隐孢子虫病

译者：司晓燕博士

北京协和医院内科

审阅者：王焕玲教授

北京协和医院感染科

Cryptosporidium parvum is a coccidian parasite that affects the intestinal and respiratory epithelium of vertebrates. It is capable of causing disease both in immunocompetent and immunocompromised hosts.

　　微小隐孢子虫是一种侵犯脊椎动物肠道和呼吸道上皮细胞的球孢子寄生虫。在免疫功能正常和免疫功能受损宿主中均可引起疾病。

Cryptosporidium is an intracellular protozoan parasite within the phylum Apicomplexa, group Alveolata. Cryptosporidium parvum causes most of the human infections, although other species such as C. muris, C. felis and C. meleagridis have been reported to cause infection in some individuals (7, 28, 37, 63). Recent evidence suggests that C. parvum includes at least 2 genotypes that differ in host range.

隐孢子虫是囊泡虫类顶复门的胞内原生寄生虫。虽有个例报道鼠隐孢子虫（C. muris）、猫隐孢子虫（C. felis）和火鸡隐孢子虫（C. meleagridis）引起的感染 (7, 28, 37, 63)，但引起人体感染的主要是微小隐孢子虫。近期证据表明，微小隐孢子虫至少有2个基因型，其宿主不同。

Genotype 1 is mainly transmitted from person-to-person. Genotype 2 mainly infects cattle (7, 37). Cryptosporidium is capable of completing both asexual and sexual phase of development in a single host. Humans are infected by ingestion of the oocyst. Excystation occurs in the small intestine with the release of 4 motile sporozoites. The sporozoites indents and invaginates the enterocyte surface to form a parasitoferous vacuole that is confined to the microvillus region. The sporozoites mature asexually to form meronts. Meronts release merozoites that reinfect the intestinal epithelium. Some of the merozoites then differentiate into the sexual forms (gametocytes), which fuse to form the oocysts. The oocysts are then excreted into the feces. Oocysts are thought to rarely excyst within the host, resulting in autoinfection. Autoinfection plays an important role in causing serious and persistent disease in immunocompromised hosts.

基因型1主要在人和人之间传播。基因型2主要感染牛(7, 37)。隐孢子虫在同一个宿主中能够完成无性生殖和有性生殖。人在吞食卵囊后被感染。卵囊在小肠中脱囊后释放出4个有活动能力的子孢子。子孢子在肠上皮细胞表面内陷，在微绒毛区形成寄生空泡。子孢子通过无性生殖形成裂殖体。裂殖体释放出裂殖子再次感染肠道上皮。部分裂殖子分化成有性生殖形式（配子体），配子体融合形成卵囊，在粪便中排出。卵囊很少在宿主中脱囊，引起自身感染。在免疫功能低下宿主的严重、持续感染中，自身感染起了重要作用。

Cryptosporidium occurs worldwide. It is an important cause of diarrhea both in immunocompetent and immunocompromised population. Patients with AIDS are at increased risk. Transmission commonly occurs from person-person by the fecal-oral route, and rarely by fomites. Environmental transmission occurs mainly through contaminated water supply. Cryptosporidial oocysts may be found in all types of water including chlorine treated drinking water (44). The 1993 outbreak in Milwaukee, affected an estimated 403,000 persons and resulted in death of several immunocompromised patients and illness in many previously healthy people (40). Contamination of public water supply occurred due to decrease in the purity of source water and filtration effectiveness (40). Zoonotic transmission from cattle and sheep to humans is known and they serve as reservoirs of cryptosporidial infection. Population at increased risk of cryptosporidial infection includes household contacts and sexual partners of patients, health care workers, day care personnel and travelers to highly endemic regions, and users of communal swimming pools (7).

隐孢子虫病在世界各地都有发生，是免疫功能正常和免疫功能缺陷的人群腹泻的重要病因。艾滋病患者的患病风险增加。人和人之间主要通过粪口传播，很少通过媒介传播。环境传播主要是通过水源污染。各种水中都可能存在隐孢子虫卵囊，包括经过氯处理的饮用水(44)。1993年的密尔沃基发生的隐孢子虫病暴发估计感染了403,000人，引起一些免疫功能缺陷患者死亡和许多既往健康人群发病(40)。水源纯净度和过滤果的下降导致了公共供水的污染(40)。牛和羊作为储存宿主，也可以将隐孢子虫传播到人。感染隐孢子虫的高危人群包括：患者的共同生活者、性伴侣、医疗工作人员、护工、流行地区旅行者、公共泳池使用者 (7)。

Cryptosporidiosis presents with a range of clinical manifestations, which vary with the immune status of the individual.

Immunocompetent Host: Cryptosporidium is confined to the gastrointestinal tract. The three major clinical presentations include asymptomatic carriage, acute diarrhea, and persistent diarrhea that may continue for several weeks. The incubation period is usually a few days. Diarrhea is the commonest complaint. Onset is often abrupt. Watery diarrhea lasts several days to 2 weeks and is often self-limited. In children in developing countries, cryptosporidiosis causes malnutrition and growth retardation.

免疫功能正常的宿主：隐孢子虫局限于胃肠道。三种主要的临床表现包括，无症状携带、急性腹泻和连续数周的持续性腹泻。一般有数天的潜伏期。腹泻是最常见的症状。腹泻常呈水样泻，突然发生，持续数日至2周后自限。在发展中国家儿童中，隐孢子虫病可引起的营养不良和生长迟滞。

Immunocompromised Host: In AIDS patients the severity of symptoms depends upon the CD4 count. Four clinical syndromes are recognized and include 1)asymptomatic infection, in which there is no change in bowel movements and the patients pass less than 4 stools/day, 2)transient infection, in which diarrhea lasts for less than 2 months and is followed by complete remission, 3)Chronic diarrhea, lasting 2 months or more, with persistence of parasites in stool and biopsy specimens and 4)fulminant cholera like illness, in which patients pass 2 liters of stool per day, and occurs in AIDS patients with CD4 less than 50 per cubic millimeter. In AIDS patients the stool frequency is often 10 per day, and the patients suffer from severe malabsorption and weight loss (12, 29).

