Blastocystis species

INTRODUCTION — Blastocystis species (previously referred to as Blastocystis hominis) are anaerobic protozoan parasites found in the human gastrointestinal tract [1]. The organism was initially discovered in 1911 and for many years was considered to be a harmless yeast. Studies in the 1970s demonstrated that Blastocystis spp are protozoans [2,3].

Blastocystis spp are the most common eukaryotic parasites found in human stool specimens, but there is considerable controversy regarding whether they represent a commensal organism or a true pathogen. Foci of particular study are how the presence of Blastocystis spp influences immune inflammatory responses in the gut microbiome and whether it is a potential marker of intestinal dysbiosis.

Issues related to nonpathogenic enteric protozoa are discussed further separately. (See "Nonpathogenic enteric protozoa".)

EPIDEMIOLOGY — Blastocystis spp have been observed worldwide. The organism resides in the colon and cecum of children and adults. The mode of and risk factors for transmission are not fully understood. The parasite is ubiquitous in the environment, and contaminated food, water, and soil are potential sources of infection through faecal-oral transmission [4-7]. The occurrence of Blastocystis spp in environmental water sources may be associated with climatic factors (eg, temperature) and water contamination (coliform count, turbidity, and total dissolved solids) [8-10]. Blastocystis spp have also been found in animals including pigs, monkeys, rodents, and poultry. There seems to be poor host specificity; transmission occurs from human to human and between humans and animals [11-13]. Blastocystis is more commonly found among individuals with occupational exposure to animals, supporting the potential for zoonotic transmission.

The prevalence of Blastocystis spp varies between countries and between communities, and according to the diagnostic techniques used [1]. In general, the estimated prevalence of Blastocystis spp is higher in resource-limited settings than resource-rich settings (30 to 50 percent versus 5 to 10 percent, respectively). Prevalence is highly variable, which may be related to poor hygiene, animal exposure, and consumption of contaminated food or water [1]. In one study from Senegal, 100 percent of 93 fecal samples were positive for Blastocystis spp [14]. In a study from Canada, 8 percent of stool samples submitted to a reference laboratory were positive for Blastocystis spp [15]. Blastocystis spp are also commonly found in the stool of returned travelers from resource-limited settings [4,16]. In one study of nearly 2000 stool specimens from travelers in Nepal, the prevalence of Blastocystis spp was 30 percent [17] (see "Travelers' diarrhea: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Evaluation of fever in the returning traveler"). However, Blastocystis carriage in travelers is highly dynamic. In a study including more than 470 Dutch travelers who had stool samples taken before and after travel, 36 percent carried Blastocystis prior to travel; in 28 percent of these travelers, no Blastocystis or a different subtype was detected following travel [18].

MICROBIOLOGY — Blastocystis spp demonstrate marked morphologic variability and measure between 5 and 40 mcm (picture 1). The organism lacks a cell wall but contains mitochondria, Golgi apparatus, and smooth and rough endoplasmic reticula typical of protozoa [19]. It reproduces asexually, usually by binary fission. It grows only under anaerobic conditions in culture, and it is highly susceptible to changes in temperature and in environmental tonicity.

Four different forms have been described: vacuolar, granular, ameboid, and cystic (figure 1) [20,21]. It is unknown whether transmission occurs more frequently during a particular stage or stages. The vacuolar form has a characteristic large central vacuole-like body that compresses the cytoplasm and nuclei to the periphery of the cell [2]. The vacuolar and cystic forms have been observed most frequently in stool samples. The ameboid stage is most frequently observed in old cultures or after antibiotic administration [2]. Some have suggested that the ameboid form of the organism is more likely to be associated with clinical disease [22]. The granular form is rarely seen in fresh stool.

Genetic variability — Extreme genetic diversity has been described among Blastocystis isolates [1,23]. There are at least 28 different subtypes, at least 12 of which have been identified in humans. As a result, Blastocystis in humans is referred to as Blastocystis spp rather than Blastocystis hominis (the previously used term for Blastocystis in humans). This genetic and species diversity may account for the disparities of previous data in assessing the morphology, life cycle, and pathogenic role of Blastocystis spp.

