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Balantidium coli is a cosmopolitan parasitic-opportunistic pathogen that can be found throughout the world. Pigs are its reservoir hosts, and humans become infected through direct or indirect contact with pigs. In rural areas and in some developing countries where pig and human fecal matter contaminates the water supply, there is a greater likelihood that balantidiosis may develop in humans. The infection may be subclinical in humans, as it mostly is in pigs, or may develop as a fulminant infection with bloody and mucus-containing diarrhea; this can lead to perforation of the colon. The disease responds to treatment with tetracycline or metronidazole. Balantidiosis is a disease that need never exist given access to clean water and a public health infrastructure that monitors the water supply and tracks infections. Its spread can be limited by sanitary measures and personal hygiene, but it is a disease that will be around as long as there are pigs. Immunocompromised individuals have developed balantidiosis without any direct contact with pigs, perhaps with rats or contaminated produce as a possible source of infection. For the clinician, balanatidiosis should be included in the differential diagnosis for persistent diarrhea in travelers to or from Southeast Asia, the Western Pacific islands, rural South America, or communities where close contact with domestic swine occurs. Warming of the earth's surface may provide a more favorable environment, even in the now-temperate areas of the world, for survival of trophic and cystic stages of Balantidium, and its prevalence may increase. Effective sanitation and uncontaminated water are the most useful weapons against infection. Fortunately, balantidiosis responds to antimicrobial therapy, and there have been no reports of resistance to the drugs of choice.
Protozoan parasitism covers a broad spectrum of diseases. Balantidium coli and balantidiosis, the subjects of this review, barely register among infectious protozoan diseases.
Balantidium is the only ciliated protozoon known to infect humans and is the largest protozoon infecting humans and nonhuman primates. Balantidiosis is a zoonotic disease and is acquired by humans via the fecal-oral route from the normal host, the pig, where it is asymptomatic. Water is the vehicle for most cases of balantidiosis. Human-to-human transmission may also occur. Balantidium's habitats in humans are the cecum and colon. Humans may remain asymptomatic, as does the pig, or may develop dysentery similar to that caused by Entamoeba histolytica. Death is an infrequent consequence of balantidiosis, but in developing countries with undernourished and overparasitized populations, it can make the difference between a healthy life and chronic debilitation.
The organism is cosmopolitan and can be found wherever pigs are found. Disease appears to be a problem mostly of developing countries, where water sources may be contaminated with porcine or human feces. B. coli can become an opportunistic parasite in immunosuppressed hosts living in urban environments, where pigs are not a factor in infection.
Balantidium is an often-neglected pathogen. Research on Balantidium has been sparse. Zaman (80) published an inclusive review on Balantidium 30 years ago, but recently the organism has come to be regarded as an emerging protozoan pathogen and has been reviewed by Garcia (22).
Balantidium has a simple life cycle, as follows: dormant cyst to trophozoite and trophozoite to cyst. Transmission is direct, from a contaminated water or food supply to humans (Fig. (Fig.1).1). No intermediate host, as occurs with many other parasitic species, is needed.
Malmsten (44) was the first to recognize the organism in two humans with dysentery in the year 1857. Malmsten identified it as a species of Paramecium and named the organism Paramecium coli. Leuckart described a morphologically similar species from the pig intestine in 1861 (39). Shortly thereafter, Stein equated the two organisms and placed them in the genus Balantidium (G. balanto-, bag), and because of priority, the species name (B. coli) was retained (64). Ironically, Malmsten first described balantidiosis, usually regarded as a disease of tropic or subtropic regions, from patients in Sweden (44).
Morphologically similar organisms have been detected in a variety of mammals, including rats, chimpanzees, orangutans, and infrequently, dogs or cats. The species found in pigs, Balantidium suis, is likely identical to B. coli from humans. Other species have been isolated from guinea pigs (Balantidium caviae), cockroaches (Balantidium blattarum), fish, birds, and amphibia. In all, there have been about 50 species described (4). Morphology has been the basis for identification to the species level, and some of the different species that have been created are in reality B. coli showing polymorphism in different hosts and under varied growth conditions (41). The taxonomy will ultimately be resolved once these organisms undergo sequencing of their small subunit rRNAs.
The trophic ciliate measures 30 to 150 μm in length by 25 to 120 μm in width; the cyst, which may be spherical or slightly ovoid, measures 40 to 60 μm in diameter (41). Size, however, varies, with some balantidia being up to 200 μm in length. The mouth (oral apparatus) is located at the tapering anterior end, and the cytopyge (anus) is at the rounded posterior end (Fig. (Fig.2).2). A sausage-shaped macronucleus and a rounded micronucleus are located in the cytoplasm (Fig. (Fig.3).3). Asexual division occurs as it does in most ciliates. A transverse furrow forms, dividing the mother cell into two asymmetric daughter cells, an anterior (proter) and a posterior (opisthe) cell. The proter retains the oral apparatus, and the opisthe develops a new apparatus. An anterior stomatogenic field appears in the opisthe, leading to formation of the new oral apparatus, but the old oral apparatus may also undergo reorganization (37). The swimming organism exhibits a rotary-type motion by means of its somatic cilia that may facilitate movement through the contents of the colon.
Sexual reproduction as conjugation has been reported for Balantidium, but information is lacking about details of nuclear events. Two successive fissions (meiosis) occur preceded by formation of the conjugants, by either equal or unequal divisions (37). The two conjugants attach at the oral apparatus and exchange micronuclear products of meiosis.
Although the organism lives in an anaerobic environment, Zaman (80) described mitochondrion-like bodies in electron micrographs of Balantidium; in contrast, Entamoeba histolytica and Entamoeba dispar, found in the human colon, are anaerobes and lack mitochondria. Cristae or tubuli, however, were reportedly absent from the mitochondrion-like bodies, raising the possibility that these organelles are hydrogenosomes (80). Hydrogenosomes, relict mitochondria, have been identified in balantidia as well as in other anaerobic ciliates (25, 27). Other cytoplasmic components include endoplasmic reticulum, ribosomes, and numerous vacuoles filled with food particles. A Golgi apparatus was not seen, but vesicles of endoplasmic reticulum function in lieu of Golgi vesicles (49). Mucocysts are also seen (61). Two contractile vacuoles, functioning as osmoregulatory organelles, pulsate at a low rate even though the surrounding environment is isotonic or close to it (79). Undigested residue from food vacuoles is eliminated through the cytopyge.