免疫功能缺陷的宿主：在艾滋病患者中，症状的严重程度和CD4细胞计数有关。临床征候群分四种，包括：1)无症状感染：肠道运动正常，患者每日大便少于4次；2）短暂感染：腹泻持续时间小于2月，可自行完全缓解；3）慢性腹泻：持续时间超过2月，粪便和活检标本中能持续检出寄生虫；4）暴发性霍乱样疾病：每日排粪便2升以上，一般发生在CD4细胞计数小于50/uL的艾滋病患者中。在艾滋病患者中，每日大便次数在10次以上，并有严重的吸收不良和体重减轻(12, 29)。

Extraintestinal cryptosporidiosis can involve the lungs, middle ear, biliary tract, pancreas and stomach. Biliary cryptosporidiosis is the commonest extraintestinal manifestation. Patients present with acalculous cholecystitis or sclerosing cholangitis. Diarrhea may or may not accompany the illness.

肠外隐孢子虫病可以累及肺、中耳、胆道、胰腺和胃。其中胆道隐孢子虫病最常见，表现为无结石性胆囊炎或硬化性胆管炎，可伴或不伴腹泻。

Diagnosis of Cryptosporidium is primarily based on identification of the oocysts in stool (8). Oocysts stain with a modified acid-fast technique. However, the accuracy of the acid-fast stained smear is highly dependent on technician experience and the time put into the examination. Sensitivity may be poor in light infections (67). Oocysts can also be detected by direct immunofluorescent assays that are commercially available utilizing monoclonal antibodies raised to Cryptosporidium antigens. In addition, enzyme linked immunosorbent assays may be used to detect Cryptosporidium antigens in fecal specimens (18). There is no consensus on the optimal oocyst detection method in fecal samples, although one recent comparison of a modified acid-fast stain and a fluorescein labeled monoclonal antibody technique showed comparability for diarrheal samples but improved detection with the immunofluorescent method for formed specimens (67). Diagnosis of cryptosporidial enteritis can also be made on small intestinal biopsy sections by identification of developmental stages, found individually or in clusters, on the brush border of the mucosal epithelial surfaces. Organisms project into the lumen and appear basophilic with hematoxylin and eosin staining.

隐孢子虫的诊断主要依靠大便中检出卵囊(8)。卵囊用改良的抗酸染色技术。但是，其准确性很大程度上取决于技术员的经验和检查的认真程度。在轻症感染者中敏感性差(67)。卵囊也可通过直接免疫荧光法来检测，此方法是利用针对隐孢子虫特异抗原的单克隆抗体进行检测的，已有商业化产品。此外，也可用ELISA法检测粪便中的隐孢子虫抗原(18)。粪便标本中卵囊检测方法无统一标准。今年有项研究比较了利用改良抗酸染色法和荧光标记单克隆抗体法检测大便中隐孢子虫的结果，发现结果相似，但是对于成形粪便标本则荧光免疫法更好(67)。隐孢子虫肠炎的诊断需要行小肠活检，发现粘膜上皮刷状缘单个或成簇的发育期的卵囊。卵囊向腔内突出，HE染色呈嗜碱性。

Cryptosporidium does not infect tissue beyond the superficial surface epithelia. In the intestines it causes villous atrophy, crypt hyperplasia, and infiltration of lymphocytes, neutrophils, plasma cells and macrophages into the lamina propria. While in immunocompetent individuals, infection is confined to the intestine, in immunocompromised patients, Cryptosporidium is found in the entire gastrointestinal tract and within the epithelial cells of the biliary tree, the pancreatic duct and the airways (38). Infection induces increased intestinal permeability and chloride secretion, which are thought to result from the host inflammatory response (8, 24, 37, 51). Control of infection depends on the host cellular immune response and production of cytokines such as interferon gamma (7, 72).

隐孢子虫感染局限于肠道上皮细胞表面。引起小肠绒毛萎缩，隐窝增生，固有层中淋巴细胞、中性粒细胞、浆细胞和巨噬细胞浸润。在免疫功能正常的个体中，感染局限于小肠；在免疫功能缺陷的患者中，隐孢子虫可累及整个胃肠道、胆道系统、胰腺导管和气道的上皮细胞(38)。感染导致肠道通透性增加，氯化物分泌，这些被认为是宿主的炎症反应(8, 24, 37, 51)。控制感染依赖宿主的细胞免疫反应和细胞因子，如γ-干扰素的产生(7, 72)。

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

In vitro studies have demonstrated that paromomycin has limited activity against Cryptosporidium with inhibitory concentrations in the range of 100-500 µg/mL (22, 43, 65). Paromomycin is effective in animal models of cryptosporidiosis (2, 50, 64, 66), but usually require doses of 100-500 mg/kg/day. The dose usually used in most human trials, 25-35 mg/kg/d in 2-4 doses, is estimated to result in drug levels in the intestinal lumen at or barely above the amount of drug needed to inhibit the organisms in cell culture (71). Nitazoxanide and its active metabolite tizoxanide are active again C. parvum in vitro and in animal models (19, 23, 62).