Subtype 3 is the most frequently isolated genotype in epidemiologic surveys and is probably the only species of human origin [24]. Subtypes 1, 2, and 4 are the next most commonly isolated subtypes in humans [25]; other subtypes (ST5 to ST10, ST12, ST14 and ST16) represent under 10 percent of human infections [25,26]. Subtype 1 probably originates from mammals, subtype 2 is mainly from primates and pigs, subtype 4 is from rodents, subtype 5 seems to originate from cattle and pigs, and subtypes 6 and 7 are from birds [1]. A meta-analysis of Blastocystis spp prevalence in birds and rodents found estimates of 29 percent (95% CI 12-47) and 18 percent (95% CI 12-23), respectively [27]. Some subtypes have a particular geographic distribution, such as avian subtypes ST6 and ST7, which are more frequently found in Asia and the Middle East [1]. Infection with multiple subtypes has been described [28].

A review of Blastocystis spp subtypes and their distribution in humans in nine countries in North and South America showed that ST3 (37.9 percent), ST1 (33.3 percent), and ST2 (21.9 percent) were most common, with other subtypes each comprising <2 percent of isolates [29]. In Asian countries, ST1 and ST3 are also the more prevalent subtypes, followed by ST2 [10].

PATHOGENICITY

Uncertain pathogenic role — There has been significant debate regarding whether Blastocystis spp are intestinal commensals, markers of dysbiosis, or true pathogens.

Some studies have suggested a pathogenic role for Blastocystis spp [4,30-33], while many other studies have shown no correlation between Blastocystis spp and symptoms [15,19,34-36]. Some studies have found that more symptoms were reported in those without Blastocystis spp identified [37,38], and there is increasing evidence that Blastocystis spp is likely to be a member of the normal human gastrointestinal microbiome [39,40].

A number of issues contribute to the controversy:

●Many of the reports that have suggested a pathogenic role for Blastocystis spp have been case reports and uncontrolled or retrospective series. However, properly controlled prospective studies about pathogenicity or the effect of specific therapy are lacking.

●Criteria are lacking for labeling a specimen as "positive" for Blastocystis spp; diagnostic methods differ, and increasing use of PCR on stool specimens is contributing to a rise in positive test results even among asymptomatic individuals.

●The heterogeneity of Blastocystis spp strains, accompanied by variable virulence, might account for differences in pathogenicity. However, evidence remains inconclusive, with many studies showing no definite correlation between subtype or genotypes and pathogenicity [41-48]. Subtype 4 may be associated with better gut health due to beneficial impacts on the intestinal microbiome and immunity, whereas subtype 7 may be more likely to cause colonic tissue ulceration and diarrhea [49]. Emerging evidence suggests that subtype 1 and perhaps subtype 3 are most likely to be associated with symptoms, although subtype 3 isolates are not always associated with symptomatic infection [1,49-51].

●Prolonged, irregular shedding of the organism can occur. One study showed that the shedding from day to day ranged from 0 to 17 parasites per 40x microscopic field [52]. One study described observation of Blastocystis spp two months after first observation in 75 percent of individuals in which it was the sole organism detected [15]. Many reports of Blastocystis spp could reflect prior infection with residual chronic carriage [15,53].

●Data suggest Blastocystis spp are a stable component of intestinal microbiota and, by influencing the diversity of the gut microbiota composition, may be present more commonly in healthy individuals than in patients with infectious, functional, or inflammatory bowel disease [40,54,55]. Data unraveling the influence of Blastocystis spp subtype and tools differentiating asymptomatic colonization from infection are not yet available.

●Intestinal microbiota may influence the pathogenicity and likelihood of symptomatic Blastocystis spp [56]. Infection with Blastocystis spp may also influence host immunological responses and levels of pro- and anti-inflammatory cytokines [26,40,55,57-59].

Quantitation — Some authors have suggested that Blastocystis spp are more likely to be pathogenic if >5 organisms per oil immersion field are detected and that, in lower quantities, the organisms should be disregarded as a potential cause of symptoms [60,61]. However, others have found no association between parasite concentrations and symptoms [4,15,17,34].

Copathogenicity — Blastocystis spp are often found in association with other potential pathogens; reports have suggested that the majority of patients with Blastocystis spp in their stools have an alternative etiology identified on further examination [19].

