INTRODUCTION — Dientamoeba fragilis is an anaerobic intestinal protozoan parasite. Historically, this organism was among a group of enteric protozoan parasites beginning with Giardia duodenalis (previously G. lamblia) that were initially believed to be solely commensals and not capable of causing symptomatic illness. While G. duodenalis is a recognized cause of symptomatic infections, the pathogenicity of D. fragilis has been controversial. It is now recognized that D. fragilis, although it does not uniformly result in symptomatic disease, may be associated as a potential cause or a co-pathogen contributing to clinical intestinal infections. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis" and "Blastocystis species" and "Nonpathogenic enteric protozoa".)
Contributing to this uncertainty have been the challenges of conventional microscopic fecal examinations to detect labile trophozoite stages of D. fragilis. Extended microscopic methods for fecal exams can increase diagnostic detection of D. fragilis trophozoites by experienced observers [1]. Expertise with these microscopy methods, however, is rarely available and, if lacking in prior studies, may have allowed many infections to go undiagnosed. With the development of molecular nucleic acid amplification test (NAAT) methods to detect nucleic acids from D. fragilis (and other fecal pathogens), there has been an increasing diagnostic detection of D. fragilis in subjects as well as expanding insights into routes contributing to fecal-oral transmission of this parasite. That all subjects infected with D. fragilis may not experience intestinal symptoms has engendered controversies whether D. fragilis is a pathogen or alternatively only a benign commensal parasite [2,3]. For instance, in some studies, detection of D. fragilis in stool has been observed more frequently among asymptomatic individuals than among symptomatic patients [4-6]. With the increasingly prevalent detection of D. fragilis based on sensitive NAAT fecal assays, it has been suggested that this organism may be part of a healthy intestinal microbiome [7].
MICROBIOLOGY — Ultrastructural, immunologic, and genetic analyses place D. fragilis in the family of protozoan flagellates, which includes Trichomonas [2,8]. Unlike other intestinal protozoan organisms that have both trophozoite and hardy cyst stages, for a long time D. fragilis was recognized to exist only as trophozoites. Trophozoites measure 7 to 12 micrometers in diameter, contain one or two nuclei, lack flagellae, and are minimally motile. However, cyst forms of D. fragilis have been identified in experimental mouse infections and in human fecal samples [9], suggesting that cysts may be a transmissible infectious form of this organism.
There is genetic evidence for two variants of D. fragilis (genotypes [1 and 2]). There is a strong predominance of genotype 1 in both humans and some animal hosts [10]. It is unknown if these two genotypes differ in their pathogenicity, although studies have shown very low levels of genetic variability across parasite isolates collected in various geographic areas and from both symptomatic and asymptomatic cases [10].
Although the pathogenicity of D. fragilis has been debated for many years, a study has shown that D. fragilis can cause nontissue invasive inflammatory colitis in mice [11]. While this study supports a primary potential pathogenic role for D. fragilis, it remains unclear whether the pathogen's symptomatic pathogenicity is due to intraluminal environmental and combinatorial interactions amongst co-resident microbes (eg, Blastocystis and Dientamoeba) [12]. Potential symptomatic infections may be due to polymicrobial "co-pathogens" in concert with nominally "commensal" intestinal protozoans, including D. fragilis and Blastocystis. As an example, individuals harboring D. fragilis have alterations in their associated intestinal microbiota [12-15] and mice intestinal bacterial flora can facilitate "commensal" protozoan integration into the gut microbiome depending on dietary intake [16].
TRANSMISSION — As a fecally passed organism, D. fragilis transmission might occur whenever there are breaks in "fecal-oral" hygiene. For instance, in an outbreak of enteric illnesses following an episode of wastewater contamination of drinking water in Finland, D. fragilis was detected by polymerase chase reaction (PCR) in contaminated drinking water [17].
Acquisition of D. fragilis by humans may include transmission from human and animal fecal sources. Applications of sensitive molecular detections of D. fragilis are also increasingly detecting D. fragilis in nonhuman hosts. Sheep, pigs, cattle, and nonhuman primates have been identified as natural hosts of the genotypes found in humans, suggesting zoonotic potential for human transmission [18,19]. Likewise, urban rats studied in Madrid, Spain [20] and pet budgerigars [21] may be local sources of D. fragilis. Another study from the Czech Republic investigating asymptomatic humans and their pets utilized real-time PCR (qPCR) assays of feces and found D. fragilis in 24 percent of 296 human subjects and also in some of their pets, including dogs, rabbits, horses, a cat, and a guinea pig [22].
PATHOGENESIS — Infections with D. fragilis are acquired by the fecal-oral route, but how the fragile trophozoites survive outside of the body and do not succumb to stomach acid following ingestion are not fully understood (figure 1). One hypothesis suggests that trophozoites might survive within and be ingested with the eggs of the pinworm Enterobius vermicularis. D. fragilis DNA has been recovered from pinworm eggs [23,24]. In some studied cohorts, there have been co-associations with D. fragilis and pinworm infections. In a study from Turkey, two-thirds of subjects with fecal studies positive for D. fragilis by microscopy and polymerase chase reaction (PCR) also had positive cellophane tape tests for E. vermicularis [25]. While concomitant pinworm infections might explain coinfection in some children, whether E. vermicularis provides a privileged mode of D. fragilis transmission or whether such commonalities are indicative principally of ongoing breaks in fecal-oral hygiene remains to be ascertained [23,24]. Moreover, a role for pinworms in D. fragilis transmission does not explain most D. fragilis infections. Some studies have specifically failed to find a correlation between D. fragilis and E. vermicularis infections [26].