Balantidium jocularum, from the herbivorous surgeonfish, was found to harbor endosymbiotic bacteria in its macronucleus (26). The bacteria were unusually large, measuring up to 4 μm in length, but apparently without pathogenic potential for the ciliate. They are probably gram-positive organisms because of an endospore-like inclusion within the bacterium. No other reports of endosymbionts from Balantidium have appeared.
The cyst of Balantidium is the transmissive stage of the organism. Because of its thickened wall, it is protected from desiccation and other environmental stress (Fig. (Fig.4).4). It survives best in humid surroundings protected from direct sunlight. The trophic ciliate is reportedly unable to survive passage through the stomach because of the low pH of gastric fluid, but Balantidium trophozoites inoculated into the stomach of guinea pigs have been found in the colon (56). The process of encystment begins in the colon and rectum of the host, and cysts are generally found in formed feces (56). Cysts, however, were not produced in cultures of balantidia (32, 80), nor are they produced in cases of acute dysentery. Attempts to simulate in vitro the colorectal environment in which cysts form (resorption of water and increased salt concentrations) were unsuccessful in inducing encystations; overfeeding or starvation was also unsuccessful (32). Loss of the ability to encyst is seen in some other protozoa (e.g., soil amebae) maintained in culture, due in part to less than optimal growth conditions and/or limiting amounts of nutrients essential for encystment. E. histolytica, an agent of amebic dysentery, resembles Balantidium in producing cysts in formed stools but trophozoites in dysenteric stools. In vitro encystment of E. histolytica depends upon a number of factors, including withholding rice starch, the composition of the bacterial flora, and the encystment medium, and may require a complex protocol to induce cyst formation (10).
The diet of the ciliate is made up of bacteria and food particles present or passing through the colon. If extensive damage has been done to the wall of the colon, red blood cells may also be seen in trophic organisms, as well as blood in the stool. The ciliates produce flask-shaped lesions in the submucosa, where they form clusters called nides or nests (4).
Protist taxonomy was recently revised by a committee of the International Society of Protistologists and allied groups, based on the wealth of new information that has accumulated about these organisms since the last “official” taxonomy published in 1980 (1). Since that time, an increased understanding of ultrastructural morphology, biochemical properties and relationships, studies of nuclear and mitochondrial DNAs, and protist ecology has developed. The revised taxonomy does not use the classic categories of phylum, class, order, etc., in order to maximize taxonomic plasticity as additional information on phylogenetic relationships, particularly from genomic studies, becomes available (1).
The following definition is based on the new taxonomy and represents a characterization of the genus Balantidium, from the more general ciliate features to those of the genus Balantidium.
Balantidium spp. are ciliated binucleate protozoa with macro- and micronuclei (features of Ciliophora) covered by uniform rows of monokinetid somatic ciliation, i.e., rows of cilia arising from single rows of subsurface kinetosomes and their associated fibrils; a slit-like anteroventral oral cavity depressed below the surface (a feature of Litostomea); an oral apparatus with dense ciliation but lacking specialized oral membranelles, with features of endosymbiosis in many animals (“hairy” mouths; features of Trichostomatia); a vestibular groove leading into the oral apparatus (feature of Vestibulifera); a vestibular groove of less than one-half the body length, with features of commensals of vertebrate, amphibian, and insect hosts or, in some cases, parasites that may attack the intestinal lining (feature of the “family” Balantidiidae). Representative species in mammals are B. coli, B. suis, and B. caviae.
Nucleotide sequences from two studies on Balantidium are on file at GenBank, one based on small subunit rRNA (AF029763) and the second based on internal transcribed spacers 1 and 2 (AF045030) (65, 66, 73). Sequencing was used to construct a phylogenetic tree placing Balantidium coli with the trichostome ciliates Isotricha spp. and Dasytricha spp., but not necessarily in the same subgroup (“order” Vestibulifera). These ciliates have a sunken oral apparatus but lack toxic trichocysts, which aid in subduing prey (51). As yet, a definitive taxonomy of the group awaits additional information.
Are B. coli from humans and B. suis from pigs the same organism? Persons infected with porcine strains of Balantidium are usually assumed to have B. coli infections (72). The answer awaits further studies of the organisms' DNAs. Although pigs are the major reservoir for balantidiosis in humans, laboratory studies indicate that humans are not readily infected with B. suis or, for that matter, B. coli. The two organisms appear to be different from one another—one is larger (B. coli) and one is smaller (B. suis)—which is evidence enough for some to regard them as different species. According to Levine (41), however, a clonal isolate of B. coli showed both morphotypes after being maintained in culture. The size difference between the two was attributable to growth conditions of the ciliates. Jameson (32) favored the view that there is a single species of Balantidium that splits into two size variations. Similarly, B. caviae from the guinea pig was described as being indistinguishable in vitro from B. suis from swine (56). An agar diffusion study of antigens of Balantidium spp. found only minor antigenic differences between B. coli and B. suis (36).
Few studies have examined the energy metabolism of these organisms. Balantidia are equally able to survive under anaerobic as well as aerobic conditions. Carbohydrates are the chief source of energy for the ciliates growing in vivo (80).
In studies of B. coli combining ultrastructure with cytochemistry, peroxisomes were identified in the ciliate. These vesicles contain peroxidase, an enzyme affording protection from the destructive effects of highly oxidative compounds, such as hydrogen peroxide (60). A comparison of the cytoplasm of ciliates from asymptomatic swine and those with acute balantidiosis was made. Peroxisomes were more numerous but smaller (0.6 to 0.8 μm) in balantidia from asymptomatic pigs than in those with acute disease (>0.8 μm). Likewise, nucleic acid contents (particularly RNA, but also DNA) from symptomatic and asymptomatic hogs differ, with the former having more content (62). The difference may depend on the degree of metabolic activity of the ciliates and, in the case of RNA, may be indicative of enhanced protein synthesis. Ciliates with higher nucleic acid content produced more robust cultures, at least in the initial stages of in vitro growth (62).
The enzyme glucose-6-phosphatase was present in small vesicles attached to the endoplasmic reticulum or in the membrane itself (61). Alkaline phosphatase was found in the ciliate cortex, nuclear and ciliary membranes, and kinetosomes as well as in vesicles of the endoplasmic reticulum (61). Phosphatase enzymes are important for their role in making glucose available as an energy source.
