (57). After a one-month course of 100 mg thalidomide, complete clinical response was observed in seven, and partial clinical response in 3 patients, but parasite load as determined in biopsy specimens did not decrease in any patient. There was a significant decrease in stool frequency from 5.3 to 3.1 per day, and body weight increased by 1.2 kg. The investigators speculated that thalidomide may have been effective via an anti-HIV or anticytokine effect, an antagonist of hormonal and chemical mediators of diarrhea, a direct antimicrobial effect on the Microsporidia, or as a nonspecific side effect of the drug. In vitro thalidomide was found to lack antimicrosporidial activity (53). Preliminary results of a double blind placebo controlled trial in a small number of HIV-infected patients with chronic diarrhea suggested that thalidomide can effectively decrease the number of bowel movements in patients without an identified intestinal pathogen or with a pathogen that is non-responsive to specific treatment (52). 在18个存在重度免疫缺陷的HIV感染者中试用了反应停这一抗肿瘤坏死因子-a药物，这些患者均有比氏肠微孢子虫感染引起的慢性腹泻，且阿苯达唑治疗无效（57）。100mg反应停治疗一个月后，7人获完全临床缓解，3人部分缓解，但活检标本证实所有患者的寄生虫负荷均无降低。患者的大便频率显著减少，由5.3次/天降至3.1次/天，体重也增加了1.2kg。研究人员推测反应停的作用机制可能是抗HIV或抗细胞因子的效应、拮抗腹泻相关的激素或化学介质、直接抗微孢子虫作用或是其非特异的副作用。在体外反应停并无抗微孢子虫活性（53）。一项针对HIV感染者慢性腹泻的小样本双盲、安慰剂照实验的初步结果证实反应停可有效减少无可鉴定肠道致病原或对特效治疗无反应的致病原感染患者的肠蠕动次数（52）。 Furazolidone, a synthetic nitrofuran with antiprotozoal activity against trichomonas, giardia, and entamoeba, was studied in six patients with AIDS and Enterocytozoon bieneusi infection (26). Transient clinical remission was reported in most patients, and ultrastructural changes of all stages of E. bieneusi were described in four patients who underwent endoscopic evaluation after treatment (25). Others did not find any clinical efficacy of furazolidone in patients with E. bieneusi infection (47). 呋喃唑酮是一种具有抗毛滴虫、贾第鞭毛虫和阿米巴变形虫活性的合成硝基呋喃类药物，曾被研究用于6名感染比氏肠微孢子虫的AIDS患者中（26）。大多数病人获一过性临床缓解，4人治疗后行内镜检查发现所有阶段比氏肠微孢子虫的超微结构均发生了改变（25）。其他比氏肠微孢子虫感染者中未发现呋喃唑酮有任何临床效应（47）。 Oral purified fumagillin was recently used in a pilot study to treat 9 HIV-infected patients with E. bieneusi-associated chronic diarrhea (47). The investigators reported a rapid and lasting eradication of the parasite. The drug, however, induced severe but rapidly reversible thrombocytopenia in all patients. A further open-label study confirmed that fumagillin may eradicate the parasites transiently in many patients but serious adverse events and parasitic relapse were frequently observed (48). Twenty-one out of 29 patients transiently cleared Microsporidia from their stools. By week 6, however, all patients in groups treated with doses below 60 mg/day had parasitic relapse. Of note, eight out of 11 patients treated with 60 mg/day cleared Microsporidia from their gastrointestinal tract and gained weight. No parasitic relapse were reported in these eight patients during a mean follow-up of 11.5 months (48). Parasitologic clearance and clinical