Blastocystis hominis
Authors: David R. Shlim, M.D., Charles W. Hoge, M.D.
Parasitology
B. hominis is an anerobic protozoan parasite that inhabits the gastrointestinal tract of humans. The organism has four different distinct parasite forms-the cyst forms, the ameboid forms, the granular forms and the vacuolar forms. The distinctive vacuolar cell appears as a thin pheripheral band of cytoplasm surrounding a large membrane-enclosed central vacuole. An unresolved question remains as to whether B. hominis could exist as different subspecies, some of which might be pathogenic. Different morphologic forms have been shown to exist (26) and a recent paper demonstrated that there are at least 7 different genotypes of B. hominis, with genetic variation greater than the differences between Entamoeba histolytica and Entamoeba dispar (6). No attempt was made in these studies to correlate isolates with symptoms. Bohm-Gloning demonstrated 5 different subgroups of B. hominis, but could not correlate the subgroups to symptomatic or asymptomatic patients (3). It remains unresolved as to whether the phenotypic and genotypic differences in B. hominis are clinically relevant in human disease.
Epidemiology
B. hominis is found more often in developing countries than in developed countries. In various populations, the rate of B. hominis in the stool ranges from 8% in asymptomatic Canadians, (23) to 36% in asymptomatic expatriates in Nepal (25). Fecal-oral route is the presumed route of transmission, although the role of cyst forms is unknown.
Clinical Manifestations
No distinct syndrome has come to be associated with B. hominis infection. Authors have described acute gastroenteritis, chronic gastroenteritis, and intermittent gastroenteritis, along with patients whose only complaints were abdominal pain, increased gas, or constipation. Two case reports have implicated B. hominis in cases associated with colonic inflammation (1,5). The wide range of symptoms can also be interpreted to support the notion that B. hominis is not a pathogen, and that these clinical descriptions represent the wide variation in underlying clinical problems for which persons receive stool examinations.
Laboratory Diagnosis
B. hominis can be identified in wet preparations of fresh stool. It does not survive the concentration process very well. Larger quantities of B. hominis are often seen in liquid specimens compared to more formed stool. It is worth reporting a rough quantification (few, moderate, many), as with any other protozoal pathogen. When a patient presents with B. hominis in the stool, one should be cautious about interpreting this finding as a need to provide specific treatment.
SUSCEPTIBILITY IN VITRO AND IN VIVO
Three in vitro studies have been done using B. hominis grown in culture tubes.
The first study described the following drugs as "inhibitory": emetine, metronidazole, furazolidone, co-trimoxazole, Entero-vioform, and pentamidine. Moderately inhibitory drugs were: Floraquin and chloroquine. Diloxanide furoate and paromomycin were "not inhibitory" (31).
The second study used metronidazole as a standard, assigning it the arbitrary relative value of 1.0. Drugs that had a higher inhibitory effect on B. hominis were: emetine (5.5), furazolidone (4.0), and quinacrine (1.5). Drugs that were less effective than metronidazole were: tinidazole ( 0.7) , ketoconazole (0.3) , trimethoprim (0.6) , Entero-vioform (0.4), chloroquine di-phosphate (0.4), and Amphotericin B (0.1). Iodoquinol (0.04), often recommended for the treatment of B. hominis, was 25 times less active than metronidazole (9).
The third study looked at one isolate of B. hominis each from 4 different Asian countries (12). In vitro studies demonstrated a difference in susceptibility to metronidazole between countries. Whether this represents true geographic variation, or simply different susceptibility between B. hominis subgroups is difficult to conclude with such small numbers.
ANTIPARASITIC THERAPY
No drug has been shown to be consistently effective in eradicating B. hominis. In evaluating the pharmacologic treatment of this organism, one should be aware that patients sometimes get symptomatic relief while the organism persists in the stool. In other cases, the organism is eradicated and the symptoms persist. In addition, some studies have shown that the natural history of persons with symptoms and B. hominis as the only finding in the stool is that they get better just as quickly as people who undergo antibiotic treatment. The definitive study -- a double-blind, placebo-controlled therapeutic trial to treat B. hominis -- has not yet been performed.