It is sometimes inferred that identification of Blastocystis spp in a stool specimen suggests another unidentified pathogen. As an example, one study examined up to six samples from 32 patients with stool specimens positive for Blastocystis spp; another pathogen was identified in 84 percent of cases [34]. Initiation of treatment for the other pathogen led to resolution of symptoms despite the persistence of Blastocystis spp in follow-up stool specimens. However, another study of patients with diarrhea in Nepal showed that Blastocystis spp did not serve this marker function for other enteric pathogens, which were detected in 68 and 71 percent of patients with and without Blastocystis spp, respectively [17].

An alternative explanation that has been suggested for the association between Blastocystis spp and other pathogens is that the parasite may be easier to identify in nonformed, watery stools [17,19,62]. It is also possible that an increase in symbiotic bacterial flora during diarrhea might enhance the growth of Blastocystis spp [19]. There is also increasing emerging evidence to support the hypothesis that Blastocystis might be linked to the changes in the gut microbiome, with gut bacteria potentially impacting on Blastocystis spp growth or pathogenicity and Blastocystis spp impacting on intestinal flora health or imbalances [56,63-70].

Carrier state — The large number of asymptomatic individuals with stools positive for Blastocystis spp suggests either nonpathogenicity or the existence of a carrier state. Other protozoa such as Giardia are often found in asymptomatic patients but are pathogens when associated with appropriate clinical symptoms. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis".)

It is possible that individuals with immunity due to prior exposure may be more likely to have an asymptomatic infection [71,72]. Alternatively, pathologic effects might depend upon host factors such as lowered immunity or on disturbances of gastrointestinal function from other causes [71].

CLINICAL MANIFESTATIONS — Symptoms that have been associated with identification of Blastocystis spp in stool include watery diarrhea, nausea, anorexia, abdominal cramps, bloating, flatulence, urticaria, itch, and fatigue, although (as discussed above) whether there is a causal association is uncertain. Both acute diarrhea and chronic diarrhea have been reported. Fever is usually absent. Association with body mass index and nutritional status in children is variable [73,74].

Some studies have suggested a possible link between Blastocystis spp and irritable bowel syndrome (IBS) and inflammatory bowel disease, although findings have been inconsistent across studies. A causal relationship has not been proven and the association with different Blastocystis subtypes remains uncertain [63,65,75-84]. An association between Blastocystis spp and urticaria (acute and chronic) has also been described [85-89].

Symptoms have been described in both immunocompromised and immunocompetent hosts, including patients with HIV and transplant recipients [32,90]. While there are some reports of greater prevalence or pathogenicity in immunosuppressed patients, such as those with HIV and transplant recipients, these patients do not necessarily appear to have more severe symptoms [91-94].

Disseminated infection is rare; two case reports have described identification of the organism in synovial fluid and peritoneal fluid, respectively [95,96]. In another report, a child with appendicular peritonitis was found to have Blastocystis organisms in the stool, appendix, peritoneal fluid, and recto-uterine pouch [97].

Patients with Blastocystis do not have peripheral leukocytosis or eosinophilia. White cells in stool specimens are usually absent.

If endoscopy is performed, findings usually demonstrate a macroscopically normal-appearing mucosa, and histopathology generally does not demonstrate intestinal inflammation or mucosal invasion [91,98,99]. Not all studies exclude patients who have other pathogens found, so results can be difficult to interpret.

DIAGNOSIS — Blastocystis spp are identified by examination of stool specimen(s) by light microscopy of stained smears or wet mounts. Microscopic identification can be complicated by the variety of forms of the organism that appear in stool specimens, difficulties in finding it in wet mounts, and disruption of the organism with stool concentration techniques (picture 1 and figure 1) [31]. Commonly used microscopic methods include a formol ethyl acetate concentration technique permanent stained smears (usually trichrome stained). Fecal leukocytes are generally absent.

A stool culture method is available but is not performed routinely even though it may be more sensitive than microscopy [100,101]. An enzyme-linked immunosorbent assay for detecting serum antibodies to Blastocystis spp has been developed but is also not routinely used [102].