体外研究显示，巴龙霉素抗隐孢子虫的活性有限，在100-500 ug/ml范围对隐孢子虫有抑制作用(22, 43, 65)。巴龙霉素在隐孢子虫动物模型中是有效的(2, 50, 64, 66)，但是常常需要100-500mg/kg/d的剂量。在人体试验中常用的剂量为25-35mg/kg/d，据估计此剂量下，肠腔里药物水平仅能接近或刚好达到体外细胞培养中抑制寄生虫所需的药物量(71)。硝唑尼特和它的活性代谢产物替唑尼特在体外和动物模型中有效。

The role of antiparasitic therapy in cryptosporidiosis remains controversial. No agent has proven reliably curative in the absence of effective immune response. This poor response to treatment may result from the unique location of the parasite, separated from the lumen by the host membrane but also segregated from the host cytoplasm by the base of the parasitophorous vacuole. Thus, there is limited exposure to drugs in the lumen, serum, and even in the enterocyte cytoplasm (26).

抗寄生虫治疗隐孢子虫病的作用目前还有争议。在缺乏有效免疫反应的情况下，尚未发现能够治愈隐孢子虫病的药物。疗效差与寄生虫的独特感染部位有关，其既被宿主的细胞膜从肠腔中隔离，又被寄生空泡和宿主胞浆隔离。因此，肠腔、血浆和肠道细胞胞浆内的药物均无法保证有效到达寄生虫而发挥作用(26)。

Much of the literature on treatment of cryptosporidiosis is in case reports or uncontrolled trials. Since the disease is self-limited in normal hosts and can be variable in immunocompromised hosts, these data are problematic. The voluminous secretions and altered intestinal absorption caused by cryptosporidiosis may interfere with drug absorption. Furthermore, for the agents tested in clinical trials, most of the trials were not designed to detect partially active agents. Few of the studies of AIDS patients have rigorously excluded patients co-infected with Mycobacteria, microsporidia or cytomegalovirus, all of which are common co-infections which can cause dampen the effects of anti-cryptosporidiial treatments (60, 69). Thus, partially active drugs (which might prove useful in combination or in situations in which the patients immune response can be boosted) may been labeled as ineffective.

有关治疗隐孢子虫病的文献多是病例报道或者未设对照组的临床试验。因为在正常免疫功能的宿主中，此病为自限性，在免疫功能缺陷宿主中，临床类型多样，因此很难据此得出正确结论。隐孢子虫病引起的大量肠道分泌和吸收不良可以干扰药物的吸收。此外，大多数临床试验未将可能部分有效药物的作用考虑在内。很少有艾滋病患者的研究能严格排除分枝杆菌、微孢子虫、巨细胞病毒等合并感染的影响，而合并上述感染均可能会低估抗隐孢子虫药物的疗效(60, 69)。部分有效的药物（在联合治疗中有效药物或能增强患者免疫反应的药物）可能因此被误认为无效。

Nitazoxanide: Nitazoxanide is a nitrothiazole compound with activity against a broad range of parasites. In a randomized, placebo-controlled trial in apparently immunocompetent children and adults, nitazoxanide significantly decreased the duration of C. parvum-associated diarrhea and oocysts shedding (52). The dose used in the trial was 500 mg bid for 3 days (with doses of 200 mg and 100 mg bid in children). The AIDS clinical trials group (ACTG) conducted a dose-ranging study of Nitazoxanide in AIDS patients with cryptosporidiosis. The study suggested that the drug could be given safely and might be partially effective (10). A larger randomized trial, however, had to be abandoned due to slow patient accrual. A randomized trial in HIV infected patients with cryptosporidiosis conducted in Mexico demonstrated shorter duration of symptoms and cure of oocyst shedding with treatment of patients with CD4 cell counts above 50. However, no effect was noted among patients with CD4 cell counts below 50 (53). Unfortunately, the latter group includes the patients most in need of an effective anti-parasitic therapy. Nitazoxanide is approved for use in some countries and is available in the United States by expanded access from the manufacturer, Romark Laboratories.

硝唑尼特：硝唑尼特是具有广谱抗寄生虫活性的硝基噻唑类化合物。一项在免疫功能正常儿童和成人中进行的随机、安慰剂对照试验中，硝唑尼特可显著缩短微小隐孢子虫相关腹泻的病程和卵囊排出 (52)。试验中所用的剂量为500mg bid（儿童中用200mg bid和100mg bid），疗程3天。艾滋病临床试验组（ACTG）在AIDS合并隐孢子虫病患者中进行了硝唑尼特剂量范围的研究。结果表明，此药安全性好，部分有效。但是另一项更大范围的随机试验因为患者纳入缓慢而被迫放弃。一项在墨西哥进行的HIV感染者合并隐孢子虫病的随机研究表明，在CD4细胞大于50的患者治疗后，症状持续时间明显缩短，停止卵囊排出。但是在CD4细胞低于50的患者中无效(53)。不幸的是，后者更需要有效的抗寄生虫治疗。硝唑尼特在一些国家已经被批准使用，在美国，可以经过很多途径从生产商Romark实验室获得。

Paromomycin: Paromomycin is a non-absorbable aminoglycoside that was approved by the FDA in the 1960s for using in amebiasis. Anti-cryptosporidial activity was initially identified when desperate AIDS patients were treated with every available antiparasitic drugs and some improved when treated with paromomycin (21).

