贝氏等孢球虫

 

David S. Lindsay, Ph.D.

 

Louis M. Weiss M.D., M.P.H.

Albert Einstein College of Medicine, 

1300 Morris Park Avenue, Room 504 

Forchheimer, Bronx, New York, 10461

 

译者：赖雅敏 博士

      北京协和医院 消化科

      Email：laiyamin@gmail.com

 

审阅者：王焕玲 教授

        北京协和医院 感染科

 

GENERAL DESCRIPTION

概述

Parasitology Guided Medline Search

寄生虫学

Life Cycle

生活史

            Isospora belli is a protozoan parasite in the Phylum Apicomplexa. This group of parasites are referred to as coccidia. The parasite is acqiuired by ingestion of sporulated oocysts that are in contaminated food or water. These stages are 23-36 by 12-17 µm and are much larger than the oocysts of the related coccidial species Cryptosporidum parvum and Cyclospora cayetanensis. Sporulated oocysts of I. belli survive for years in the environment. Endogenous stages of I. belli consist of schizonts (multinucleated asexual stages), merozoites (uninucleate asexal stages), macrogomonts (female sexual stages [ovum-like stage]), microgamonts (male sexual stages) with microgametes (sperm-like stages) and oocysts (formed by fertilization of macrogamont by a microgamete). The endogenous stages are usually located in a vacuole within enterocytes lining the villi of the small and large intestine (2,24) or rarely bile duct epithelium (1). Some merozoites can also be observed in lamina propria (4) and probably give rise to extra-intestinal infections. Extra-intestinal infections with tissue cyst-like stages have been observed in the mesenteric, periaortic and mediastinal lymph nodes, liver and in the spleen of AIDS patients (20,15) and probably occur in immunocompetent patients. These extra-intestinal tissue cysts represent a dormant form of the infection and contain a single merozoite stage (14). It is these extra-intestinal tissue cysts that are probably responsible for the recurrences seen in immuocompromised and immunocompetent patients (14).

        贝氏等孢球虫是一种复合原虫感染。这一类寄生虫属于双孢子虫。人可通过摄入被孢子卵囊污染的食物或水而感染。卵囊的大小为23-36x12-17um大小，比双孢子虫类中同属的微小隐孢子虫（Cryptosporidum parvum）和 圆孢球虫（Cyclospora cayetanensis）大得多。贝氏等孢球虫（l.belli，以下简称LB）的卵囊阶段在自然环境中可存活数年。内源性LB包括裂殖体（多核无性生殖阶段），裂殖子（单核无性生殖阶段），macrogomonts（雌配子体【卵泡样期】），microgamonts（雄孢子体期）、和microgametes雄配子体【精子样期】，和卵囊（由雄配子体和雌配子体受精后形成）。内源阶段中，LB大多存在于小肠和大肠绒毛细胞内的内吞小泡里，少数存在于胆管上皮细胞内。一些裂殖子也见于肠道固有层，可引起肠外感染。肠外感染时，LB在组织以包囊形式存在，见于AIDS患者或免疫功能正常者的肠系膜、主动脉周围、纵隔淋巴结、肝和脾脏。这些肠外组织包囊感染可以引起免疫抑制和免疫缺陷患者的复发。

Epidemiology Guided Medline Search

流行病学

            Isospora belli infections are essentially cosmopolitan in distribution but are more common in tropical and subtropical regions, especially Haiti, Mexico, Brazil, El Salvador, tropical Africa, Middle East, and Southeast Asia (7,22).

        贝氏等孢球虫感染分布于世界各地,但较常见于热带和亚热带地区,比如海地,墨西哥,巴西,萨尔瓦多,赤道非洲,中东和东南亚。

Clinical Manifestations Guided Medline Search

临床表现

            Isospora belli causes serious and sometimes fatal disease in immunocompetent patients. Symptoms of I. belli infection include diarrhea, steatorrhea, headache, fever, malaise, abdominal pain, vomiting, dehydration, and weight loss (2,12,24). Blood is not usually present in the feces. The disease is often chronic with parasites present in the feces or biopsies for several months to years. Recurrences are common. Isospora belli infections in AIDS patients are often severe with very fluid, secretory-like, diarrhea that may lead to dehydration requiring hospitalization. Fever and weight loss are also common findings. Again recurrences are common and present the most challengeing aspect of treating this infection.