Polymerase chain reaction (PCR) techniques with excellent sensitivity have also been developed, with increasing widespread availability [103,104]. However, since Blastocystis spp can often be found in asymptomatic individuals and since its pathogenicity is unclear, the clinical relevance finding a positive PCR result is debatable. Loop-mediated isothermal amplification (LAMP) techniques have also been developed [105]. Molecular tests to differentiate between strains are limited to research settings.

TREATMENT

Asymptomatic patients — Asymptomatic patients with Blastocystis spp identified on stool examination do not warrant therapy given that it may be a commensal organism. This is discussed in detail elsewhere. (See 'Uncertain pathogenic role' above.)

Symptomatic patients

Whether to treat — Treatment in symptomatic patients is controversial. Our approach is to confirm that there is no other potential pathogen through review or repeat of a concentrated stool specimen and cultures for bacterial enteric pathogens. If another potential pathogen is identified, we direct therapy against that pathogen and evaluate for symptom resolution. Noninfectious causes of symptoms should also be excluded.

When no other pathogen or etiology is identified or if patients continue to have bothersome symptoms following treatment of another pathogen, we generally suggest a trial of treatment with agents that have reported efficacy against Blastocystis spp. However, given the ongoing debate regarding the pathogenicity of Blastocystis spp (see 'Uncertain pathogenic role' above), the aim of treatment is to try to improve symptoms or treat another unidentified pathogen rather than specifically to eradicate Blastocystis spp.

Therapy with various agents has been associated with a clinical response in observational studies and a few randomized trials, as discussed below. However, it is uncertain whether this response is related to eradication of Blastocystis spp or elimination of some other undetected pathogen. Additionally, therapeutic efficacy for Blastocystis spp is difficult to determine, as the infection is often self-limiting, with many mild cases resolving within approximately three days.

Preferred treatment agents — As with the decision to treat symptomatic patients, the optimal approach to regimen selection is also uncertain. We generally suggest either metronidazole (500 to 750 mg orally three times daily for 5 to 10 days) or tinidazole (2 g orally once). If this fails to improve symptoms, paromomycin (500 mg three times daily for 7 to 10 days) can be tried, if available, either alone or in combination with a repeat metronidazole or tinidazole course. Our recommendation for monotherapy with metronidazole or tinidazole as a reasonable initial option is based on limited comparative data on monotherapy versus combination therapy, as well as uncertainty of whether Blastocystis spp is pathogenic and limited paromomycin availability. However, clinical context should be considered, and initial combination therapy is justifiable in the setting of acute and/or severe symptoms. Tinidazole is better tolerated than metronidazole, but its availability may also be limited. For those who cannot take metronidazole or tinidazole, we recommend paromomycin monotherapy. Other alternatives are discussed below. (See 'Alternative treatment agents' below.)

Efficacy data for metronidazole are mixed. As an example, in a randomized controlled trial of 50 patients with diarrhea in whom Blastocystis spp was the only stool pathogen identified, randomization to receipt of 10 days of metronidazole had no effect on stool consistency or abdominal symptoms compared with placebo [106]. In another RCT among 76 patients with diarrhea and Blastocystis as the only pathogen detected, metronidazole (1.5 g/day for 10 days) resulted in a higher rate of symptom resolution at one month (88 versus 14 percent) and six months (75 versus 33 percent) compared with placebo [101]. Some in vitro studies have shown good sensitivity of the organism to metronidazole [107], but other studies have reported resistance [108-111].

No efficacy data on tinidazole is available; efficacy is assumed based on evidence with metronidazole, since it is a closely related drug.  

Observational studies and case series have reported clinical and parasitologic responses to paromomycin [112-114]. As an example, in one retrospective study, paromomycin was associated with the highest clinical response rate (77 percent) compared with metronidazole (38 percent) and no treatment (22 percent) [114].

Alternative treatment agents — Other agents which have been tried include trimethoprim-sulfamethoxazole (TMP-SMX) and nitazoxanide. Sometimes clinical improvement is reported as described below, but both parasitologic and clinical responses are variable, and whether treatment should be pursued remains controversial. Although we do not routinely use them, these agents are reasonable options in patients who have contraindications or intolerance to the preferred agents discussed above. (See 'Preferred treatment agents' above.)  