The clinical literature also offers no conclusive evidence as to what constitutes effective treatment for the eradication of B. hominis. The two main drugs that have been utilized are iodoquinol and metronidazole. Qadri treated 43 persons who had B. hominis as the only finding in their stool exam with metronidazole 250 to 500 mg BID for 7 to 10 days. All persons became asymptomatic and all stools became negative for B. hominis over a 3 to 6 month follow-up period (21). Telalbasic reported that metronidazole 500 mg TID for 10 days resulted in clinical and microbiologic cure for 12 patients with B. hominis in the stool (28).
Other authors have had less success. Grossman found that only 2/16 (13%) of patients treated with metronidazole (750 mg TID for 10 days) had a microbiologic cure; four of 21 (19%) of patients who were followed without therapy had the disappearance of B. hominis from their stool in the same time period (11). Markell and Udkow found that metronidazole failed to eradicate B. hominis in 12 of 12 patients (unspecifi dosage) (18). Kain et al treated 18 persons with gastrointestinal symptoms and B. hominis in the stool with metronidazole (250 to 750 mg TID for 5-10 days). Fourteen (78%) became asymptomatic or had an improvement in their symptoms. Data on microbiologic cure was not provided. However, a control group of 11 individuals who had gastrointestinal symptoms associated with B. hominis were followed without drug intervention; 9/11 (82%) became symptom free or improved during the same time period (15). Thus, the efficacy of metronidazole for the treatment of B. hominis infections is not clearly established.
Iodoquinol has also been used to treat B. hominis infections in several studies. However, its efficacy has always been poor. Grossman reported that 23/56 (41%) of patients had B. hominis eradicated after a course of 650 mg TID for 20 days (11). Markell and Udkow noted that iodoquinol 650 TID for 10 to 20 days failed to eradicate B. hominis in 25 of 25 patients (18). With its poor in vitro performance noted above, this drug is probably not a good choice for the treatment of B. hominis.
Co-trimoxazole has rarely been used to treat B. hominis. However, a study among Peace Corps volunteers in Nepal showed that B. hominis was detected in only 1/47 (2%) of stool exams in which the volunteer had treated his or her self with co-trimoxazole prior to the exam; B. hominis was detected in 202/747 (27%) of stool exams in which the volunteers had no prior medication (p= 0.0004) (22). This observation was followed up 8 years later by a prospective trial of treatment of 53 patients who had B. hominis in the stool, and intestinal symptoms. After 7 days of treatment with co-trimoxazole, B. hominis was no longer observed in 50/53 (94%), and 39/53 (74%) noted a disappearance of clinical symptoms. This means, though, that at least 11 patients had B. hominis eradicated without improving their clinical symptoms (20).
Nitazoxanide in a dose of 500mg q12 hours for 3 days in adults (200 mg q12 hours in children) was used as a broad-spectrum treatment of mixed parasitic infections in Mexico. Of 10 patients who had B. hominis in the stool before treatment, none had B. hominis after treatment. A single patient has been treated with ketoconazole 200 mg daily for 14 days, with reported resolution of symptoms, and apparent microbiologic cure (7).
ADJUNCTIVE THERAPY
No adjunctive therapies have been tested in relation to B. hominis infection.
ENDPOINTS FOR MONITORING THERAPY
The eradication of B. hominis is not always associated with elimination of symptoms. Conversely, patients whose symptoms are improved by treatment may have persistence of B. hominis in the stool. In order to understand the benefit or lack of benefit of treatment, a follow-up stool examination should always be performed.
VACCINES
There are no vaccines against B. hominis.
PREVENTION
Antiparasitic Agent Prophylaxis
Since the pathogenicity of B. hominis is in doubt, even in severely immunocompromised patients, there would appear to be no indications for antiparasitic prophylaxis. In any event, no prophylactic studies have been carried out.
CONTROVERSIES ON PATHOGENICITY
The pathogenicity of Blastocystis hominis remains uncertain 85 years after the first observation of the organism in human stool in 1912 (4). At that time, the taxonomy of the organism was unclear, and it was often referred to as a "yeast-like" organism and placed in textbooks as a nonpathogenic "pseudoparasite." In 1983, an article by Charles Zierdt postulated that B. hominis was really a protozoan, and was a cause of diarrhea in some patients (30). He made the observation that it must be present in large numbers in the stool in order for it to cause diarrhea.