巴龙霉素：巴龙霉素是一种口服不吸收的氨基糖苷类药物，在60年代被FDA批准用于治疗阿米巴。治疗困难的艾滋病患者在试用各种抗寄生虫药物过程中，部分患者用巴龙霉素治疗后病情得到改善，从而发现了巴龙霉素的抗隐孢子虫作用(21)。

Most of the data on paromomycin in human cryptosporidiosis has been from case series or uncontrolled trials studying patients with AIDS. Among the first 11 published case series including 300 patients, the response rate was reported to be 67% (3, 29). Many of those with initial improvement later relapsed. Three randomized controlled trials have studied paromomycin in AIDS patients with cryptosporidiosis. Kanyok and colleagues presented preliminary data from a small trial in 1993 demonstrating efficacy of paromomycin (34). White and colleagues conducted a small placebo-controlled trial that incorporated quantitation of oocyst excretion. There was a significant reduction in oocyst shedding (about 70%) and decreased stool frequency in those treated with paromomycin (69). However, cures were unusual and many patients subsequently developed biliary involvement. The ACTG also compared paromomycin with placebo in a group of 35 patients (30). On treatment analysis demonstrated no significant difference between groups. However, dropouts only occurred in the placebo arm. Thus, by intent-to-treat analysis with dropouts grouped with failures, the response were similar to those described by White and colleagues with a trend favoring paromomycin over placebo (70). Only limited efforts were made to exclude co-infection with other enteric pathogens. Furthermore, the trial was prematurely terminated due to poor enrollment and thus was not powered to detect this limited response. Thus, the bulk of evidence suggest that paromomycin is partially active against Cryptosporidium parvum.

绝大多数关于巴龙霉素治疗人隐孢子虫病的资料来源于艾滋病病例系列或无对照的临床研究。在最初报道的11个病例总结研究中包括了300个患者，有效率为67%(3, 29)。其中很多最初有效后又复发。巴龙霉素治疗艾滋病患者合并隐孢子虫病效果的随机对照试验研究有三个。1993年Kanyok及其同事从小规模试验中证实了巴龙霉素的有效性(34)。在White及其同事进行的一个小规模研究中，增设了安慰剂对照组，并对卵囊排泄进行了定量。巴龙霉素治疗组，卵囊排出减少了约70%(69)，并且腹泻次数显著减少。但是，少有治愈病例，很多患者治疗后出现胆道受累。ACTG也在35个患者中比较了巴龙霉素和安慰剂的疗效(30)。结果两者没有显著性差异。但是，只有安慰剂组的患者退出试验。因此，通过对治疗失败的退出者的意向-治疗分析，得出的有效率和White的结论类似(70)，巴龙霉素优于安慰剂。在排除合并其它肠道病原体感染的工作比较有限。此外，试验因为入选率低而提前终止，限于例数，没能检测有效率。因此，大量的证据表明，巴龙霉素治疗微小隐孢子虫病部分有效。

Since paromomycin levels are likely to vary between individuals and within individuals depending on the amount of intestinal secretions, preclinical testing already suggests limitations with this agent. Dose escalation might improve efficacy. However, a trial incorporating dose escalation demonstrated no further improvement with higher doses (30) and high doses of paromomycin can actually cause malabsorption (36).

巴龙霉素浓度因为受到肠道分泌量影响在个体间及同一个体中差别很大，临床前的试验研究提示此药存在局限性。增加剂量可能会提高疗效。但是，在一项研究中增加剂量后其疗效并未提高(30)，却导致吸收不良(36)。

Macrolide Antibiotics: Spiramycin is a macrolide antibiotic that is marketed in Europe for treatment of toxoplasmosis and respiratory tract infections. As early as 1983, anecdotes were reported of patients with cryptosporidiosis with improvement or cure after spiramycin therapy. Two controlled trials of spiramycin were performed on children with cryptosporidiosis. Sáenz-Lloren and colleagues reported shorter duration of symptoms and oocyst shedding with spiramycin treatment at 100 mg/kg/d of spiramycin (55). However, this was not confirmed in a second trial using 75 mg/kg/d (73). The ACTG conducted several studies of oral and intravenous spiramycin in adult AIDS patients with cryptosporidiosis. A randomized controlled trial in 75 AIDS patients, spiramycin dosed at 3 million International Units per day in 3 doses was no better than placebo. A trial of intravenous spiramycin at 3 million followed 4.5 million International Units per day noted a significant decrease in oocyst shedding and at least a partial response in 75% of subjects. However, there were high rates of adverse events including drug-associated intestinal injury (68).

大环内酯类抗生素：螺旋霉素是一种大环内酯类抗生素，在欧洲被批准用于治疗弓形虫病和呼吸道感染。早在1983年，就有关于螺旋霉素可改善和治疗隐孢子虫病的报道。螺旋霉素在儿童隐孢子虫病中的两个对照试验已经完成。Sáenz-Lloren和他的同事报道，100mg/kg/d的螺旋霉素可以减少症状的持续时间和卵囊的排泄(55)。但是，在75mg/kg/d的试验中此结果没有得到证实(73)。ACTG进行了数个口服和静脉使用螺旋霉素治疗成人艾滋病患者合并隐孢子虫病的研究。在一项有75个艾滋病患者纳入的随机对照试验中，每天3百万IU螺旋霉素，使用3个剂量，疗效并未优于安慰剂组。静脉给予4.5百万IU螺旋霉素后再继以3百万IU/日，可显著减少卵囊的排出，至少75%的患者显示部分有效。但是副作用的发生率高，包括药物相关的肠道损伤(68)。

Azithromycin is an azalide antibioitic that is FDA approved for respiratory infections as well as treatment and prevention of AIDS-associated Mycobacterium avium complex infection. In vitro and animal studies suggest some activity against Cryptosporidium parvum. Case reports suggest activity in cryptosporidiosis (1, 11, 20, 31, 46, 54). In a multicenter, double blind trial, AIDS patients with cryptosporidiosis were randomly assigned to receive azithromycin 900 mg PO daily or placebo. Overall, there was no significant difference is oocyst shedding, stool frequency or weigh loss between groups (2, 61). A post-hoc analysis revealed a significant decrease in oocyst shedding in those with the highest serum levels of azithromycin. A pilot trial of intravenous azithromycin failed to demonstrate any changes in oocyst shedding or stool frequency (2, 15).