●TMP-SMX – In a case series of 53 symptomatic patients with two consecutive stool specimens positive for Blastocystis spp and negative for other pathogens, treatment with TMP-SMX (6 mg/kg TMP [maximum 320 mg] and 30 mg/kg SMX [maximum 1600 mg] per day for 7 days) was associated with symptom resolution in 74 percent, improvement without full resolution in another 19 percent, and microbiologic eradication in 94 percent of patients [22]. Additionally, in vitro studies have demonstrated good susceptibility to TMP-SMX in isolates resistant to other agents [107,111].

●Nitazoxanide – In a randomized study of 84 individuals with diarrhea and Blastocystis spp in stool, treatment with nitazoxanide resulted in a higher rate of symptom resolution (86 versus 38 percent) compared with placebo [115]. Nitazoxanide dosing differed by age (patients 12 years or older: 500 mg tablet twice daily; patients 4 to 11 years: 200 mg in 10 mL suspension twice daily; patients 1 to 3 years: 100 mg in 5 mL suspension twice daily for 3 days). It is uncertain whether clinical responses were due to the effect on Blastocystis spp or on other unidentified pathogens, and other studies have not shown universal benefit [112].

In vitro studies have shown good sensitivity of the organism to furazolidone, quinacrine, pentamidine, emetine [107], and ivermectin [111]. Diloxanide furoate is inactive. Clinical experience with using these agents for Blastocystis spp is limited.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Blastocystis spp have been observed worldwide; in general, the estimated prevalence of Blastocystis spp is higher in resource-limited than resource-rich settings. The mode of transmission is not fully understood; fecal-oral transmission has been postulated. Blastocystis spp have also been found in animals, and Blastocystis spp are more commonly observed in the stool of individuals with occupational exposure to animals. (See 'Epidemiology' above.)

●Microbiology – Blastocystis spp (previously referred to as Blastocystis hominis) are anaerobic protozoan parasites found in the human gastrointestinal tract. Blastocystis spp demonstrate marked morphologic variability. They measure between 5 and 40 mcm (picture 1), and four different forms have been described: vacuolar, granular, ameboid, and cystic (figure 1). Extensive genetic diversity has been described among Blastocystis isolates; nine different subtypes have been identified in humans. (See 'Microbiology' above.)

●Pathogenesis – There has been considerable controversy regarding whether Blastocystis spp represent a commensal organism, a marker of intestinal dysbiosis, or a true pathogen. Blastocystis spp are often found in association with other potential pathogens; reports have suggested that the majority of patients with Blastocystis spp in their stools have an alternative etiology identified on further examination. The number of organisms does not necessarily correlate with symptoms. (See 'Copathogenicity' above.)

●Clinical manifestations – Symptoms that have been associated with identification of Blastocystis spp include diarrhea, nausea, anorexia, abdominal cramps, bloating, flatulence, urticaria, and fatigue. Watery diarrhea is usually described. Both acute diarrhea and chronic diarrhea have been reported. Fever is usually absent. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis can be made by examination of stool specimen(s) by light microscopy of stained smears or wet mounts. Endoscopy usually shows a macroscopically normal-appearing mucosa, and histopathology generally does not demonstrate intestinal inflammation or mucosal invasion. Polymerase chain reaction (PCR) testing, including multiplex PCR on stool, is increasingly being used. (See 'Diagnosis' above.)

●Treatment

•Asymptomatic patients – Asymptomatic patients found to have Blastocystis spp on stool examination do not warrant treatment. (See 'Treatment' above.)

•Symptomatic patients – Whether or not any treatment should be given for symptomatic patients with Blastocystis spp is controversial. For patients with bothersome symptoms, we ensure that other pathogens and noninfectious causes have been evaluated. If no other pathogen or etiology is identified, we suggest a trial of antimicrobial therapy for Blastocystis spp (Grade 2C). We generally suggest metronidazole (500 to 750 mg three times daily for 5 to 10 days) or tinidazole (2 g once) as monotherapy. If symptoms are severe and/or persist after monotherapy with metronidazole or tinidazole, paromomycin (500 mg three times daily for 7 to 10 days) can be used as an alternative, either as monotherapy or in combination with metronidazole or tinidazole (Grade 2C).