and Blastocystis hominis, and helminths, mostly Anisakis simplex, Strongyloides stercoralis, and Toxocara canis.
From: Reference Module in Biomedical Sciences, 2021
Intestinal Protozoa
Mark Feldman MD, in Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 2021
Blastocystis hominis
B. hominis is an intestinal protozoan that commonly infects the human colon. After many years of confusion regarding its taxonomy,Blastocystis is now recognized as a stramenopile, which is one of the major groups of eukaryotes and includes brown algae, diatoms, water molds, etc.139 To date, only one other stramenopile (i.e.,Pythium) is known to infect humans. Diameter ranges from 3 to 30 μm. In culture,B. hominis has ameboid, vacuolated, granular,65 and cystic forms. The distribution ofB. hominis is worldwide, but infection is most common in the tropics.81 In a large study of intestinal parasitism in the USA,B. hominis was identified in 2.6% of stool specimens submitted to state health departments; more than 70% of positive samples were from California.85 Among American travelers and expatriates, the prevalence often exceeds 30%.81
The significance ofB. hominis as a pathogen remains controversial. Several studies have suggested an association with IBS, but neither cause nor effect has been established, and in most series,B. hominis infection is not more common among patients with GI complaints than among asymptomatic control subjects.81 Interestingly, there is tremendous genetic heterogeneity amongB. hominis isolates, which may explain the apparent differences in clinical manifestations of infection.139 Multiple studies have used metronidazole (750 mg orally 3 times a day for 10 days) or iodoquinol (650 mg orally 3 times a day for 20 days) for treatment of symptomatic patients, with an overall improvement rate of about 50%.80 Clinical improvement in some patients may relate to treatment of more virulent isolates, but it may also be a result of treatment of unrecognized infections with other organisms, because many people infected withB. hominis simultaneously harbor known pathogens.128 In one series of patients withB. hominis infection, 84% of patients were found to have at least one recognized pathogen other thanB. hominis (E. histolytica,G. intestinalis, orD. fragilis) when repeated stool examinations were obtained.128
Amebiasis, Giardiasis, and Other Intestinal Protozoan Infections
Abinash Virk, in The Travel and Tropical Medicine Manual (Fifth Edition), 2017
Blastocystis hominis
Blastocystis hominis is a common stool commensal (up to 19% of normal controls in the United States are colonized). There is evidence that heavy infestations may be associated with cramps, vomiting, dehydration, abdominal pain, sleeplessness, nausea, weight loss, lassitude, dizziness, flatus, anorexia, pruritus, and tenesmus.
B. hominis infections in primates have been cured with trimethoprim-sulfamethoxazole. In vitro susceptibility tests show that the following drugs may be effective, in descending order: emetine, metronidazole, nitazoxanide, furazolidone, trimethoprim-sulfamethoxazole, iodochlorhydroxyquin (Entero-Vioform), and pentamidine. Chloroquine and iodoquinol have also been reported as effective treatments.
The role of B. hominis as a human pathogen is still controversial. Some published reports, based on clinical and laboratory studies, have suggested that when B. hominis-associated diarrhea appears to respond to therapy, improvement may, in fact, be due to some other undetected organism that is actually causing the problem.
Amebiasis, Giardiasis, and Other Intestinal Protozoan Infections
Abinash Virk, in The Travel and Tropical Medicine Manual (Fifth Edition), 2017
Blastocystis hominis
Blastocystis hominis is a common stool commensal (up to 19% of normal controls in the United States are colonized). There is evidence that heavy infestations may be associated with cramps, vomiting, dehydration, abdominal pain, sleeplessness, nausea, weight loss, lassitude, dizziness, flatus, anorexia, pruritus, and tenesmus.
B. hominis infections in primates have been cured with trimethoprim-sulfamethoxazole. In vitro susceptibility tests show that the following drugs may be effective, in descending order: emetine, metronidazole, nitazoxanide, furazolidone, trimethoprim-sulfamethoxazole, iodochlorhydroxyquin (Entero-Vioform), and pentamidine. Chloroquine and iodoquinol have also been reported as effective treatments.
The role of B. hominis as a human pathogen is still controversial. Some published reports, based on clinical and laboratory studies, have suggested that when B. hominis-associated diarrhea appears to respond to therapy, improvement may, in fact, be due to some other undetected organism that is actually causing the problem.