        免疫功能正常者的LB感染病情严重，甚至导致死亡。LB感染的症状包括腹泻、脂肪泻、头疼、发热、乏力、腹痛、呕吐和脱水、体重下降。一般无血便。该病常为慢性，可在数月到数年内大便或肠活检中检出寄生虫。复发很常见。AIDS患者感染LB通常会引起稀水样分泌性腹泻，导致严重脱水，需要住院治疗。发热和体重下降也很常见。由于复发很常见，治疗困难。

Laboratory Diagnosis Guided Medline Search

实验室诊断

            Isospora belli is diagnosed by detection of the parasite oocysts in wet preparations or acid fast stained smears of concentrated stool specimens. Histological examination of small intestinal tissue sections may reveal the parasite within the enterocytes.

        采用浮聚法制备的新鲜大便标本涂片，经过抗酸染色，若发现寄生的卵囊则可确诊。小肠组织活检可以发现肠细胞内的寄生虫。

Pathogenesis Guided Medline Search

病理

            Isospora belli can cause marked villous atropy, and crypt hyperplasia in the small intestine. Inflammatory infiltrates in the lamina propria include eosinophils, neutrophils, lymphocytes and plasma cells. The exact mechanism causing these changes are unknown, but they result in steatorrhea and malabsorption.

        LB可以导致明显的小肠绒毛萎缩和隐窝不典型增生。固有层内炎性细胞浸润包括嗜酸性细胞、中性粒细胞、淋巴细胞和浆细胞。这些病理改变可引起脂肪泻和吸收不良，尽管确切的机制尚不清楚。

II. Susceptibility in vitro and in vivo Guided Medline Search In Vitro and In Vivo

II体内外的药物敏感性

            There are no reports of in vitro cultivation of I. belli. There are no animal models of I. belli  infection.

        没有体外培养的报告。没有LB的动物模型。 

III. AntiParasitic Therapy Smart search

III抗寄生虫治疗

III.A. Drug of choice Guided Medline Search

III．A．药物

            Combination therapy with oral trimethoprim (160 mg)-sulfamethoxazole (800 mg) 4 times a day for 10 days results in a decrease in diarrhea and abdominal pain within 1 to 6 days (mean = 2.5 days) after treatment (18). Stool samples examined after 10 days usually do not contain oocysts. Combination therapy with oral trimethoprim (320 mg) -sulfamethoxazole (1,600 mg) 2 times a day for 10 to 14 days is as effective and may be an easier course of therapy for some patients. It is important to note here that HIV patients should receive secondary prophlyaxis (see below).

        治疗采用口服甲氧苄氨嘧啶（160mg）-磺胺甲噁唑（800mg）一天四次，疗程10天。治疗1-6天内（平均2.5天）腹泻和腹痛缓解。治疗10天则大便检测卵囊转为阴性。口服甲氧苄氨嘧啶（320mg）-磺胺甲噁唑（1600mg）每日两次，疗程10-14天同样有效，可能对于某些患者更为方便。需要注意的是，HIV患者经过治疗后应该接受2级预防用药，以防止复发（如下）。

III.B. Special situations

III.B.特殊情况

Sulfonamide allergies: Pyrimethamine used alone is effective in patients with sulfonamide allergies (27). Dosages between 50 and 75 mg per day are comparable to treatment with trimethoprim-sulfamethoxazole. Diclazuril (see below) has also been used effectively in patients with sulfonamide allergies. 

磺胺过敏：单用乙胺嘧啶对于磺胺过敏的患者有效。每天50到75mg，疗效和甲氧苄氨嘧啶-磺胺甲噁唑相当。地克珠利也是磺胺过敏患者的有效选择。

            Immunosuppressed hosts including HIV patients, transplant recipients, etc. Isospora belli  infections have been observed in a wide variety of immunocompromised patients including patients with concurrent Hodgkin's disease (2), non-Hodgkin's lymphoproliferative disease (10), human T-cell leukemia virus type I-associated adult T-cell leukemia (9), and acute lymphoblastic leukemia (28). These patients will respond to specific anti-I. belli  treatment. It was suggested in one report that treatment with prednisolone (60 mg/daily for 13 days) led to transient immunosuppression and severe I. belli  infection in one patient (16). This patient recovered without specific treatment.