阿奇霉素是一种氮杂内酯类抗生素，FDA批准用于呼吸道感染和艾滋病相关的鸟型分枝杆菌感染防治。体外和动物研究显示有一些抗微小隐孢子虫的活性。有病例报道阿奇霉素治疗隐孢子虫病有效(1, 11, 20, 31, 46, 54)。在一项多中心双盲试验中，将艾滋病合并隐孢子虫病患者随机分为口服治疗组和安慰剂组，治疗组给予阿奇霉素900mg/d。在卵囊排泄、大便次数和体重下降方面，两组没有显著性差异(2, 61)。其后的分析显示，阿奇霉素血清水平最高的病人中，卵囊排出显著减少。Pilot研究未能证实静脉使用阿奇霉素在卵囊排泄和大便次数方面有效(2, 15)。

Clarithromycin is also active in vitro and in animal studies. The data on use of clarithromycin in cryptosporidiosis are limited to a few case reports. However, the drug may be useful in chemoprophylaxis (see below).

克拉霉素在体外和动物研究中有效。但临床资料仅限于少数病例报道。但是，此药可用于药物预防（见下文）。

Other Agents: A number of anecdotal reports have noted improvement in chronic cryptosporidiosis in patients treated with oral anti-Cryptosporidium immunoglobulin preparations (25). Two well-controlled trials have examined oral bovine anti-Cryptosporidium Immunoglobulin (BACI) preparations in cryptosporidiosis. In one, volunteers received BACI or placebo before or after being challenged with C. parvum. There was no significant decrease in symptoms or oocyst shedding if BACI was given after challenge (47). In a large randomized, dose-escalating trial of BACI in AIDS patients with chronic cryptosporidiosis, there was no effect of BACI on symptoms. Quantitation of oocyst shedding only demonstrated a modest 50% decrease in oocyst excretion at a dose of 20g/d (16). At higher doses, oocyst excretion decreased, but the immunoglobulin preparation caused diarrhea. Thus, current data do not support a role for this therapy.

其它药物：很多非对照研究发现，口服隐孢子虫免疫球蛋白制剂对慢性隐孢子虫病治疗有效(25)。两项对照试验检测了口服牛隐孢子虫免疫球蛋白（BACI）制剂的疗效。其中一个试验，志愿者在接触微小隐孢子虫前、后口服BACI或安慰剂。研究发现，在接触后服用BACI对减轻症状或减少卵囊排出均无效(47)。在艾滋病合并慢性隐孢子虫病患者中进行的一项大规模随机、BACI剂量递增的试验研究显示，BACI对改善症状无效。20g/d剂量组的卵囊排出可以减少约50% (16)。随着剂量增加，虽然卵囊排出减少，但却会引起腹泻。因此，目前的资料不支持此治疗。

Diclazuril and letrazuril are agents that have been used in avian coccidiosis. Initial studies of diclazuril in AIDS patients with cryptosporidiosis demonstrated poor bioavailability. Studies of letrazuril were initially thought to demonstrate marked reduction in oocyst excretion with minimal change in symptoms. Subsequent studies revealed that the treatment mainly interfered with the acid fast staining of oocysts.

地克珠利和来曲珠利是用于治疗禽类球虫病的药物。最初在艾滋病合并隐孢子虫病患者中的研究显示，地克珠利生物利用度较差。最初曾有研究结果提示，来曲珠利能够显著减少卵囊排出，但是对改善症状作用有限。此后的研究揭示，其不同主要是因为干扰了卵囊的抗酸染色，而卵囊排出并未减少。

Since currently available agents are only partially effective, it is logical to try and combine these agents to improve efficacy. Smith and colleagues conducted a pilot open-label study of paromomycin combined with azithromycin in AIDS patients with chronic cryptosporidiosis (60). Overall, there was a marked improvement in oocyst shedding (decreased by over 2 logs). However, few patients were cured. Most of the clinical failures were associated with biliary disease, co-infection with other enteric pathogens (especially CMV), or side effects of the medications. Thus, while unproven, combination therapy merits further study.

鉴于目前的药物仅部分有效，因此需要尝试联合治疗来提高疗效。Smith及其同事在艾滋病合并慢性孢子虫病的患者中进行了巴龙霉素和阿奇霉素联合治疗的开放、对照研究(60)。卵囊排出显著减少（超过2个数量级）。但是，少有治愈者。大多数的临床治疗失败与胆道受累、合并其它肠道病原体（尤其是巨细胞病毒）感染及药物副作用有关。因此，联合治疗的优势尚待证实。

In summary, currently available antiparasitic drugs have only limited activity in cryptosporidiosis. Nitazoxanide can hasten cure in immunocompetent patients and patients with HIV with CD4 cell counts above 50. For patients with advanced AIDS and chronic infection, the most important aspect of therapy is treatment with effective anti-retroviral therapy. Since cryptosporidiosis-induced gastrointestinal injury may interfere with anti-retroviral therapy, it is probably prudent to initially include anti-parasitic drugs and anti-motility agents in the treatment regimen. However, this may require combinations of drugs. Paromomycin alone or in combination with a macrolide (such as azithromcyin or spiramycin) is an available treatment that may be useful in this context. However, further studies are needed to design optimal combinations of agents.