Other Intestinal Protozoa
Martin S. Wolfe, in Netter’s Infectious Diseases, 2012
Blastocystis Hominis
Blastocystis hominis is a common inhabitant of the human intestinal tract. For many years it was regarded as a harmless yeast, but it is now considered by most to be a protozoan. The potential for B. hominis as a pathogen is a subject of debate. Reported symptoms associated with heavy B. hominis infection in the absence of other recognized pathogenic organisms include mild diarrhea, nausea, anorexia, and fatigue. It remains uncertain whether B. hominis itself is the cause of symptoms or if it is only a marker of some other unidentified pathogen. Markell and Udkow have given an interesting and compelling perspective to this controversy. In 32 symptomatic subjects initially found with B. hominis alone or in combination with nonpathogenic protozoa, an additional series of stool specimens (up to six) were rigorously examined. In 27 of those 32 patients, at least one known pathogenic protozoa in addition to B. hominis was found. B. hominis persisted, but symptoms improved in all 27 patients treated specifically for these other pathogenic protozoa. It was concluded that B. hominis is not a pathogen, that treatment with common antiprotozoal drugs may not eliminate it from the stool, and that “symptomatic blastocystosis” was attributable to either an undetected parasite or parasites in some patients or functional bowel problems in others.
Protozoa
Lynne S. Garcia, in Infectious Diseases (Fourth Edition), 2017
Blastocystis Species
Blastocystis spp. (formerly Blastocystis hominis) are transmitted via the fecal–oral route through contaminated food or water; the cysts survive in water for up to 19 days at normal temperatures.2,8 Although other modes of transmission are not defined, the incidence and apparent worldwide distribution suggest the traditional route of infection. When genotypic results from animal isolates were compared with the diversity of genotypes of human Blastocystis spp. isolates, the human isolates were defined as the same as the subtypes of the pet isolates, as well as the tapwater isolates. Thus, the possibility of zoonotic transmission appears to be very likely.9
There are a number of different subtypes/strains/species included in this complex, some of which are considered pathogenic and some are nonpathogenic. Prevention would involve improved personal hygiene and sanitary conditions.
Miscellaneous Intestinal Protozoa
Lynne S Garcia, in Hunter’s Tropical Medicine and Emerging Infectious Disease (Ninth Edition), 2013
Epidemiology
Blastocystis hominis is found worldwide with a prevalence in some studies as high as 58% and generally exceeds that of other organisms; even 15% of stool submitted in the USA for O&P examination may be positive. Fecal-oral transmission is postulated. Studies suggest the existence of numerous zoonotic isolates with frequent animal-to-human and human-to-animal transmission and of a large potential reservoir in animals for infections in humans. The pathogenicity of B. hominis has long been controversial. Several case-control analyses show no increase in prevalence in patients with diarrhea, with high carriage rates in asymptomatic individuals. Many patients infected with Blastocystis also carry other pathogens; endoscopic studies have not found intestinal pathology, thus causality can be difficult to discern.View chapterPurchase book
Blastocystis hominis and Blastocystis spp. Infection
James D. Cherry MD, MSc, in Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 2019
Treatment
Given the controversy surrounding the pathogenicity ofB. hominis, a prudent approach is to refrain from treating asymptomatic immunocompetent persons.21 In patients who have gastrointestinal illness, including IBS, and in whom other pathogens have been excluded, administering a course of antiprotozoal chemotherapy may be reasonable. The results of several drug studies, including three that were placebo controlled, indicate that therapeutic improvements with parasite clearance in symptomatic patients were noted with the use of metronidazole (15–30 mg/kg per day for 7 to 10 days), nitazoxanide (200 mg twice daily for children 4–11 years old and 100 mg twice daily for children 1–3 years old for 3 days), and trimethoprim-sulfamethoxazole (6 mg/kg trimethoprim and 30 mg/kg sulfamethoxazole daily in two equal doses for 7 days in children; 320 mg trimethoprim and 1600 mg sulfamethoxazole daily in two equal doses for 7 days in adults).22,38 However, because these drugs are broad spectrum, it is possible that clinical improvement may have been a consequence of treating an unidentified enteric pathogen.38 To date, the scientific community has been unable to fulfill the Koch postulates for members of the genusBlastocystis.38 Some investigators have reported symptomatic improvement in patients receiving either metronidazole or tinidazole.5,11