Balantidia produce no known toxins, but their ability to produce ulceration of the colon wall is attributed to hyaluronidase, an enzyme that digests hyaluronic acid, a component of the “glue” holding mucosal epithelial cells together (68). The dissolution of group C Streptococcus hyaluronic acid-containing capsules and the breakdown of potassium hyaluronate by living B. coli were taken as evidence of hyaluronidase activity. Entamoeba histolytica, the classic protozoan dysentery agent, attacks the mucosal surface of the colon and was long claimed to possess hyaluronidase activity. Attempts to demonstrate its presence, however, using E. histolytica extracts, did not support the claim (50). In the case of B. coli, other factors may affect the results, including associated bacteria, waning of virulence (see next paragraph) in long-term cultures, up- and downregulation of presumptive virulence genes, and strain differences. Thus, the matter of hyaluronidase production by Balantidium warrants further study. Levine (41) noted that invasion of colonic epithelium by Balantidium might be secondary to damage caused by intestinal bacteria.
The term “virulence” is used here as the degree of pathogenicity of a parasite and involves substances elaborated by a pathogen that facilitate infection and disease (e.g., toxins, enzymes that promote invasiveness, and adhesive properties).
Balantidia are available from fresh pig feces, particularly from animals with evidence of acute balantidiosis, and from slaughterhouses. An insulated bottle is used for transport of porcine intestinal contents to the laboratory. There were a number of early attempts at maintenance or cultivation in vitro. Gastric mucin media were developed for Balantidium and maintained growth for as long as 30 months. Calf serum and rice starch or rice powder were also required. Starch grains, if present in culture medium, are ingested and serve as a carbohydrate source (80). The addition of soluble sugars to growth media encourages overgrowth of accompanying bacteria, whereas starch particles are efficiently ingested and digested by the phagotrophic ciliates (10). A defined medium with cysteine HCl and i-inositol was used for short-term physiologic experiments with the organisms, but little in the way of results appeared in the literature (35). Trophic ciliates, however, did not survive agitation in attempts at manometric studies.
Biphasic media in tubes were often used with an agar, inspissated egg yolk, or serum butt overlaid with nutrient medium. Bacteria present in the sample can overgrow in an enriched medium, requiring the addition of antibiotics (e.g., penicillin-streptomycin) to suppress bacterial proliferation. When growing in tubes, balantidia favor the bottom of the tube, where conditions are microaerophilic or anaerobic. Zaman maintained monoxenic cultures of B. coli with Escherichia coli, using antibiotics to control bacterial overgrowth (80). Diamond's TYSGM medium for Entamoeba and other enteric parasites will also support the xenic (with bacteria) growth of balantidia (10). The medium contains Trypticase (casein digest), yeast extract, serum, and porcine gastric mucin. Starch powder is added to tubes at the time of inoculation of medium. Zaman (80) noted that B. suis from the pig is not as readily cultured as B. coli from humans. Others apparently encountered no difficulties with cultivation of B. suis (62). Among the variables involved in cultivation are the growth medium and pH (optimal range, 5.4 to 8.0) (32), associated undefined bacterial flora, strain differences, and differences in nutritional requirements between ciliates from different hosts.
In the case of many pathogens maintained in vitro, prolonged cultivation attenuates virulence, and animal passage may be required to restore it. The difficulty in infecting laboratory animals (e.g., the guinea pig) and the absence of an animal model of disease are obstacles in attempts to study the pathogenicity of the ciliate.
Balantidium grows at temperatures between 20°C and 40°C, a range that is adaptive for mammalian endosymbionts but can also allow for survival and growth outside the host (10). Trophic ciliates did not survive longer than 24 to 48 h in cultures maintained at temperatures over 40°C (12). The trophic organism from pig intestine has been reported to survive room temperature and exposure to air for 24 h to as long as 10 days (56). There is no information about the ability of balantidia from poikilothermic animals to make the transition to mammalian body temperature.
In pigs, as in some humans and other mammals, Balantidium infects but causes no serious disease of the gastrointestinal tract. It can thrive there in balance with its host without causing dysenteric symptoms, such as severe diarrhea and bloody stools. The problem with this détente is that malnutrition, alcoholism, or a compromised immune system (as in human immunodeficiency virus [HIV]/AIDS, etc.) can tip the balance in favor of the ciliate, leading to disease (3, 20, 70). In acute disease, explosive diarrhea may occur as often as every 20 min (38). Perforation of the colon may also occur in acute disease, with life-threatening consequences.
Hosts vary in their susceptibility to Balantidium, and attempts at infecting humans have been disappointing (76). This may be due to virulence of the particular strain used for infection, the intrinsic health of the host, and/or the dosage of the ciliate administered to the host. There is no evidence that other intestinal flora of humans, whether bacteria, protozoa, or viruses, render the host more susceptible to infection. It is known, however, that the presence of pathogenic bacteria (e.g., Salmonella) in the intestine can worsen an infection by invading colonic lesions caused by balantidia (41, 57, 59, 60).
Nonhuman primates, particularly the great apes and Old World monkeys, can develop Balantidium infections. This is of concern since some of these animals are endangered species or close to it because of disease, encroachment by humans on their natural habitats, and resultant density-dependent changes in their populations. Orangutans, for example, are less likely to be infected by Balantidium in their natural setting, while those in “rehabilitation” centers for injured or orphaned animals have a higher prevalence of the ciliate (34). Reasons for this include overcrowding at the centers, with increased stress on individuals; contacts with humans and other animal species and their associated bacterial, viral, and protozoan organisms; and water sources contaminated by fecal material in confined areas (34). In the wild, the orangutan population density is 2 individuals km−2 (34).
Few intensive studies have been carried out on the host's immune response to Balantidium. One study examined a population of captive rhesus macaque monkeys with and without chronic diarrhea (57). The study detected a broad array of bacterial and protozoan organisms, as well as viruses. A significantly larger proportion of animals with chronic diarrhea harbored pathogenic bacteria (Campylobacter spp., Shigella flexneri, and Yersinia enterocolitica) than those without diarrhea. The prevalence of Balantidium was ~12% (estimated from the graph in reference 57). The presence of Balantidium in the colon appeared not to be the cause of disease. Monkeys with chronic diarrhea showed a significantly increased production of interleukin-1α, interleukin-3, and tumor necrosis factor alpha, to a level of 60 to 70% from about 20 to 30% in nondiarrheic animals. This was not necessarily due to Balantidium, however, because of the variety of other intestinal organisms.