总之，目前的抗寄生虫药物对于隐孢子虫病的疗效有限。硝唑尼特在免疫正常的患者和CD4细胞大于50的HIV感染患者中能够加速治愈。对于晚期艾滋病患者的慢性隐孢子虫感染，最重要的治疗是经过有效的抗逆转录病毒药物重建免疫功能。因为隐孢子虫病导致的肠道损伤可能会干扰抗逆转录病毒的治疗，所以最初疗程中可以考虑给予包括抗寄生虫药物和减慢胃肠蠕动的药物。但是，这可能需要联合用药。可以选择单用巴龙霉素或联合大环内酯类（如阿奇霉素或螺旋霉素）。但是，需要进一步研究最佳的联合用药方案。

Extraintestinal Cryptosporidiosis: There are reports of cases of cryptosporidiosis outside of the intestinal and biliary tract. These patients likely require antiparasitic therapy. There are case reports of patients responding to macrolides or inhaled paromomycin.

肠外隐孢子虫病：有病例报道肠道和胆道之外的隐孢子虫病。这些患者需要抗寄生虫治疗。部分患者对大环内酯类和吸入巴龙霉素有反应。

Immunocompetent Hosts: Since cryptosporidiosis is a self-limited infection in immunocompetent hosts, the mainstay of therapy is supportive measures including fluid and electrolyte replacement and anti-motility agents. While data are limited, apparently immunocompetent hosts with symptoms lasting more than one week may benefit from anti-parasitic therapy. If it is available, Nitazoxanide at a dose 500 mg PO twice a day should be the treatment of choice (52). Macrolides such as spiramycin and azithromcyin may be used as alternatives.

免疫正常的宿主：在免疫功能正常的宿主中，隐孢子虫病是自限性感染，主要以支持治疗为主，包括水和电解质的补充和抗动力药物的应用。虽然资料有限，却提示免疫正常的宿主症状持续一周或者更长时，能从抗寄生虫治疗中获益。如果可能，可以选择硝唑尼特500mg bid(52)。也可选用大环内酯类，如螺旋霉素和阿奇霉素。

Immunocompromised Hosts Other Than Patients with AIDS: Patients with leukemia, primary immunodeficiencies, inflammatory bowel disease, and a number of chronic diseases are at increased risk of chronic cryptosporidiosis (33, 39). Case reports suggest that a limited number of patients with uremia or malignancy and chronic cryptosporidiosis have improved after anti-parasitic therapy. Most reports include a macrolide (azithromycin 600 mg per day or spiramycin 750 mg PO 3 to 4 times a day) alone or in combination with paromomycin (25-35 mg/kg/d in 2-3 daily doses). Nitazoxanide alone or with paromomycin and/ or a macrolide may also benefit some patients with chronic infection.

非艾滋病的免疫功能缺陷患者：白血病、原发性免疫缺陷、炎性肠病和很多慢性病患者感染慢性隐孢子虫病的风险增加(33, 39)。有病例报道，尿毒症或者恶性肿瘤合并慢性隐孢子虫病患者在使用抗寄生虫药物后有效。多数报道中单用大环内酯类（阿奇霉素 600mg /日或螺旋霉素750mg 3-4次/日）或合用巴龙霉素（25-35mg/kg/d使用2-3日）。某些慢性感染患者单用硝唑尼特或合用巴龙霉素和/或大环内酯类在也可获益。

Patients Infected With HIV: For patients with HIV, the key to management of cryptosporidiosis is to reverse their immunosuppression with anti-retroviral therapy. However, anti-parasitic drugs may be very important, especially for treatment of patients with prior anti-retroviral treatment. For patients with relatively intact immune function (e.g. CD4 cell count above 50), nitazoxanide may hasten resolution of cryptosporidiosis (53). However, the dose should be higher than in immunocompetent hosts (1g b. i. d. for 14 days). Recent studies suggest that partially-active anti-parasitic agents such as paromomycin alone or with azithromycin may be effective in the context of anti-retroviral agents (41, 48). Thus, anti-motility agents and anti-parasitic drugs should generally be started before initiation of anti-retroviral therapy.

HIV感染患者：对于HIV感染患者，控制隐孢子虫病的关键是应用抗逆转录病毒治疗来逆转免疫抑制。但是，抗寄生虫药物也是非常重要的，尤其是对于抗逆转录病毒治疗过的患者。对于免疫功能相对正常的患者（例如，CD4细胞超过50），硝唑尼特可以加速隐孢子虫病的清除(53)。但是，使用剂量要比免疫正常患者高（1g bid，使用14日）。最近研究表明，抗寄生虫部分有效的药物如巴龙霉素单用或与阿奇霉素合用在抗逆转录病毒过程中可能有效(41, 48)。因此，在开始抗逆转录病毒治疗前应常规予抗动力药和抗寄生虫药物。

Supportive therapy is critically important in cryptosporidiosis. Watery diarrhea results in significant losses of fluids and electrolytes and may contribute to malnutrition. Replacement of fluid and electrolyte losses by either the oral or intravenous route is of paramount importance. Aggressive efforts at oral rehydration should be made with Gatorade, bouillon, or oral rehydration solution that contains glucose, sodium bicarbonate, and potassium. Intravenous therapy may be required to correct losses of bicarbonate, potassium, magnesium, and phosphorus. Nutritional support may also improve responses to therapy (58).