efficacy of oral fumagillin (20 mg three times daily on an empty stomach) was finally proven in a randomized, double-blind placebo-controlled trial including 10 patients with AIDS and two patients who had received organ transplants. Serious adverse events (neutropenia and thrombocytopenia) occured in three patients. During a follow-up of 10 months, two out of 12 patients had a relapse of microsporidiosis indicating that the parasites were not completely eradicated (50). 在近期一项初步研究中，口服纯化的烟曲霉素用于治疗9名比氏肠微孢子虫相关慢性腹泻的HIV感染者（47）。其发现寄生虫可被快速、持久的清除。然而，所有患者均出现严重但快速可逆的血小板减少。一项进一步的开放标记研究证实烟曲霉素可以暂时清除大多数患者体内的寄生虫，但严重的不良事件和寄生虫复发常见（48）。29位患者中有21人粪便中微孢子虫被暂时清除。但是6周后，所有接受治疗剂量低于60mg/天的患者均出现了寄生虫感染复发。引人瞩目的是，11个接受60mg/天治疗剂量的患者中有8个胃肠道内微孢子虫被完全清除，且体重增加。平均随诊11.5个月，未发现这8名患者出现感染复发（48）。口服烟曲霉素（20mg 每天三次，空腹服用）清除寄生虫的作用和临床效果最终在一项随机双盲安慰剂对照研究中得到证实。这项实验包括10名AIDS患者，和2名器官移植后患者。3位患者中出现了严重的不良事件（中性粒细胞减少和血小板减少）。在10个月的随访时间内，12例患者中有2例出现微孢子虫感染复发，提示寄生虫并未被彻底清除（50）。 Finally, one case report suggests potential clinical efficacy of nitazoxanide for the treatment of an HIV-infected patient with Enterocytozoon infection (5). 有一个案报道指出硝唑尼特可能对患肠微孢子虫病的HIV感染者有临床疗效（5）。 Other Microsporidia: An HIV-infected patient with myositis due to a newly described microsporidian, Trachipleistophora hominis, was successfully treated with a combination of albendazole (400 mg twice daily), sulfadiazine (1 g four times daily), pyrimethamine (50 mg daily), and folinic acid (7.5 mg daily) (29). 其他微孢子虫：应用阿苯哒唑（400mg 每天两次）、磺胺嘧啶（1g 每天四次）、乙胺嘧啶（50mg 每天一次）和亚叶酸（7.5mg 每天一次）联合治疗一名感染了Trachipleistophora hominis,这一新发现的微孢子虫而引起肌炎的HIV感染者获得成功。 Two immunocompetent patients with corneal ulcers due to Vittaforma corneae (formerly Nosema corneum) and Nosema ocularum, respectively, underwent successful keratoplasty after topical therapy and antimicrobial agents proved to be of no benefit (10, 18). In vitro cultivation of Vittaforma corneae has been achieved; albendazole had in vitro activity against this microsporidian (59). 两位分别感染了Vittaforma corneae (formerly Nosema corneum) 和 Nosema ocularum引起角膜溃疡的免疫力正常患者，经局部治疗和已证实无效的抗微生物制剂治疗后，均成功进行了角膜移植术（10，18）。Vittaforma corneae的体外培养已获成功；阿苯哒唑在体外有杀伤该微孢子虫的活性（59）。 Special Situations 特殊情况 Cerebral Microsporidiosis: Two cases of presumably immunocompromised (but HIV-seronegative) children with seizure disorders attributed to Encephalitozoon infection have been described (4, 44). One child was treated with penicillin and sulfisoxazole and seemed to improve but the role of chemotherapy remained unclear. Unfortunately, no follow-up data on these children have been published. 颅内微孢子虫病：曾报道有两例感染脑炎微孢子虫引起症状发作的儿童，可能有免疫力低下，但血清HIV抗体阴性（4，44）。其中1例患儿经青霉素和磺胺治疗后症状似有改善，但药物所起的作用仍不明确。遗憾的是，并无这些患儿的随访数据。 