Experiments to demonstrate an immune response to Balantidium were done by Zaman, who studied an immobilization reaction to Balantidium (78). Using anti-Balantidium antibodies raised in rabbits, the serum immobilized the ciliates within less than a minute (titers of 1:4 and 1:8); higher dilutions took longer to immobilize. Heat-inactivated rabbit serum did not immobilize. Ultimately, the treated organisms disintegrated. Demonstrating a humoral response to the ciliates in patients with balantidiosis by indirect fluorescent-antibody (IFA) staining would be of interest. Dzebenski (18) tested pigs for anti-Balantidium antibodies by IFA staining but had difficulty in detecting any activity in pig sera. He attributed the lack of response to the small sample of animals tested and the absence of evidence of tissue invasion in the animals used.
Availability of an IFA test would sidestep the labor-intensive examination of stool samples (except for validation) and might give a better estimate of Balantidium exposure if applied to persons living in regions of endemicity and to groups at risk.
Populations with constant exposure to Balantidium may develop some degree of immunity (19). In areas where contact with pigs is common, such as the Altiplano region of Bolivia, most of the schoolchildren examined had asymptomatic infections, but few had diarrheic stools, suggesting resistance to fulminant disease (19). In an outbreak of balantidiosis on the Western Pacific island of Truk (see below), immunity may have been a factor in the relatively rapid resolution (estimated at ~6 weeks) of the outbreak among inhabitants (72).
Immunocompromised individuals appear to be less resistant to balantidiosis. There have been no concerted studies, however, to determine the prevalence of balantidia in immunosuppressed hosts. Reports in the literature are more of an anecdotal nature. Two reports of balantidiosis in HIV/AIDS patients point to Balantidium as both a pathogen and an opportunist (8, 11).
There have been several reports in the literature of Balantidium spreading to the lungs, causing a pneumonia-like disease. Most of these infections have occurred in elderly or otherwise immunocompromised persons. A 71-year-old woman (Greece) with anal cancer, diabetes, fever, and intermittent diarrhea was found to have Balantidium in her lungs when a bronchial secretion was examined as a wet mount slide preparation (70). Although the patient was treated with metronidazole, a drug of choice for treating balantidiosis, and several other antimicrobials, she died of cardiac arrest. Computerized tomography scans and X-rays showed lung lesions in a 58-year-old woman (Greece) with leukemia who also suffered weight loss, weakness, abdominal cramps, and a cough. Since a fungal infection was suspected, bronchoalveolar lavage was performed, and balantidia were found in the wash fluid (3). The authors postulated that the ciliates were spread hematogenously from the site of colonic ulceration to the lungs. Antimicrobial treatment with metronidazole was successful in resolving the infection.
Nonpulmonary infections have also developed in immunosuppressed patients. A 54-year-old alcoholic pork butcher (France) with acute diarrhea suffered colonic perforation but recovered after doxycycline treatment and colectomy (20). Balantidia were detected in stools of a 47-year-old female (Turkey) with non-Hodgkin's lymphoma, accompanied by abdominal pain and bloody diarrhea; she, too, was treated successfully with metronidazole (75).
Except for the pork butcher in the preceding paragraph, the other patients had no contact with pigs and lived in urban areas. The leukemic patient had also received corticosteroids and chemotherapy, which may have increased vulnerability to opportunistic infections by muting the immune response. Other possible sources of infection may have been consumption of uncooked vegetables and/or food contaminated by rat droppings or mechanically by cockroaches or flies.
A Barbary sheep (Korea) from a zoological park died after showing signs of emaciation, lethargy, and weakness (9). At autopsy, B. coli was found in the gastric lymph ducts and in the submucosa of the abomasum of the animal. The sheep was also infected with the coccidian Eimeria and with parasitic worms. Balantidia, however, were not found in the animal's stool. It was hypothesized that balantidia initially infected the abomasum, where damage to the mucosal surface by Eimeria facilitated invasion of the lymphatics.
Among possible pathways by which balantidia in the colon wall could colonize the lungs are the circulatory (hepatic portal circuit) or lymphatic systems (3, 9, 70), perforation of the colon and spread through the peritoneal cavity (70), invasion of the lungs across the diaphragm (58), and colonization of the nasopharynx with spread to the lungs, resulting from aspiration of fluid from the oral cavity (58). It is interesting that there was no indication of Balantidium trophic ciliates or cysts in the stool samples of most of these individuals.
A parasite passing from one species to another faces the problem of species specificity, both for the host and for the parasite. Although humans are susceptible hosts for balantidia, efforts to infect humans have not been successful (76). Balantidium has no problem in passing from pigs to humans under appropriate conditions (e.g., the outbreak in Truk). For transmission to be successful, it would appear that proximity and persistent contact between pigs and humans are factors.
Gelatin capsules containing human feces with active ciliates and cysts were given to volunteers (76). The capsules contained 250 trophic ciliates and 250 cysts. Volunteers were followed over a period of 10 years, but no evidence of infection based on stool examination was found. The study may have been extended to detect asymptomatic or cryptic infections that were not readily apparent in stool samples from the volunteers. In another study, a human fecal homogenate containing considerably larger numbers of cysts of B. coli (1.2 × 104 to 4.8 × 104) was used to infect piglets and monkeys (74). Severe diarrhea developed in about half of the piglets (4 of 10) and in monkeys that had been pretreated with hydrocortisone (2 of 4). Other animals suffered moderate diarrhea (piglets) or were asymptomatic (monkeys).
Attempts were also made to infect guinea pigs by using porcine balantidia (56). Ciliates harvested from culture, containing starch grains as markers, were injected into the stomach of a guinea pig. Starch-filled ciliates were subsequently found in its esophagus and cecum. A second attempt transferred ciliates directly from the pig by use of a stomach tube, and trophic ciliates were detected in the ileum, jejunum, and cecum. Both animals died soon after infection as a result of the experimental procedure.
Balantidiosis has a range of mild to severe clinical presentations. The following three clinical manifestations of balantidiosis can occur (71): (i) asymptomatic hosts who are carriers of disease and serve as reservoirs of infection in the community; (ii) chronic infection that presents with nonbloody diarrhea, cramping, halitosis, and abdominal pain secondary to trophozoite invasion of the large intestine (71, 75); and (iii) patients with fulminating balantidiosis passing mucoid, bloody stools.