        免疫功能低下的宿主包括HIV患者、移植物受体等。LB感染可见于各种免疫功能低下患者，包括何杰金、非何杰金淋巴瘤患者、人类T细胞白血病病毒I相关的成人T细胞白血病和急性淋巴细胞白血病患者。这些患者经特异性抗LB治疗有效。一篇文献报告一名患者因服用强地松龙（每天60mgx13天）导致短暂的免疫而出现严重的LB感染，未经特殊处理自愈。           

             Isospora belli  infections have been widely documented in AIDS patients. Anti-I. belli  treatment is usually effective in controlling symptoms but recurrences are common after treatment is stopped. This is most likely because the agents used to treat the infection are not active against the extra-intestinal tissue cyst stage of the parasite. Prophylaxis is required to prevent reoccurrence in AIDS patients. 

        AIDS患者感染LB常见报道。抗LB的治疗通常能有效控制症状，但停药后复发较常见。原因是由于药物对肠外感染的组织包囊阶段无效。因此需要对AIDS患者进行2级预防，防止复发。

Alternative therapy

其它治疗选择

Pyrimethamine:  Pyrimethamine is related to trimethoprim and is an dihydrofolate synthetase inhibitor. Pyrimethamine has been used alone at dosages of 50 to 75 mg per day as an alternative to trimethoprim-sulfamethoxazole (27). In the two patients reported resolution of diarrhea occured with 2 days of starting therapy. It is particular use in sulfonamide allergic patients. Pyrimethamine has been used for secondary prophylaxis following primary isosporiasis. The major limiting toxicity of pyrimethamine is bone marrow suppression, which can be prevented by using folinic acid (5 to 10 mg/day) when pyrimethamine is administered.

乙胺嘧啶：乙胺嘧啶 与甲氧苄氨嘧啶相似，是双氢叶酸合成酶的抑制剂。单药治疗，每日50-75mg。是除甲氧苄氨嘧啶-磺胺甲噁唑外的另一个选择。有报道两名患者在用药2天后腹泻停止。特别适用于磺胺过敏的患者。乙胺嘧啶可用于二次预防用药。乙胺嘧啶的主要不良反应是骨髓抑制，可在治疗同时服用叶酸（每日5-10mg）预防。

Ciprofloxacin:  Ciprofloxacin is a fluoroquinolone that inhibits DNA gyrase (topoisomerase). Many of these quinolones have demonstrated activity against protozoa including apicomplexa such as malaria. A recent study (26) compaired trimethoprim-sulfamethoxazole to ciprofloxacin (500 mg BID) for the treament of isosporiasis in HIV infected patients. Of 22 patients with isosporiasis, 10 were randomized to revieve trimethoprim-sulfamethoxazole and 12 ciprofloxacin. All of the patients treated with trimethoprim-sulfamethoxazole responded to treatment with clearing of the organism and resolution of diarreha which ceased within a median of 2 days. Ciprofloxacin was effective in 10/12 (83%) of patients with a median time to ceasation of diarrhea of 4.5 days. All three patients (2 with diarrhea and one without) who had persistant isosopora in their stools at the completion ciprofloxacin treament responded to trimethoprim-sulfamethoxazole by elimination of organisms and resolution of diarrhea. In those patients responding ciprofloxacin continued prophylaxis with ciprofloxacin prevented recurrence of disease. Ciprofloxacin, therefore, while not as effective as trimethoprim-sulfamethoxazole can be used as an alternative agent. Ciprofloxacin is contraindicated in children and pregnant women as quinolones have been associated with cartilage problems in animal models.