支持治疗在隐孢子虫病治疗过程中非常重要。水样泻导致明显的体液和电解质丢失，可能引起营养不良。通过口服或静脉途径补充丢失的体液和电解质至关重要。应予强有力的口服补液，如运动饮料、肉汤、含有糖、碳酸氢钠和钾的口服补液溶液。纠正碳酸氢盐、钾、镁和磷的丢失可能需要静脉补液。营养支持可能会提高对治疗的反应(58)。

Treatment with antimotility agents is also an important adjunctive therapy. Loperamide or diphenoxylate/atropine will often reduce the stool frequency. Tincture of opiate may decrease transit time in patients who have not responded to loperamide or diphenoxylate/atropine. Octreotide, a synthetic peptide analog of somatostatin is FDA approved for the treatment of tumor-induced secretory diarrhea. Several trials have examined octreotide therapy in AIDS patients with diarrhea (6, 17, 59). Overall, octreotide was not consistently more effective than other oral antidiarrheal agents. Due to its high cost, its use is generally limited to refractory cases. For patients with AIDS and chronic cryptosporidiosis, the key to management is to reverse the immunodeficiency with effective anti-retroviral therapy (5, 14, 27, 42, 45). This should generally take the form of combinations of 3 or more potent anti-retroviral drugs including reverse transcriptase inhibitors with or without protease inhibitors. Patients with severe cryptosporidiosis may not response optimally to anti-retroviral therapy in the setting of profuse watery diarrhea from cryptosporidiosis. Thus, aggressive therapy with anti-motility agents is essential. The role of antiparasitic drugs is controversial in this context, but, as noted above, patients may have a better response to anti-parasitic drugs if they can be treated for HIV as well.

抗动力药物治疗在辅助治疗中也很重要。易蒙停或苯乙哌啶/阿托品常可减少腹泻次数。对于易蒙停或苯乙哌啶/阿托品反应不好的患者，阿片酊剂可以缩短胃肠道通过时间。奥曲肽是人工合成的生长抑素类似物，FDA批准用于肿瘤引起的分泌性腹泻。几个研究验证了奥曲肽治疗艾滋病患者腹泻的疗效(6, 17, 59)。总体上奥曲肽并不胜于其它口服止泻药。由于奥曲肽价格昂贵，仅用于难治病例。对于艾滋病合并慢性隐孢子虫病患者，关键是使用有效的抗逆转录病毒治疗重建其免疫功能(5, 14, 27, 42, 45)，这需要三联或者更多的强效抗逆转录病毒药物联合应用，包括逆转录酶抑制剂含或不含蛋白酶抑制剂。重症隐孢子虫病患者在大量水样泻时可能对抗逆转录病毒治疗反应不佳。因此需要有效的抗动力药物。抗寄生虫药物的作用在这种情况下是有争议的，如果同时治疗HIV，可能对抗寄生虫药物有更好的反应。

Biliary involvement in cryptosporidiosis usually requires specific interventions. Acalculous cholecystitis should be treated with cholecystectomy. Patients with sclerosing cholangitis can usually be treated by ERCP. Sphincterotomy may result in temporary improvement (4). However, symptoms usually recur unless a stent is placed (9, 29).

隐孢子虫病的胆道受累常需要特殊处理。无结石性胆囊炎可行胆囊切除术治疗。用ERCP治疗硬化性胆管炎。括约肌切开术可能使病情暂时得到改善(4)。但是，如果没有放置支架，症状常常会复发(9, 29)。

Since the primary clinical manifestation of cryptosporidiosis is diarrhea, resolution of diarrhea should be the main clinical endpoint of therapy. Stool frequency and character (e. g. watery, loose, formed) remain important symptoms. Electrolytes and volume status should also be monitored carefully. In immunocompromised patients, it is also important to follow the patients for symptoms, signs, and laboratory tests suggestive of biliary tract involvement. Right upper quandrant discomfort and/or elevations of alkaline phosphatase should prompt the clinician to obtain imaging studies of the biliary tract (ultrasound, ERCP) to exclude acalculous cholecystis or sclerosing cholangits, which may require surgical therapy. Persistent diarrhea should prompt aggressive testing for possible co-infections, including atypical Mycobacteria, microsporidia, and CMV.

因为隐孢子虫病的主要临床表现为腹泻，腹泻的消失成为治疗的主要临床终点。大便次数和性状（如水样、糊状、成形）仍然是重要症状。需要密切监测电解质和水平衡。对于免疫功能缺陷的患者，需密切随访其症状、体征和实验室检查，警惕胆道受累情况的出现。右上腹不适和/或碱性磷酸酶升高提示医生需要行胆道影像学检查（超声、ERCP）以除外无结石性胆囊炎或硬化性胆管炎，以上情况需要行外科治疗。对持续的腹泻病人应筛查可能存在的混合感染，包括非典型分枝杆菌、小孢子虫和巨细胞病毒。

Clinical trials should routinely incorporate quantitative studies on oocyst excretion. Goodgame and colleague have demonstrated that careful quantitation of oocyst shedding correlates well with the level of gastrointestinal dysfunction (24). Since there concentration of oocysts may vary up to a log between stools in an individual, quantitation is better if multiple stools are collected. While clinical laboratories often provide semi-quantitative data on oocyst concentration (1+ to 4+), these data are not adequate to document the effects of partially active agents. Several studies have incorporated careful quantitation (16, 60, 69).

临床上应该常规对大便中的卵囊排出进行定量测定。Goodgame及其同事发现卵囊排泄的数量和胃肠功能紊乱水平有很好的相关性(24)。因为同一病人的大便中卵囊的浓度变化可以为一个数量级的差异，所以最好收集多次大便进行定量测定。临床实验室一般只进行卵囊浓度的半定量检测（1+到4+），不能充分反应部分活性药物的作用。已有几个研究应用了准确的定量(16, 60, 69)。

No vaccines against Cryptosporidium are commercially available. Animal studies have demonstrated protection using recombinant DNA vaccines (49, 56, 57). Further studies will be required to see if any of these constructs can prove safe and effective in humans.