The most severe presentation of B. coli occurs with weight loss, tenesmus, and bloody stools (71). Intestinal hemorrhage and perforation can also occur and are mediated by the production of B. coli proteolytic enzymes (3). Direct evidence for the presence of proteolytic enzymes is lacking, but proteolysis is generally assumed to be a factor in digesting the mucous coating of the colon and facilitating tissue invasion, abscess formation, ulceration, and perforation of the intestine (3). Entamoeba histolytica, which has a similar pattern of pathogenicity, has been shown to possess and secrete cysteine, serine, aspartic, and metallo-proteases, some of which can target the mucus layer of the intestinal wall and aid in penetration of the underlying tissue (43, 69).
Hemorrhage and perforation were reported for fatal cases of B. coli infections (17). Fulminating balantidiosis has a case fatality rate of 30% (19). Vasquez and Vidal (71) described the case of a 60-year-old pig farmer with pancolonic damage and microperforation who died despite antiparasitic treatment. Another fatal case of balantidiosis occurred in a 63-year-old pig farmer, who died of dysentery and subsequent hemorrhage after 8 days; an autopsy revealed ulcerative colitis (54). Fatal cases of balantidiosis have also been associated with sepsis secondary to intestinal disease (51, 58). A malnourished 2-year-old girl with an anorectal malformation who was diagnosed with balantidiosis developed septic shock and died despite antimicrobial treatment with ampicillin and amikacin for sepsis and metronidazole for balantidiosis (7).
Although the intestine is the most common site of B. coli disease, there are extraintestinal sites of infection. These include the appendix but rarely the liver (16). Dodd (16) reported a case of a 16-year-old who presented with abdominal pain, fever, and elevated white blood cell count and who had a gangrenous appendix. Pathological examination of the appendix revealed inflammation, ulceration, necrosis, and B. coli trophozoites (16). Genitourinary sites of infection, including uterine infection, vaginitis, and cystitis, are thought to occur via direct spread from the anal area or secondary to rectovaginal fistulas created from infection with B. coli (58). Lung infections with Balantidium are infrequent but noteworthy. A necrotizing lung infection was reported for a 42-year-old organic farmer who routinely used pig manure to fertilize his vegetables, probably as a result of aerosolizing the manure and inhaling airborne cysts (58). Airborne transmission of cysts is unlikely. Cysts of Balantidium are large and would not be carried over great distances, either on air currents or in water droplets. Thus, infection by inhalation would require direct contact with aerosol droplets.
Nutritional status, intestinal bacterial flora, parasite load, achlorhydria, alcoholism, or any chronic disease may affect the severity of disease (19). As previously noted, some degree of immunity may be present in populations that are exposed to Balantidium on a regular basis (19, 72).
B. coli infection is uncommon in humans despite its potential for worldwide distribution. The organism, though pathogenic, is of low virulence. The worldwide prevalence is estimated at 0.02 to 1% (19), but it varies widely by geographic location (3).
Areas of high prevalence include regions of Latin America, the Philippines, Papua New Guinea and West Irian, and areas of the Middle East (63, 75). In New Guinea, the rate of infection among pig farmers is as high as 28% (53), and in the Altiplano area of Bolivia, balantidiosis rates range between 6 and 29% (19).
The major factors leading to human balantidiosis include (i) close contact between pigs and humans, (ii) a lack of appropriate waste disposal such that swine and human excrement contaminate drinking water sources (e.g., wells and streams) and food, and (iii) subtropical and/or tropical climatic conditions (e.g., warmth and humidity) favoring survival of cysts. Balantidia, however, are adaptive to less than ideal conditions, as evidenced by their ability to infect compromised hosts living in urban settings and to survive in hogs in decidedly nontropical locations, such as Denmark (31) and Poland (62). Human-to-human spread by the fecal-oral route can take place as with other enteric diseases.
What factors are responsible for balantidiosis outbreaks in humans? What is regarded as the largest outbreak of balantidiosis occurred following a typhoon that hit the island of Truk in the Caroline Islands (Western Pacific), where many of the residents kept pigs. A typhoon destroyed homes and rooftop catchment systems for collection of rainwater, leaving people without a source of uncontaminated water. Instead, they used water from streams and wells that were contaminated with pig and human feces, resulting in balantidiosis in 110 persons on the island, as well as an increase in E. histolytica and Ascaris infections (72). Neither age nor gender was a factor in infection and disease, as it appears to be in “normal” transmission in areas of endemicity. Symptoms of disease appeared an average of ~6 days (range, 0 to 27 days) before laboratory diagnosis was made by stool examination (72).
In institutional populations (mental hospitals, prisons, and orphan asylums), where pigs are an unlikely source of infection, outbreaks are the result of asymptomatic carriers and the difficulties involved in maintaining hygienic control (6). Cases developing in urban areas generally occur in immunocompromised hosts and are self-limiting outbreaks (3, 9, 20, 70, 75).
The bacterial flora of the host can influence its susceptibility and course of infection, particularly if pathogenic or potentially pathogenic bacteria are found in the gut. This has been the case for nonhuman primates (57) and supports a secondary role of Balantidium in causing disease (41, 59, 62).
Are there virulent and avirulent strains of B. coli and B. suis? What factor(s) triggered the balantidiosis outbreak in Truk described above? Because the prevalence of Balantidium in the population was low before the typhoon hit the island, Walzer et al. (72) postulated that the source of the infection was pigs rather than humans.
In theory, a virulent strain entering a population, whether from contaminated water or human or pig contacts, is a likely source of disease outbreak. In contrast, avirulent strains are either ineffectual in causing disease or produce asymptomatic infections. But no evidence for such a dichotomy in balantidia is available. Humans are not easily infected, and the prevalence of Balantidium among humans (estimated at 1% worldwide) is lower than that in pigs, which can be as high as 100% in surveyed swine populations (31). The distribution of pathogenic Entamoeba histolytica and its nonpathogenic look-alike E. dispar in human populations helps to explain the anomaly of persons having entamoebae in stools without symptoms of invasive disease (15). Many more persons are infected asymptomatically with E. dispar than with the pathogenic organism E. histolytica. Among those diagnosed as having Entamoeba in their stools, only 10 to 20% exhibit diarrheic disease. Furthermore, even the avirulent organism E. dispar may erode the colon wall and cause symptoms such as bloating and cramps (15).