An HIV-infected patient with cerebral Encephalitozoon cuniculi infection was treated with albendazole (70) based upon the clinical observation of successful use of albendazole in cerebral cysticercosis which suggested that the drug may diffuse across the blood-brain barrier; however, no data on cerebrospinal fluid drug levels are available. During the first 4 to 8 weeks, albendazole therapy appeared to be successful as indicated by a decrease of the brain lesions on MRI scan and a substantial reduction of spore shedding in the urine. Persistent parasite excretion in urine, however, was documented, and the patient eventually died, probably due to cerebral Encephalitozoon infection. The small number of spores that continued to be excreted appeared morphologically intact but were not viable because spores could not be propagated in cell cultures. Nevertheless, persistence of viable parasites despite albendazole was assumed because of continued shedding of spores during the three-month treatment period (70). 临床上阿苯哒唑可有效治疗脑囊虫病，推测其可以透过血脑屏障，但尚不清楚脑脊液中的药物浓度。曾用其治疗一名颅内兔脑炎微孢子虫感染的HIV患者。开始4-8周疗效显著，MRI提示脑损伤减小，尿中排出的孢子也明显减少。但患者尿中持续有孢子排出，且患者最终死亡，可能颅内脑炎微孢子虫感染有关。尿中持续性排出的少量孢子，看似形态完整，但已丧失活力，不能于细胞培养基中繁殖。然而，3个月治疗过程中孢子持续排出，说明仍有活菌存在。 Keratoconjunctival Microsporidiosis: Topical application of fumagillin in some HIV-infected patients with keratoconjunctivitis due to Encephalitozoon hellem was associated with clinical improvement (23). Topical treatment, however, appears rarely indicated because keratoconjunctival encephalitozoonosis is almost always a manifestation of disseminated infection and the parasites are rarely, if ever, limited to superficial ocular structures (68). Consequently, detection of Microsporidia in keratoconjunctival tissue of HIV-infected patients should prompt a thorough search of other sites and bodily fluids, and systemic treatment with albendazole is usually indicated in these immunodeficient patients. 角结膜炎微孢子虫病：在一些脑炎微孢子虫（Encephalitozoon hellem）感染引起角膜炎的HIV患者中局部应用烟曲霉素可改善临床症状（23）。然而，脑炎微孢子虫角结膜炎几乎均为全身播散性感染临床表现之一，罕见寄生虫局限于角膜表面，因此，并不推荐局部治疗（68）。如在HIV感染者角膜组织中发现微孢子虫，需彻底检查其他部位和体液，并全身性应用阿苯哒唑治疗。 Alternative Therapy 备选疗法 In vitro studies have indicated that ten other benzimidazole derivatives including mebendazole and fenbendazole can inhibit growth of Encephalitozoon spp. in cell culture systems (36). Nevertheless, there are no clinical data available on possible alternative options for antimicrobial treatment of patients infected with Encephalitozoon spp. who cannot tolerate albendazole. There are no data on the use of fenbendazole in humans, and mebendazole is poorly absorbed. Therefore, it is unclear whether either would provide an appropriate alternative to albendazole. 体外试验提示，包括甲苯哒唑和芬苯哒唑在内的十种其他苯丙咪唑类衍生物均可在细胞培养系统中抑制兔脑炎微孢子虫的生长（36）。然而，对于不能耐受阿苯哒唑的脑炎微孢子虫患者，并无备选药物方面的临床数据。尚无芬苯哒唑用于人体的数据，甲苯哒唑又难于吸收，因此，尚不清楚这两种药物是否可以替代阿苯哒唑。 ADJUNCTIVE THERAPY Guided Medline Search 辅助治疗 Antimotility drugs including loperamide, diphenoxylate, tincture of opium, and octreotide have been useful as palliative treatment in HIV-infected patients with severe, refractory Enterocytozoon bieneusi associated diarrhea. Also, nutritional therapy that emphasizes diets with low fat and simple carbohydrates may be beneficial (39). 在伴有腹泻的重度难治性比氏肠微孢子虫感染的HIV感染者中，可使用包括洛哌丁胺、地芬诺酯、阿片酊和奥曲肽在内的抑制胃肠动力药物对症治疗。