目前尚无市售的隐孢子虫疫苗。动物的研究发现，使用重组DNA疫苗具有保护作用(49, 56, 57)。此类疫苗在人体中的安全性和有效性还需要进一步研究。

Current water purification standards do not uniformly remove viable oocysts. Filtration is particularly important when surface contamination may occur in water sources such as during spring runoff, or in households using well water. If personal-use water filters are utilized, they should be capable of removing particles 1 µm in diameter (35). Boiled or filtered drinking water should be considered by HIV-infected persons with CD4 counts under 200/mm3. HIV-infected persons who travel in developing countries should meticulously avoid drinking tap water and contaminated water resources. At-risk persons should avoid contact with obvious sources of Cryptosporidium oocysts, such as people with diarrhea (especially regarding sexual practices that involve oral exposure to feces), farm animals (particularly cattle), and domestic pets that are either very young (< 6 months), have diarrhea, or have been stray.

目前标准的水净化不能完全消除有活性的卵囊。泉水或家用井水水源表面受到污染后，过滤就尤为重要。应该使用能够除去直径1µm的颗粒的个人用途滤水器(35)。建议CD4细胞小于200/mm3的HIV感染者饮用沸水或过滤水。在发展中国家旅行的HIV感染者必须避免直接饮用自来水和有污染的水。高危人群应该避免接触明显的隐孢子虫卵囊源，如腹泻的患者（尤其是性生活中可能感染经粪口途径传播传染病的行为）、牧畜（尤其是牛）和特别年幼的（小于6个月）、患腹泻及被遗弃的宠物。

Infection control measures are limited by resistance of the Cryptosporidium oocysts to common disinfectant. Enteric precautions with good hygiene, such as hand washing, and proper disposal of contaminated materials, such as diapers, are important.

隐孢子虫卵囊能抵抗普通的消毒剂，因此感染控制措施十分有限。良好的肠道病预防的卫生措施非常重要，如洗手、妥善处理尿布等污染物。

While cryptosporidiosis is self-limited in immunocompetent individuals, some groups of immunocompromised patients are at high risk of severe disease. These groups include patients with AIDS, especially in developing countries, and some children with congenital immunodeficiencies. At present, there are limited human data on chemoprophylaxis of cryptosporidiosis. Two retrospective studies have examined data on rifabutin, azithromycin, or clarithromycin for prophylaxis of Mycobacterium avium infection asking the question whether the rates of cryptosporidiosis differed between drug-treatment arms. Holmberg and colleagues retrospectively analyzed data from the HIV Outpatient Study cohort comparing the incidence of cryptosporidiosis in those given rifabutin, clarithromycin, or no drug for prevention of Mycobacterium avium complex. There was a dramatic reduction in the incidence of cryptosporidiosis in those treated with rifabutin (hazard ratio 0.15) and a significant reduction in those treated with clarithromycin (hazard ratio 0.25) (32). Fichtenbaum and colleagues performed a cross-protocol analysis of patients enrolled in controlled trials of clarithromycin, rifabutin, both, or no drug for M. avium complex prophylaxis. They also noted a lower incidence of cryptosporidiosis than in groups treated with rifabutin (relative risk 0.42) (13). However, they could not confirm the efficacy of clarithromycin.

尽管在免疫正常的个体中隐孢子虫病是自限性的，但是某些免疫缺陷的患者则有引起重症的风险。其中包括艾滋病患者，尤其是在发展中国家，和患有先天免疫缺陷的儿童。目前，预防人感染隐孢子虫病的药物资料有限。两项回顾性研究利福布丁、阿奇霉素或克拉霉素预防鸟分支杆菌感染的试验中分析数据时探索了隐孢子虫病的发病率是否会因为药物治疗而变化。Holmberg及其同事回顾分析了门诊的HIV患者队列，比较了使用利福布丁、克拉霉素和没有使用药物患者之间隐孢子虫病的发病率。发现服用利福布丁的患者隐孢子虫病的发病率降低得非常显著（危害比0.15），服用克拉霉素的患者有中发生率也有显著性减低（危害比0.25）(32)。Fichtenbaum及其同事将入选患者分成4组，分别服用克拉霉素、立福布丁、两药联合或不用药组以观察预防鸟分支杆菌效果进行横断面分析。他们同时发现利福布丁治疗组隐孢子虫病发病率更低（相对风险度0.42）(13)。但是，他们没能证实克拉霉素的疗效。

While rifabutin (generally dosed at 300 mg PO per day) and clarithromycin (500 mg PO BID) may have prophylactic efficacy, the risk of infection remains small in most patient groups (35). Whether these drugs can help children with congenital immunodeficiencies (such as X-linked immunodeficiency with hyperimmunoglobulin M) remains to be established (39). Instead, precautions aimed at preventing exposure are considered the main prophylactic measure. These include avoiding unfiltered water and fecal-oral exposure to animals, young children, or patients with diarrhea.

因为使用利福布丁（一般口服剂量为300mg/日）和克拉霉素（口服500mg bid）有预防效果，多数患者的感染风险较低(35)。这些药物能否保护先天性免疫缺陷的儿童（如X-连锁高免疫球蛋白M的免疫缺陷）还有待证实(39)。事实上，预防暴露是主要的预防措施。包括避免饮用非过滤水和避免接触可能暴露于对动物、小孩、腹泻的患者的粪口传播途径。

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