Although pigs are a major source of balantidiosis, a number of other mammalian species have been found to harbor the ciliate. In a study done in Japan with fecal samples from 56 mammalian species, 6 were found to harbor the ciliate (49). The species were mainly nonhuman primates but also included wild boars. Rodents and carnivores (cats and dogs) tested negative. From the small number of infections found, Nakauchi (49) concluded that the disease was not a veterinary concern in Japan.
Studies that have examined the prevalence of Balantidium in pigs in the United States are few. Morris et al. (47) studied intestinal parasites of pigs, including B. coli, from Oklahoma hog farms. Balantidium was detected in 55.1% of pigs examined, with adult swine having a higher prevalence (18.6%) than shoats (14.6%) and nursing pigs (5%). Pigs on pasture land or dirt lots had a somewhat higher percentage (16.4%) of balantidia than pigs kept on wood slats (13.2%) or on cement surfaces (7.4%) (36). A study of hogs in southern Georgia found a higher prevalence of B. suis in gestating hogs than in lactating animals, but differences were attributed to locations (different units) where hogs were confined and to age differences (45). Weaned pigs were negative for balantidia but soon became infected either from the mother or from caprophagy of residual fecal material in the holding pens. In general, however, prevalence increased in pigs with age, as also shown in the Oklahoma survey.
In two reports from Europe, the prevalence of Balantidium in pigs from a Danish research farm increased from 57% for suckling piglets to 100% for most other age groups (31). In a survey of 15 of 20 pig-raising farms (n = 514 fecal samples) in Germany, the prevalence of infection was 60% for suckling pigs (13).
Wild boars in rural Western Iran were a reservoir for Balantidium, and since wild boars scavenge farms, Solaymani-Mohammadi et al. (63) examined boars to assess the potential for spread of ciliates to livestock and humans. Sixty-seven percent of the animals were infected, with females and older animals carrying a heavier parasite load than males and younger boars. Because pork is proscribed for Moslems, raising pigs in Iran is not an important factor in zoonotic infections, and cases that occur are assumed to be the result of human-to-human transmission. A study of fecal material from 292 feral pigs in water catchment areas in southwest Australia identified 10 positive cases (3%) in genetically distinct populations (29). Infections were not uniformly distributed among all genetic groups; most of the infected pigs (nine animals) were from a single genetic subpopulation. Balantidium was uncommon or absent from other subgroups. It was concluded that feral pigs pose a public health threat to drinking water supplies, as the animals wallow in creeks feeding into reservoirs providing water to local municipalities.
A study of 910 fecal samples from 222 nonhuman primates confined in groups was carried out at four zoological gardens in Belgium (40). Entamoeba spp. and Giardia were the most common endocommensals, with infection rates of 44% and 41%, respectively, and Balantidium was detected in 13% of the fecal samples, mostly from Old World monkeys (Celebes crested macaques, mandrills, and hamadryas baboons); prosimians (e.g., lemurs) and New World monkeys were uninfected. Thus, though infection with the ciliate was found in some groups, it was not a pervasive problem in zoo populations. Its incidence in Old World monkeys might relate to these simians spending more time on the ground than other animals and being more likely to come into contact with feces containing Balantidium cysts (40).
Nursing rhesus macaque monkeys at a research center were studied for milk production (30). Animals with B. coli infections produced milk with a lower fat content than that in animals without B. coli. Furthermore, the heavier the infection, the less fat was in the milk (about 6.5% in “clean” animals versus 4.2% in animals with heavy infections). The lower fat concentration, however, did not affect infants' weights.
Baboons (Papio doguera) captured in the wild in Kenya were the basis for a study of intestinal protozoa (48). At the time of capture, 63% of the animals harbored Balantidium, the most frequently found protozoon. After transfer and captivity in the United States for a year and a half, none of the animals were infected, although most other intestinal protozoa (e.g., Entamoeba spp.) did not diminish in numbers.
A comparative survey of parasites of semicaptive (at a rehabilitation center) versus free-ranging orangutans in Sabah, Malaysia, found that the prevalence of B. coli was 14% in the free-ranging group, while it was 42% among semicaptive young animals (34).
A number of species of Balantidium have been described from amphibia (e.g., Rana, Xenopus, and Bufo species). A recent finding by Li et al. showed that Balantidium occurred in the feces of the giant Chinese salamander (42). A new species, Balantidium andianusis, was described from a single animal; a second species from the salamander, Balantidium sinensis, had previously been described from the frog. The basis of identification to the species level was detailed measurements of the oral apparatus, length, width, etc.
The prevalence of human balantidiosis is higher in populations in regions of endemicity having close contact with pigs or pig feces, such as farmers and workers in abattoirs (51, 58). Contacts between humans and pigs are necessary but not sufficient to cause disease. Other factors must be taken into account, such as (i) host factors, including resistance and/or possible immunity; and (ii) the etiologic agent itself and its ability to invade host tissues.
Balantidiosis is an uncommon human disease mostly restricted to tropical and subtropical regions because of sanitary standards, climatic conditions, and cultural mores. The major factors in spread of the disease to humans are the presence of infected swine and little or no means of disposal of animal and human waste. It is a disease of poor, rural areas where people are likely to live in close proximity to their livestock, with their homes offering protection not only for themselves but also for their domestic animals. It is the close association of people and pigs that leads to infection. Pigs pass Balantidium cysts in their feces, which can contaminate wells and groundwaters, serving as a vehicle for transmission of parasites.
In a survey of 325 waterborne diseases in North America and Europe, Balantidium infections accounted for 0.3% (n = 1) of the outbreaks (33).
A comprehensive study of stool samples from >2,000 Aymara Indian children from the Altiplano region of Bolivia found widespread infection with balantidia but a low level of fulminant disease among the children (19). The overall prevalence of B. coli was 1.2% (range, 1.0 to 5.3%). More than half of the pigs (n = 50) in the same communities were infected with balantidia, as determined by examination of stool samples. One-third of the children in the survey showed stunted growth as a result of chronic malnutrition. The authors of the study concluded that the children were asymptomatic carriers of balantidia but showed the consequences of long-term infections.