此外，强调低脂、简单的碳水化合物的饮食治疗也可能是有益的（39）。 Keratoplasty has successfully been performed in otherwise healthy immunocompetent persons with corneal ulcers due to localized microsporidial infection (without systemic dissemination). 角膜成形术已成功用于治疗免疫力正常患者局部感染微孢子虫（无全身播散）引起的角膜溃疡。 ENDPOINTS FOR MONITORING THERAPY Guided Medline Search 治疗终点 Cessation of microsporidial spore excretion and clearing of the parasites from tissue has been well documented in HIV-infected patients with microsporidiosis who responded to chemotherapy. Such a response to treatment can be monitored by light microscopical examination of bodily fluids, i.e. stool specimens to follow patients with Enterocytozoon bieneusi or Encephalitozoon intestinalis infection (72), or urine sediments to follow patients with Encephalitozoon cuniculi and Encephalitozoon hellem infection (70). 已证实，如患微孢子虫病的HIV感染者对药物的反应，如微孢子虫孢子停止外排，组织中的寄生虫清除，已有明确报道。可使用光镜检测比氏肠微孢子虫或肠脑炎微孢子虫患者的粪便等体液标本（72），或肠脑炎微孢子虫和 Encephalitozoon hellem患者的尿沉渣来监测疗效（70）。 An intermittent decrease in parasite load as concluded from examination of a limited number of biopsy specimens or from semiquantitative assessment of microsporidial spores in stool samples should be interpreted with caution because of a focal distribution of infected enterocytes, and a wide day-to-day variation in spore-shedding in untreated patients (62). 受微孢子虫感染的肠上皮细胞是呈灶状分布的，未经治疗的患者中孢子脱落量每天也有巨大变化（62），因此应谨慎理解通过检测少数活检标本或半定量评估粪便标本中微孢子虫孢子得出的寄生虫负荷会间断性减少这一结论。 VACCINES Guided Medline Search 疫苗 Vaccines to prevent microsporidial infections are not available. 尚无预防微孢子虫感染的疫苗。 PREVENTION OR INFECTION CONTROL MEASURES Guided Medline Search Smart search 防治措施 Antiparasitic Agent Prophylaxis 寄生虫预防制剂 Primary chemoprophylaxis to prevent Enterocytozoon bieneusi infection among patients at risk, i.e. severely immunodeficient patients, is not possible because there is no effective drug available. Primary prevention of encephalitozoonosis using albendazole seems not to be indicated because this microsporidial infection is rare even among HIV-infected or immunodeficient persons. 目前尚未发现可有效预防比氏肠微孢子虫感染的药物，因此不能在重度免疫缺陷等高危患者中行一级预防。即使在HIV感染者或免疫缺陷患者中脑炎微孢子虫感染都很少见，因此并无指征使用阿苯达唑行一级预防。 As long as HIV infected patients, who were treated for clinically manifest Encephalitozoon spp. infection, remain severely immunodeficient (i.e. have CD4 lymphocyte counts below 0.1 x 109/L), secondary prophylaxis using antiparasitic maintenance therapy appears to be indicated. Albendazole was shown to significantly delay the occurrence of relapse in patients with AIDS and E. intestinalis infection who were prospectively followed in a controlled trial (46). 有症状的兔脑炎微孢子虫感染的HIV感染者，经药物治疗后如仍有严重免疫功能缺陷（如CD4阳性T淋巴细胞计数小于0.1Ś109/L），有维持抗寄生虫药物治疗行二级预防的指征。前瞻性随访中发现，与对照组比较，阿苯达唑可显著延迟AIDS患者中肠脑炎微孢子虫感染的复发（46）。 