Zierdt's article was followed by published case reports and case series of patients with gastrointestinal symptoms and the presence of B. hominis in the stool (24, 21, 8). In many of these patients, another pathogen was also found, but in some patients, B. hominis was the only finding. A number of case-controlled series have since demonstrated that B. hominis is not present more often in persons with gastrointestinal symptoms than in asymptomatic controls (29, 14, 13). The idea that B. hominis has to be present in the stool in large numbers in order to be associated with symptoms has been refuted by a number of studies (18,29, 25).
Assigning pathogenicity to B. hominis should not be made lightly. Since the evidence that it is a pathogen is weak at best, it is likely that some other pathogen or non-infectious cause of disease could be playing a role in an individual patient. Deciding that the diagnosis is B. hominis may prematurely end the search for the correct diagnosis. In addition, people with chronic diarrhea often have long histories of intestinal disturbances, and informing them that B. hominis is the cause of their illness may lead them to seek multiple courses of treatment to eradicate an infection that may not be relevant. Since most studies of the infectious etiology of diarrhea do not detect a pathogen in 20-50% of cases, there is ample opportunity for B. hominis to be the only detected "pathogen" in many of these cases. This tendency to assign pathogenicity "by default" was noted in a 1991 editorial in Lancet (2).
Markell and Udkow reported on a series of 32 patients who initially had B. hominis identified on a single stool examination. An additional 5 stool examinations were done on all 32 patients by a parasitologist. After this exhaustive search, 27/32 patients were found to have another pathogen (Entamoeba histolytica, Giardia lamblia, Dientamoeba fragilis). Only five patients had B. hominis alone. Of these 5 patients, one patient was asymptomatic, and four others were followed for 30 months, during which time their symptoms did not change. All four were felt to have irritable bowel syndrome (18).
Recently, 2 articles have attempted to show a correlation between the presence of B. hominis (or a history of B. hominis infection) and irritable bowel syndrome. In the first paper, the control group consisted of persons in a higher socioeconomic class in a developing country who may not have been exposed to stool pathogens as often as the case group. In the second article, antibody testing was used to show that patients with irritable bowel syndrome had higher levels of this antibody than a control group. However, many of the irritable bowel patients no longer had B. hominis in their stool, and the findings are difficult to interpret.
The possibility exists that B. hominis elicits an antibody response in some hosts. However, the studies to date have used different techniques, and have not been validated by other laboratories (10). If B. hominis were pathogenic, one would expect it to cause particular problems in patients suffering from HIV infection. However, several studies have pointed out that B. hominis is not more prevalent in persons infected with HIV, regardless of the stage of HIV infection (19, 27).
In the best effort to date to try to determine if B. hominis in the stool is clinically relevant, 189 persons with diarrhea were compared to 112 asymptomatic controls in a population of expatriates and tourists in Nepal (25). B. hominis was detected in 30% of patients with diarrheal symptoms, and 36% of asymptomatic controls. The presence of B. hominis in the stool among the diarrhea patients did not make it less likely that another pathogen would be found (71% of non-B. hominis diarrhea patients had a pathogen detected; 68% of B. hominis positive diarrhea patients had a pathogen detected). In contrast, diarrhea patients infected with the new pathogen Cyclospora cayetanensis, in the same study population, had only a 33% rate of a second pathogen detected, which was the same rate detected in the asymptomatic controls. Thus, unlike B. hominis, the presence of Cyclospora made it less likely that another pathogen was present in the stool exam. In unpublished data that we reviewed after the article was printed, we found that the diarrhea patients with B. hominis got well just as quickly as diarrhea patients without B. hominis.
Keystone (16) and Markell (17) have pointed out in separate editorials that the case-control method cannot prove conclusively that B. hominis can never be a cause of diarrhea. However, in the absence of any controlled study that shows that the presence of B. hominis is associated with diarrhea, the editorials suggested that the burden should now be to prove that B. hominis is a pathogen, not that it is not a pathogen. Until this question is resolved, one should interpret the finding of B. hominis in the stool with a great deal of caution.
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