Areas of endemicity are regions where balantidiosis is a present and constant threat. Included among these are the Philippines, parts of Papua New Guinea and West Irian (Irian Jaya) in the western Pacific, and rural areas of South America. As described above, conditions for spread of disease are close contact with pigs and water contaminated by human and porcine feces. Tropical temperatures and high humidity favor survival of excreted Balantidium cysts in pig or human feces. The disease is also in found in highland areas of Papua New Guinea and Irian Jaya, where temperatures are cooler than in the lowlands. Because of the highland temperatures, pigs often seek shelter and warmth in human habitats. Prevalence studies based on surveys carried out in the 1950s and onward have put the numbers at 28%, 20%, 11%, and in more recent times (1970s), 1.7%, in only 3 of a total of 60 villages (53). Other studies found prevalence rates of <1% to 20% among people in the Central Highlands of Papua New Guinea (5). Infections among women were twice as common as those among men because women tend to the pigs.
Balantidiosis is a cosmopolitan disease with potential for developing almost anywhere. The absence of pigs in strict Moslem societies makes human-to-human transmission more likely. Rats may be carriers of Balantidium, but it is not known if the rat Balantidium species can infect humans. The cockroach, which has its own species of Balantidium, may serve as a mechanical agent of transmission from feces to food (67).
Sewage sludge may be another source of infection. Activated sludge, a by-product of sewage treatment, can contain bacterial, protozoan, and metazoan parasites and is a potential threat to health if it is applied as a fertilizer. Such was the case in Bahrain (Arabian Gulf), where sludge was found to contain balantidia (range of 66 to 528 ml−1, with a mean of 234 ml−1). The origin of the balantidia remained uncertain, since neither pigs nor monkeys, both possible sources, are found in the country. The occurrence of the ciliate appeared to have been a one-time event, since ciliates were not found in subsequent sludge samples (2).
The major risk factor for humans is close contact with pigs. This is particularly so in areas of endemicity (e.g., Papua New Guinea), where swine are kept in dirt lots; pig and human feces are scattered indiscriminately, allowing contamination of water sources; and residents may suffer from chronic malnutrition or other predisposing factors, such as parasitic infections. Crowding in dwellings can facilitate the spread of infection. Others at risk are workers in abattoirs where pig intestines are handled. Farmers working with pig feces are at risk of contracting the infection. Given the numbers of simians carrying balantidia, zookeepers are another such group, but at low or containable risk. Likewise, veterinarians and veterinary students working with sick hogs are at risk of infection.
Both residents and workers in asylums, orphanages, and prisons are potential candidates for balantidiosis. A study of four mental institutions in Italy examined the prevalence of parasites in stool samples from 238 residents (24). About 13 different, mostly protozoan parasites, including B. coli, were found in stool samples. B. coli and the more common organism Cryptosporidium parvum were detected in 9.2% of the residents. A study done in the United States found a 5% incidence of B. coli infections at a mental hospital, and this appeared to increase with length of residence (77). Poor hygiene among residents of the mental institution was associated with spread of parasites on hands, tableware, and dishes and with the practices of pica, coprophagy, and geophagy. The conclusion is that hygienic surveillance and antimicrobial therapy are necessary in such facilities to limit the spread of parasites among institutional residents.
Because of their large size and spiraling motility, balantidia can readily be recognized in wet mount slide preparations, even at a low magnification (×100). This is the case with freshly collected diarrheic stool samples, which are likely to contain actively swimming trophic ciliates, as well as bronchoalveolar wash fluid. Stool samples for examination should be collected over several days because excretion of parasites can be erratic. Cyst stages are more common in formed stools. To search for cysts, a portion of formed stool is broken up in phosphate-buffered saline or fixative (10% phosphate-buffered formalin or polyvinyl alcohol) and coarsely filtered through gauze or a sieve to remove large pieces of debris. The resulting fluid can be examined microscopically for cysts in formed stools or for trophozoites in diarrheic stools. A phase-contrast microscope is helpful for viewing internal structures of unstained living or fixed ciliates. Staining can be done using Lugol's iodine (1:5 to 1:100 dilutions), but the stain concentrates progressively in the cytoplasm, obscuring details such as the macronucleus. The same is true for permanent stains, such as hematoxylin-eosin, as cells can take up excess stain, obscuring all internal detail. Heavily stained cysts can be mistaken for helminth ova, leading to misdiagnosis. Biopsy of the colon, if performed, followed by hematoxylin-eosin staining of sections may be useful in evaluating the extent of damage to the wall (Fig. (Fig.4).4). Methods for concentration of parasites from stool samples, making them easier to find, include sedimentation and flotation (21). Since balantidiosis is a rare disease in developed countries, most technicians would not normally be looking for trophozoites or cysts of Balantidium in examining stool samples. Thus, it is particularly important that balantidiosis be considered a possibility for patients from areas of endemicity and travelers returning from such areas. The number of balantidia in a stool sample may be high; 1,230 organisms g−1 feces was reported for the stool of a chimpanzee in Japan (49). A Danish study of pigs at a research farm found an average of 865 cysts g−1 feces from pigs of 28 to >52 weeks of age (31).
Diagnosing lung infections with B. coli can present a problem because of possible confusion between ciliated epithelial cells (CEC) and trophic balantidia. Bronchoalveolar wash fluid containing Balantidium has been reported (3, 58, 70) but may also contain motile CEC from the trachea that can be mistaken for ciliates in wet mounts. CEC have relatively few cilia on their surfaces compared to the uniformly ciliated surfaces of balantidia, and the cilia may be clumped in the case of columnar epithelial cells; CEC are smaller (<30 μm) than balantidia (150 to 200 μm), elongated rather than ovoid, and more likely to swim aimlessly in circles, unlike the pronounced spiraling movements of ciliates (14, 28). The use of a phase-contrast microscope can help to visualize Balantidium features, such as the oral apparatus, uniform somatic ciliation, and the macronucleus. During a search for respiratory syncytial virus in the nasopharynx of an infant, unusual ciliated cells were seen in wet mounts and initially thought to be parasites, most likely B. coli. Subsequent examination after staining showed ciliary distribution along one edge of the cell and identified the cells as ciliocytophthoria, degenerative fragments of epithelial cells (28). CEC can also be confused with other motile pathogens, in this case the flagellate stage of the ameboflagellate Naegleria fowleri in cerebrospinal fluid samples (14).