Using an in vitro assay that used metabolic labeling, researchers found that the drugs emetine, satranidazole, furazolidone, and quinacrine were superior in activity to either metronidazole or tinidazole.5 These authors cautioned, however, that the in vitro assay does not take into account the pharmacokinetic properties of the drugs. More recent in vitro testing of ST1, ST3, ST4, and ST8 found thatB. hominis exhibits minimal sensitivity to metronidazole, paromomycin, and triple therapy consisting of furazolidone, nitazoxanide, and secnidazole; however, sensitivity to trimethoprim-sulfamethoxazole and ivermectin was observed.31 A clinical pilot study from Australia reported on the efficacy of triple antibiotic therapy in 10 adult patients withBlastocystis-positive IBS.23 The three-drug (or drug combination) regimen comprised diloxanide furoate, trimethoprim-sulfamethoxazole, and secnidazole for 14 days, and it was shown to clearBlastocystis infection in 60% of patients, but with inconclusive effects on IBS in this small pilot study, such that larger studies may be required.23 Ultimately, additional studies that examine drug sensitivities of differentBlastocystis subtypes may help clarify this situation, but for now the status of treating humanBlastocystis infection remains controversial.35
Clinical Presentation and Management of Travelers’ Diarrhea
Thomas Löscher, Martin Alberer, in Travel Medicine (Third Edition), 2013
Other Parasitic Agents
Blastocystis hominis is a protozoon of controversial clinical significance, and probably the most common intestinal parasite of man. In various studies it has been found more frequently in stool samples of patients with TD than in healthy controls. It is hypothesized that the development of diarrhea and other gastrointestinal symptoms is associated with certain subtypes.32 Diagnosis is usually readily available by microscopy; subtypes can be determined by genotyping.
Microsporidia have occasionally been found as a cause of TD.33 Even after treatment and resolution of diarrhea, microsporidia may be found in stool. Persistent diarrhea is seen preferably in immunocompromised patients. Diagnosis is made by stool microscopy using specific staining methods or by more sensitive tests, such as PCR.
Helminthic parasites are not a cause of typical TD, but diarrhea may be a symptom of various helminth infections, such as strongyloidiasis, trichuriasis, fasciolopsiasis, intestinal schistosomiasis or trichinellosis. Blood eosinophilia is frequently present. Diagnosis by parasitological stool investigations can be difficult in travelers, as parasite burdens are usually low. Then, serology and new PCR methods may be helpful.
Blood and Tissue Protistans III
Burton J. Bogitsh, … Thomas N. Oeltmann, in Human Parasitology (Fifth Edition), 2019
Blastocystis Hominis
Blastocystis hominis is an enteric parasite of humans and a wide variety of animals. Its geographic range is global and the organism has been known since the early part of the 20th century. It is the causative agent of traveler’s diarrhea, rectal bleeding, fever, and irritable bowel syndrome. The taxonomic status of the organism is still questionable, but based on information derived from sequencing studies from multiple conserved genes, it is considered a polymorphic protozoan in the stramenopile group of protists. Its life cycle includes four stages, a vacuolated stage, most commonly found in stool samples, amoeboid, precystic, and cystic stages. The amoeboid stage reproduces by binary fission, while the cystic stages are considered, by many, the transmissible stages. The cystic stage comprises thin-walled and thick-walled types with the former probably being the autoinfective stage and the latter’s role being that of external transmission. B. hominis displays extreme genetic diversity. The forms that are infective to humans can be assigned to at least seven zoonotic subtypes based on their genotypes. It is now believed that such genetic diversity is indicative of the pathogenic and non-pathogenic nature of the organism. While no treatment is indicated, metronidazole has proven effective in a number of clinical cases.