环丙沙星:环丙沙星是一种氟喹诺酮类抗菌素，可以抑制DNA旋转酶（拓扑异构酶）。许多喹诺酮类药物治疗原虫有效，如疟疾。最近一项研究比较了甲氧苄氨嘧啶-磺胺甲噁唑和环丙沙星500mg BID治疗HIV患者的LB感染的疗效。这22名患者中，10名被随机分到甲氧苄氨嘧啶-磺胺甲噁唑组，12名被分到环丙沙星组。所有服用甲氧苄氨嘧啶-磺胺甲噁唑患者便检转阴，腹泻停止，腹泻停止的中位时间为2天。12名环丙沙星治疗组中10名患者有效，腹泻停止的中位时间是4.5天。有3名患者经环丙沙星治疗后便中仍持续发现LB（其中2名仍有腹泻，1名腹泻停止），改用甲氧苄氨嘧啶-磺胺甲噁唑治疗后便检转阴，腹泻停止。环丙沙星治疗有效的患者可继用环丙沙星预防复发。因而，环丙沙星虽然不及甲氧苄氨嘧啶-磺胺甲噁唑有效，但也可作为次选方案。由于在动物模型中发现喹诺酮可导致软骨问题，环丙沙星禁止用于儿童和孕妇。

Diclazuril: Diclazuril (Clinicox) is a triazin anticoccidial used in the poultry production industry. Diclazuril was used in a trial to treat 8 AIDS patients with I. belli  diarrhea (11). Each patient received 200 mg of diclazuril orally for 7 days. Oocysts were eliminated from the stools by 2 to 3 days. Diarrhea completely stopped in 4 of 8 patients, however severe diarrhea persisted in 1 patient. Oocysts were present in the stools of 1 of 3 patients examined over a month later. Diarrhea and oocyst excretion reoccurred 47 days after treatment had ended. Diclazuril has also been used successfully to treat an AIDS patient that was hypersensitive to trimethoprin-sulfamethoxazole or pyrimethamine (13). Diclazuril given orally at 300 mg twice daily controlled the I. belli  infection. When the dose was decreased to 300 mg once daily the patient had a reoccurrence.

地克珠利：地克珠利是三嗪环类抗双孢子虫药物，主要用于禽类饲养业。地克珠利曾在一次临床试验中用于治疗8名AIDS患者合并LB感染引起的腹泻。每名患者每日服用200mg地克珠利，疗程7天。2-3天后便中的卵囊消失。8名患者中4名腹泻完全消失，但1名患者腹泻严重，持续不缓解。1/3患者1月后便中仍持续有卵囊。 治疗结束47天后仍有腹泻反复和便检卵囊阳性。对于甲氧苄氨嘧啶-磺胺甲噁唑或乙嘧啶过敏的AIDS患者合并的LB感染，可以选用地克珠利300mg，每日2次，可以控制LB感染。但当剂量降到每日300mg时，病情可能复发。

Macrolide antibiotics:  Macrolide antibiotics have marginal efficacy in treating I. belli  enteritis. Spiramycin given at 1.5 g twice daily initially provided clinical improvement in an AIDS patient that did not responded to trimethoprim-sulfamethoxizole, furazolidone or tetracycline treatments for I. belli  enteritis (8). Response to treatment lasted about a month and then the patient suffered a reoccurence. Roxithromycin (2.5 mg/kg every 12 hours) was used successfully to treat an AIDS patient that was suffering from chronic I. belli  induced diarrhea that did not respond to trimethoprim-sulfamethoxizole or pyrimethamine treatments (17). Roxithromycin was given orally for 15 days and the diarrhea became intermittent and less severe. Although diarrhea requiring hospitalization occurred twice during the 2 months after treatment, no I. belli  was observed in stool samples.

大环类酯类抗生素：大环类酯类对LB肠炎部分有效。有文献报导螺旋霉素1.5g每日两次可用于对甲氧苄氨嘧啶-磺胺甲噁唑、呋喃唑酮或替卡西林治疗无效的AIDS患者合并LB肠炎，疗效维持1月，但停药后复发。罗红霉素（2.5mg/kg每12小时一次）成功用于对甲氧苄氨嘧啶-磺胺甲噁唑或乙嘧啶治疗无效的慢性LB感染患者的腹泻。罗红霉素口服15天后腹泻减轻。尽管在治疗后2月内仍有2次因腹泻需住院，大便标本未检出LB。

Nitazoxanide:  Nitazoxanide, a 5-nitrothiazole under development for the treatment of cryptosporidiosis, has been used effectively to treat I. belli  infections (21, 5). Each of 2 patients that received 500 mg nitazoxanide twice daily for 3 days became oocyst negative (21). A single patient treated with 500 mg nitazoxanide twice daily for 7 days became oocyst negative by day 14 after treatment (5).