Most cases of dysentery, regardless of the causal agent, including balantidial, amebic, and bacterial dysenteries, present with similar clinical profiles, including abdominal pain and diarrhea leading to dehydration and bloody stools. Balantidiosis outside areas of endemicity is relatively rare; amebiosis is more likely to be encountered, particularly in travelers from developed countries visiting areas of the world with poor sanitation and contaminated drinking water. A travel history of the patient can be helpful in making a preliminary diagnosis. Bacillary dysentery is a constant and major public health menace in developed and underdeveloped countries, with contaminated water and food and asymptomatic food handlers being involved in disease transmission. Diagnosis is made using differential or selective agars or manual or automated identification systems. Among differential diagnoses of dysenteric diseases are ulcerative colitis, diverticulosis, and inflammatory bowel disease.
The cystic organism E. histolytica, found in formed stools, measures 10 to 20 μm and has a nucleus with a small central endosome and peripheral chromatin connected to the endosome by a delicate fibrillar network. Four nuclei are typical of the mature cyst. RNA-containing club-shaped chromatoid bodies are seen in newly formed cysts but disappear as the cysts age. There may be cysts of other amebae, such as E. dispar and E. coli, both of which are harmless commensals that can be mistaken for E. histolytica, in the stool. Balantidium cysts are larger (40 to 60 μm) than ameba cysts and are binucleate (macro- and micronuclei), and at times the trophic organism can be seen spinning within the cyst wall due to ciliary activity.
The two organisms are found in the trophic state in diarrheic stools. Balantidia in wet mounts are active swimmers with uniform ciliation and a spiraling swimming pattern. Trophic Entamoeba can be seen moving on the slide surface by means of an anterior ectoplasmic pseudopod and is smaller (~25 μm in diameter) than Balantidium. Food vacuoles containing erythrocytes differentiate trophic E. histolytica from other amebae in stools. Both trophic organisms are seen optimally in freshly collected feces that have not been refrigerated or allowed to sit on a laboratory bench for hours.
In developed countries, fecal samples containing balantidia are unusual, and the risk of laboratory infections is very low. No laboratory-acquired infections have ever been reported. Because the cysts pose more of a risk than do trophic ciliates, precautions should be taken in handling formed porcine or human fecal matter that might contain cysts. The numbers of cysts in stool samples may be such that small amounts of material can be highly infective. Cysts may also survive drying on bench tops, instruments, and other laboratory surfaces. Sodium hypochlorite (1%) is an effective disinfectant (55). Procedures that produce aerosols should be avoided. Gloves and a laboratory coat are appropriate protective clothing. Biosafety level 2 precautions are recommended.
The best means of protecting human populations from balantidiosis is by providing a source of clean, uncontaminated water for drinking and other purposes. Chlorine, at the concentrations normally used for ensuring water safety, is not effective against cysts of Balantidium. Pigs should not be allowed to roam in and around feeder streams or rivers that empty into reservoirs that are used for providing municipal water supplies (29). Likewise, spreading of sludge from sewage processing as fertilizer can lead to contamination of produce or water sources with cysts of balantidia (2). Pigs should not have access to areas where crops are being raised. Judging from the occurrence of balantidiosis in immunosuppressed individuals living in urban settings, there are additional sources of infection besides pig-to-human transmission. Raising Balantidium-free pigs is an unrealistic goal. Piglets become infected from their mother or, if not that, through coprophagy.
Tetracyclines and metronidazole are treatments of choice for human Balantidium infection. A number of different dosage regimens and treatment durations exist in the literature (3, 20, 23, 75). For metronidazole (Flagyl), the treatment is typically 5 days (adult dosage, 750 mg three times a day; pediatric dosage, 35 to 50 mg kg of body weight−1 day−1 in three doses [maximum dosage, 2 g]), in contrast to tetracycline (adult dosage, 500 mg four times a day; pediatric dosage, 40 mg kg−1 dose−1 in four doses) treatment over 10 days. Iodoquinol, for a 20-day treatment course (adult dosage, 650 mg three times a day; pediatric dosage, 40 mg kg−1 dose−1 in three doses), and doxycycline are alternatives (3, 58). There is some evidence that nitazoxanide (Alinia), a broad-spectrum antiparasitic and antihelminthic drug, may be another treatment for balantidiosis (52). The reader may wish to consult The Medical Letter on Drugs and Therapeutics, Drugs for Parasitic Infections (46). Dosages given here are from the 2004 edition but are unchanged in the latest edition (2007).
Balantidium coli is a cosmopolitan parasitic-opportunistic pathogen that can be found throughout the world. Its reservoir host is the pig, and humans become infected through direct or indirect contact with pigs. In rural areas and in some developing countries where pig and human fecal matter contaminates the water supply, there is a greater likelihood that balantidiosis may develop in humans. The infection may be subclinical in humans, as it mostly is in pigs, or may develop as a fulminant infection with bloody and mucus-containing diarrhea; this can lead to perforation of the colon. The disease responds to treatment with tetracycline or metronidazole.
Balantidiosis is a disease that need never exist given access to clean water and a public health infrastructure that monitors the water supply and tracks infections. Its spread can be limited by sanitary measures and personal hygiene, but it is a disease that will be around as long as there are pigs. Immunocompromised individuals have developed balantidiosis without any direct contact with pigs, perhaps with rats or contaminated produce as a possible source of infection. For the clinician, balanatidiosis should be included in the differential diagnosis for persistent diarrhea in travelers to or from Southeast Asia, the Western Pacific islands, rural South America, or communities where close contact with domestic swine occurs.
Warming of the earth's surface may provide a more favorable environment, even in the now temperate areas of the world, for survival of trophic and cystic stages of Balantidium, and its prevalence may increase. Effective sanitation and uncontaminated water are the most useful weapons against infection. Fortunately, balantidiosis responds to antimicrobial therapy, and there have been no reports of resistance to the drugs of choice.
We thank Carol Glaser (Viral and Rickettsial Disease Laboratory) for her enthusiastic support of this project. We also thank Blaine Mathison and the CDC-DPDx Parasite Image Library (http://www.dpd.cdc.gov/dpdx/), which was the source of illustrations used in this paper, for parasite identification. F.L.S. is grateful to Govinda S. Visvesvara (Division of Parasitic Diseases, CDC) for informative discussions about Balantidium.
Neither author of this paper has any conflict of interest or financial relationship relevant to the study.