Host Immune Responses Against Intestinal Unicellular Parasites and Their Role in Pathogenesis and Protection
Raúl Argüello-GarcíaJulio César CarreroGuadalupe Ortega-Pierres, in Reference Module in Biomedical Sciences, 2020
Subtypes, pathogenicity, immune response and immunomodulation
This microorganism was historically referred as Blastocystis hominis when isolated from humans, but humans can be infected with other species (e.g., B. ratti). Molecular studies using the small subunit ribosomal RNA gene (SSU) revealed at least 17 Blastocystis subtypes (STs), all of which are morphologically similar but genetically distinct (Alfellani et al., 2013; Stensvold et al., 2007). Thereafter, the designation “Blastocystis spp. STnn” covers all subtypes, of which ST1 to ST9 and ST12 have been detected in humans, and ST1 to ST4 are involved in 90% of human cases (Stensvold and Clark, 2016). Further, subtypes ST18 to ST26 have been proposed to infect humans, but this finding is still controversial (Maloney et al., 2019; Stensvold and Clark, 2020).
To date, there is no proven relationship between Blastocystis STs and virulence, although there appears to be an association. However, key processes involved in intestinal pathogenicity have been identified. In vitro interaction experiments have shown that Blastocystis is able to (a) attach intestinal mucin; (b) promote tight junction alteration mediated by Rho/ROCK, which, in turn, disrupts epithelial barrier function, hence increasing permeability; (c) NF-κB-mediated secretion of pro-inflammatory cytokines (GM-CSF, IL-1β, IL-6, IL-8 and TNF-α) (Fig. 4A); and (d) enterocyte apoptosis by contact-independent, caspase 3-dependent mechanisms (Lim et al., 2014; Puthia et al., 2006) (Fig. 4B). The high genetic variability among Blastocystis isolates is a major contributing factor, not only to explain the distinct inter-ST and intra-ST abilities to induce the alterations mentioned above (Gentekaki et al., 2017; Wu et al., 2014), but also to define likely virulence factors and immune evasion mechanisms used by this parasite.
In spite of the non-invasive nature and controvert pathogenicity of Blastocystis spp., local-intestinal and systemic immune responses have been observed, but are somewhat conflicting. In symptomatic humans, higher levels of serum IgG have been found than in asymptomatic individuals, with variable levels of IgA in serum (Mahmoud and Saleh, 2003; Zierdt et al., 1995). On the other hand, mucosal antibody response in the intestine, mediated by secretory IgA (Fig. 4C), seems to be associated with latent infection, because this isotype is more abundant both in symptomatic patients and in immunized BALB/c mice, acting as a first-line defense against attachment and invasiveness by Blastocystis (Mahmoud and Saleh, 2003; Santos and Rivera, 2009). Further, in pigs, where ST1, ST3 and mainly ST5 predominate, a study testing IgA by immunoblot in 233 fecal samples from asymptomatic, PCR-positive pigs revealed 81% reactivity against different protein bands of a Blastocystis extract from isolate WR-1 (ST4), particularly against a 250 kDa component (Wang et al., 2014). In this context, recent experiments have identified an important role for secreted proteases as major candidate for virulence factors based on their ability to degrade secreted antibodies, disrupt epithelial barrier function and promote the production of pro-inflammatory cytokines (Ajjampur and Tan, 2016; Nourrisson et al., 2016). Particularly cysteine proteases of Blastocystis from symptomatic human cases displayed a higher enzyme activity than those from asymptomatic carriers (Mirza and Tan, 2009). Indeed, secretory dimeric IgA was degraded by cellular and secretory Blastocystis proteases of the cysteine (isolate B, ST7) and a aspartic protease (isolate WR-1, ST4) (Puthia et al., 2005). Interestingly, a variant repertoire and activity of cysteine proteases within and among STs have been reported (Gentekaki et al., 2017; Mirza and Tan, 2009), supporting the notion of variability in pathogenicity and in immune evasion ability among STs.
NO is an important component of the innate immune system, which is produced in large quantities from l-arginine through the activation of NOSII, and is a free radical causing nitrosative stress-mediated death in microbial pathogens. In Blastocystis, necrosis as well as apoptosis-like processes might be induced by NO (Eida et al., 2008; Mirza et al., 2011b) (Fig. 4D). Interestingly, Blastocystis isolate B (ST7) is more prone to apoptosis (i.e., more susceptible to NO) than isolate WR-1 (ST4) (Eida et al., 2008); nevertheless, the ST7 isolate is able to downregulate NOSII mRNA levels in colonic epithelial cell monolayers (CaCo-2) (Mirza et al., 2011b). Although the ST7 isolate contains much higher arginase activity than ST4 isolate, this feature is thought to be secondary to the decrease in NOSII expression in evasion (Mirza et al., 2011a).