COMMENTS AND CONTROVERSIES 评论和争议 Improvement of the Immune Function and Parasite Clearance 免疫力的提高和寄生虫的清除 Enterocytozoon bieneusi-associated diarrhea as well as systemic infection due to Encephalitozoon spp. are mainly observed in severely immunodeficient patients with CD4 lymphocyte counts below 0.05 to 0.1 x 109/L. Therefore, it was hypothesized that HIV-infected patients with low CD4 lymphocyte counts and microsporidiosis could benefit from the new highly active antiretroviral treatment (including potent proteinase inhibitors). Clinical observational studies indeed have suggested that an improvement of immune functions can result in complete clinical response and normalization of intestinal architecture which parallels the clearance of intestinal opportunistic parasites including Enterocytozoon bieneusi (13, 30, 32, 45). However, recurrent diarrhea and parasitological relapse was observed in HIV-infected patients with failure of antiretroviral therapy associated with declining blood CD4 lymphocyte counts (13). Also, these observations indicated that intestinal parasites can probably not be eradicated in immunodeficient patients with only transient improvement of host immune function. 比氏肠微孢子虫相关性腹泻和兔脑炎微孢子虫引起的全身感染主要见于CD4阳性T淋巴细胞计数小于0.05-0.1Ś109/L的严重免疫缺陷患者。因此，有人认为新型高效抗逆转录病毒治疗（包括蛋白酶抑制剂）可使低CD4淋巴细胞计数、患微孢子虫病的HIV感染者受益。临床观察研究确实提示提高免疫力可导致临床完全缓解以及肠道结构修复，并且是和包括比氏肠微孢子虫在内的肠道机会性寄生虫的清除相平行的(13, 30, 32, 45)。.然而，抗逆转录病毒治疗失败且血CD4淋巴细胞计数减少的HIV病毒感染者中可再次出现腹泻和寄生虫感染复发（13）。而且这些观察指出仅有一过性宿主免疫功能改善的免疫缺陷患者中肠道寄生虫可能并不能获得根除。 Are Microsporidia Pathogenic? 微孢子虫有致病性吗？ Some investigators have questioned the association between Enterocytozoon bieneusi infection and diarrhea because a case control study comparing intestinal biopsies of 55 HIV-infected patients with chronic diarrhea and 51 HIV-infected patients without diarrhea found no significant difference in the occurrence of microsporidiosis in the two patient groups (51). Most clinical and epidemiological studies, however, have indicated that E. bieneusi is consistently associated with intestinal and/or biliary illness (68). 一些研究 人员对比氏肠微孢子虫感染和腹泻间的关系持怀疑态度。一项病例对照研究比较了55例有慢性腹泻的HIV感染者和51例无腹泻HIV感染者的肠道活检标本，发现两组病人间微孢子虫病发病率并无显著性差异（51）。然而，绝大多数临床和流行病学研究都表明比氏肠微孢子虫和肠道和/或胆道疾病是有关的。 Chemotherapy-induced Ultrastructural Changes of Microsporidia 药物治疗引起的微孢子虫微观结构改变 Although intermittent symptomatic relief, a decrease in the intestinal parasite load, and ultrastructural changes in different developmental stages of Enterocytozoon bieneusi following treatment with albendazole, furazolidone and thalidomide have been described (7, 26), eradication of the parasite and long-lasting clinically relevant improvement have never been documented. Also, ultrastructural changes of Enterocytozoon bieneusi following albendazole treatment were not substantiated by other investigators (24). 尽管阿苯哒唑、呋喃唑酮和沙利度胺治疗可间断缓解症状，降低肠内寄生虫负荷，并可引起不同发育阶段比氏肠微孢子虫微观结构的改变（7，26），却从未见有关寄生虫根治和长期临床改善的报道。而且，其他研究人员并未观察到阿苯哒唑治疗后比氏肠微孢子虫出现微观结构改变（24）。 Table 1. Microsporidial species pathogenic in humans, clinical manifestations and treatment. [Download PDF] 表1 人体内致病性微孢子虫种类、临床表现和治疗措施
* 尚未分类 ** Microsporidium是一类现有信息不足，不能分类的微孢子虫的统称。
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