硝唑尼特：是在研发隐孢子虫治疗药物时发现的5-硝唑噻唑，已成功用于LB感染的治疗。2位患者接受硝唑尼特500mg，每日两次，3天后大便检测卵囊转阴。1名患者服用硝唑尼特500mg，每日两次，疗程7天，治疗14天后便检转阴。

            In the United States, nitazoxanide is an investigational new drug for treatment of diarrhea caused by C. parvum and the microsporidia in patients with AIDS. Nitazoxanide (500 mg tablets for adults) is currently undergoing registration in the United States, Canada, and the European Union for the treatment of diarrhea associated with cryptosporidiosis inpatients with AIDS. In Latin America, nitazoxanide 500 mg film-coated tablets, 200 mg dispersible tablets, and 100 mg/ 5 ml pediatric suspension are marketed for treatment of a broad spectrum of parasitic infections that are common in the developing world and for treatment of diarrhea caused by C. parvum and the microsporidia in patients with AIDS. Side effects include elevation in liver function tests and nausea.

        在美国，硝唑尼特是正在研发的新药，主要用于AIDS患者因隐孢子虫和小孢子虫而导致的腹泻。硝唑尼特（500mg成人剂片）正申请在美国、加拿大和欧盟注册。硝唑尼特的多种剂型已在拉丁美洲上市，包括500mg糖衣片、200mg分散片和100mg/5ml儿科混悬液，用于治疗发展中国家常见的寄生虫感染和AIDS患者因隐孢子虫和小孢子虫感染导致的腹泻。副作用包括肝酶升高和恶心。

Amprolium:  Amprolium (Amprol, Corid) is an anticoccidial agent used in the poultry production industry. It is structurally related to the vitamin thiamine and it competitively inhibits the active transport of thiamine in coccidial parasites. Amprolium was used in an AIDS patient suffering from severe diarrhea caused by I. belli   (25). Amprolium was given orally beginning at 10 mg/kg and increased to 90 mg/kg. The frequency of diarrhea lessened after 6 days of treatment. Amprolium treatment was stopped on day 7 because of polyneuropathy but re-initiated on day 20 at a reduced dose of 30 mg/kg. The stool became normal by day 28 of treatment and no oocysts were present after day 35.

安普罗铵：安普罗铵（Amprol,Corid）是一种用于禽类养殖业的抗双孢子虫药物，。它在结构上与维生素B1相似，主要作用是抑制双孢子虫的硫胺的主动转运。有文献报导安普罗铵用于AIDS患者因LB感染引起的严重腹泻。安普罗铵口服剂量从10mg/kg开始，逐渐加大至90mg/Kg。6天后腹泻次数减少。7天后由于出现多神经病变，安普罗铵治疗被迫停止，20天后再次应用，剂量减为30mg/kg开始。治疗28天后腹泻停止，35天后大便检测卵囊转阴。

Other agents:  Albendazole combined with ornidazole has been used successfully in 2 AIDS patients with I. belli  infections (5). One patient received albendazole 400 mg TID for 20 days and ornidazole 2 gm single dose on days 1,10 and 20 and the other patient received albendazole 400 mg TID for 30 days and ornidazole 2 gm single dose on days 1,15 and 30. Both patients had clearance of symptoms and an absence of oocysts after 4 days of treatment. 

其他药物：阿本达唑联合奥硝唑已成功用于治疗2名AIDS患者的LB感染。一名患者接受400mg，每日3次，20天，奥硝唑2g第1、10和20天，另外一名患者接受阿本达唑400mg每日3次，30天和奥硝唑2g第1、15和30天。两名患者4天后症状消失、大便检测卵囊转阴。

            Treatment with other anti-protozoal agents such as metronidazole, tinidazole, quinacrine, furazolidone are probably of little value (24, 23, 3,  27).