Cellular immune response elicited by Blastocystis spp. has been studied in vitro and in vivo. The ability of this parasite to disrupt intestinal barrier integrity allows its secreted antigens to cross epithelium and reach the lamina propria, thus reaching effector cells. In this context, cysteine proteases released by Blastocystis negatively affect enterocyte junctions through Rho kinase activation, F-actin rearrangement and ZO-1 distribution increasing epithelial permeability (Mirza et al., 2012; Puthia et al., 2006). Experimental infections with cysts in BALB/c mice (human isolate) and rats (isolate RN94-9, ST4) showed, by histological examination, an intense infiltration of pro-inflammatory cells in colonic and caecal mucosa, with a moderate increase in goblet cell numbers (Iguchi et al., 2009; Moe et al., 1997). This recruitment is, in part, mediated by soluble mediators acting on inducing granulocytes/macrophages (GM-CSF) and neutrophil recruitment (IL-8), both released by colonic epithelial cell lines (HT-29 and T84) in response to infection by Blastocystis (Long et al., 2001). Regarding mucus production by goblet cells that alleviate colitis-induced symptoms, this production is triggered via IL-22 from CD4 + cells (Leung et al., 2014). In addition, macrophages initially resident in the lamina propria or recruited to the inflamed bowel may be induced by serine proteases from Blastocystis, which may activate protease-activated receptor 2 (PAR2), which, in turn, triggers mitogen-activated protein kinase (MAPK) pathways involving ERK1/2 and JNK, thereby promoting the expression of pro-inflammatory cytokines as IL-1β, IL-6 and TNFα (Lim et al., 2014) (Fig. 4E). Interestingly, this response was found to be more intense when macrophages and even mice with colitis or mouse colon explants were exposed to lysates from isolate B (ST7) as compared with isolate WR-1 (ST4), indicating a differential pro-inflammatory potential among STs (Lim et al., 2014). Further, some IBS cases with concomitant Blastocystis infection are refractory to metronidazole treatment, as parasite isolates (e.g., isolate B) display resistance to this drug (Mirza et al., 2011a). Moreover, isolate B has a higher virulence-arsenal than isolate WR-1, as it contains more cysteine and serine proteases, and arginase activities that appear to explain isolate B’s higher IgA degradation capacity, higher phosphorylation of MAPKs leading to higher pro-inflammatory responses and lower NO production in host cells to allow parasite survival.
The relationship between cellular immune responses to Blastocystis and development of intestinal inflammation, i.e., IBS/IBD, is unclear, but there are significant insights into the activation of the immune response, loss of tolerance to the parasite and immunosuppression (Kaser et al., 2010; Strober et al., 2002). In IBS patients with concomitant Blastocystis infection, lower levels of CD3 + and CD4 + cells and CD4 +/CD8 + ratios were observed (Wang et al., 2002) (Fig. 4F). In the same context, IBS patients infected with subtypes ST1 or ST3 produced higher levels of pro-inflammatory cytokines as IL-8, IL-12 and TNFα compared to patients with only IBS (Yakoob et al., 2014) (Fig. 4G). In addition, Blastocystis carriers harbouring polymorphisms in the alleles of pro-inflammatory IL-8 + 396 (GG) and anti-inflammatory IL-10-592 (C) cytokines were at significant risk of developing IBS (Olivo-Diaz et al., 2012) (Fig. 4H).
Besides pro-inflammatory cytokines, there is limited information regarding other soluble parasite mediators. Interestingly, colorectal cancer cell line HCT116 exposed to antigen extracts of Blastocystis from symptomatic patients significantly up-regulated transcription factor NF-κB, Th-1 (IFN-γ and TNFα) and Th-2 (IL-6, IL-8 and TGFβ) mRNA responses with dominance of Th-2 pattern in comparison with the same cells exposed to extracts from asymptomatic patients (Chan et al., 2012). Considering this aspect, a comparison among subtypes ST1 to ST5 showed that ST3 evoked a higher up-regulation of Th-2 cytokines, particularly TGFβ (Kumarasamy et al., 2013). Altogether, these observations provide evidence of host immunomodulation induced by this parasite.