        其它抗寄生虫药物如甲硝唑、甲酰咪唑、quinacrine、呋喃唑酮的治疗作用很小。

IV. Endpoints for monitoring therapy Guided Medline Search

            Cessation of diarrhea and the disappearance of I. belli  oocysts from stool samples are the endpoints for monitoring therapy.

IV.治疗的终点

        腹泻停止和大便中LB卵囊的消失是监测治疗的终点。

V. Vaccines Guided Medline Search 

            There are no vaccines for I. belli  infections.

V.疫苗

        LB感染没有疫苗。

VI. InFECTION CONTROL MEASURES Guided Medline Search

VI.控制感染方式

Antiparasitic Agent Prophylaxis

抗寄生虫药物预防

Overview:  Recurrence after apparently successful treatment occurs in about 1 in 2 AIDS patients (DeHovitz et al., 1986, 18). This is probably because agents used to treat active infections have no effect on the dormant tissue cyst stage of the parasite.

概述：1/2的AIDS患者在治疗彻底后仍可复发(DeHovitz et al., 1986, 18)。这可能是因为药物治疗仅对活跃感染有效，对休眠期包囊无效。

Indications:  Secondary prophylaxis is indicated in all AIDS patients because about 1 in 2 treated patients will suffer a recurrence with in 2 months if no prophylaxis is given (18).

指征:2级预防适用于所有AIDS患者，因为约1/2患者治疗后若不予2级预防用药会在2个月内出现复发。

Doses, schedules:  Effective prophylaxis can be achieved with with oral trimethoprim (160 mg)-sulfamethoxazole (800 mg) given 3 times a week or oral pyrimethamine (25 mg) combined with sulfadoxine (500 mg) once a week (18). Effective prophylaxis can also be provided by pyrimethamine 25 mg a day combined with 5 mg a day folinic acid (to decrease haemotologic effects) (27). This is very useful in patients intolerant of sulfa drugs.

剂量，方案：有效的预防量为口服甲氧苄氨嘧啶（160mg）-磺胺甲噁唑（800mg），每周三次或口服乙嘧啶（25mg）与周效磺胺（500mg）每周1次。每日25mg乙胺嘧啶与每日5mg叶酸合用（为了降低血液学副作用）也能提供有效预防。非常适用于磺胺不耐受的患者。

VII. Adjunctive therapy Guided Medline Search

VII.联合治疗

            Severe dehydration can occur in AIDS patients with I. belli  infections and intravenous or oral rehydration is appropriate in these patients. Folinic acid 5 to 10 mg per day can be used to prevent adverse effects of trimethoprim or pyrimethamine administration (27). Antimotility drugs can be used to control diarrhea.

        AIDS患者的LB感染可有严重的脱水，静脉或胃肠道补充水份非常重要。叶酸5到10mg每天可以用于预防甲氧嘧啶或乙嘧啶的副作用。抗胃肠蠕动药物可用于控制腹泻症状。

VIII. Comments

VIII.注释

            We believe that atovaquone (Mepron) would be a useful drug for treating I. bell based on its effectiveness against Toxoplasma gondii (19). No case reports exist on this agent for I. belli  but we believe it would be effective orally at 750 mg 2 to 4 times daily for 10 to 14 days.

        由于阿托伐醌（Mepron）治疗弓形虫有效，我们认为其可用于治疗LB感染。目前尚未病例报道，但我们认为口服750mg，每日2～4次，疗程10～14天，可能也对LB感染有效。

            The effect of highly active anti-retroviral therapy (HAART) on I. belli  is not known. It is likely that if the CD4 count rises above 200-300 when HAART is given that secondary prophylaxis can be stopped. This has been the case for MAI and PCP prophylaxis (primary prevention) and is likey to be the case for PCP secondary prophylaxis (post infection). It is likely that once immune reconstitution induced by HAART has been achived that consideration should be given to stopping secondary prophylaxis for I. belli.

        鸡尾酒疗法对于LB的影响并不明确。经HAART治疗后，假如CD4计数升高到200-300，可停用2级预防用药。这与MAC和PCP1级预防、PCP2级预防的情况类似。一旦HAART达到免疫功能重建就可以考虑停止对LB的2级预防。

 

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