EPIDEMIOLOGY — D. fragilis is distributed globally but estimates of its prevalence and disease associations are dependent on the diagnostic detection methods applied. Conventional fecal microscopy lacks sensitivity and under detects fecal D. fragilis. The increasing applications of molecular nucleic acid amplification test (NAAT) methodologies for detection of D. fragilis and other organisms are expanding the detection of D. fragilis in both symptomatic and asymptomatic populations. In a Finnish study including refined microscopic criteria and polymerase chain reaction (PCR) testing, D. fragilis was found to be the most common intestinal protozoan [27]. In a study from the Czech Republic of 296 healthy subjects without gastrointestinal symptoms, 24 percent harbored fecal D. fragilis on reverse transcriptase PCR (RT-PCR) analyses [22]. In another study of healthy potential fecal donors for a fecal microbiota transplant program in Amsterdam found that 60 of 148 (40.5 percent) Dutch candidate donors were excluded due to asymptomatic fecal carriage of D. fragilis [28].
In addition to the increasing recognition of D. fragilis as an endemic organism in Europe, D. fragilis has been detected in populations including returned missionaries [29], military groups [30], and immigrants from other countries [31].
While D. fragilis has been identified in patients with traveler's diarrhea [32,33], its role in post-travel gastrointestinal symptoms is not clear. A study from Israel utilized a multiplex PCR fecal assay to detect six intestinal protozoan species in patients with persistent gastrointestinal symptoms both amongst those with and without a history of travel [34]. In those with a travel history, 18.7 percent were positive for D. fragilis, while in those without a travel history, 19.6 percent were positive for D. fragilis.
CLINICAL MANIFESTATIONS — The clinical presentation with D. fragilis is variable. Many individuals with D. fragilis are asymptomatic; the most common symptomatic presentation consists of gastrointestinal illnesses. The incubation period prior to the onset of symptoms following infection is unknown, as is the proportion of infected people who remain asymptomatic.
In one systematic review of individuals with D. fragilis in stool, 6 to 86 percent had diarrhea [3]. In 11 studies of stool samples submitted to laboratories, 4 percent of individuals had D. fragilis, of whom 54 percent had diarrhea.
The parasite localizes in the colon and can cause colitis [35]. Common complaints in those who are symptomatic include abdominal pain, flatulence, acute and recurrent diarrhea, or loose stools [2,26,35-40]. In one review, most patients presented with diarrhea and abdominal pain, frequently lasting longer than a duration of two weeks [41]. In one study of Turkish patients infected with D. fragilis, symptoms included [36]:
●Abdominal pain (81 percent)
●Diarrhea (72 percent)
●Anorexia (16 percent)
●Fatigue (9 percent)
●Nausea (6 percent)
●Weight loss (3 percent)
●Vomiting (3 percent)
In another study, patients with D. fragilis experienced abdominal pain (28 percent), anal itching (27 percent), watery diarrhea (19 percent), meteorism (16 percent), and nausea/loss of appetite (14 percent) [42]. Abdominal pain and diarrhea presumed to be attributable to D. fragilis infections may persist for several years [2,26,36,38,39,43]. D. fragilis infection may be observed in some patients fulfilling criteria for irritable bowel syndrome (IBS) [44], although one meta-analysis found no significant association [45]. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults".)
Children are susceptible to infection with D. fragilis, but clinical symptoms vary. For instance, a study of asymptomatic children in Brazil utilizing sensitive fecal polymerase chain reaction (PCR) analyses found 10.3 percent (16 of 156) harbored D. fragilis [46].Children also may present with clinical symptoms (especially diarrhea and abdominal pain) more frequently than adults; they may also have prolonged infection [47,48]. Peripheral blood eosinophilia may accompany D. fragilis infections [31,35,39,42,49,50], and an eosinophil-enriched colitis due to D. fragilis infection may be mistaken for allergic colitis [35]. Neither the mechanism of the eosinophilia nor any pathophysiologic sequelae of the eosinophilia are known. The presence of eosinophilia in this infection is in striking contrast with diseases caused by other intestinal protozoa, with the exception of Isospora belli infections. (See "Epidemiology, clinical manifestations, and diagnosis of Cystoisospora (Isospora) infections" and "Approach to the patient with unexplained eosinophilia".)
DIAGNOSIS — Conventional and real-time polymerase chain reaction (PCR) have significantly higher sensitivity and specificity than microscopy [2,51-57]. Multiplex PCR-based assays have been developed and are being increasingly used to concurrently detect D. fragilis as well as Blastocystis, Cryptosporidium, Giardia, Entamoeba, and other pathogens in human stool samples [50,58,59]. There are no available D. fragilis immunofluorescent or antigen assays.
The increased use of nucleic acid detection techniques has helped increase detection of D. fragilis compared with microscopy. A study from rural Venezuela noted a 40 percent prevalence of D. fragilis with use of combined microscopy-PCR compared with 16 percent for microscopy alone [56].
In many areas, microscopy remains the diagnostic test of choice due to lack of widely available alternatives. Microscopy detects trophozoites in microscopic examinations of fixed and stained stool samples [2]. Trophozoites are fragile and are not detectable on wet mounts, iodine-stained samples, or formalin-ethyl acetate concentrates [36]. Thus, fixation of stool samples in polyvinyl alcohol fixative, sodium acetate-acetic acid-formalin fixative, or Schaudinn's fixative is necessary, as is the use of permanent trichrome staining [40,60]. Giemsa-stained stool smears may also be helpful in detecting D. fragilis [47]. Many diagnostic laboratories lack the requisite procedures to detect D. fragilis, since trophozoites deteriorate rapidly and can therefore be missed by microscopy unless there is prompt fixation of the specimen [60,61]. In a report from Ottawa, Canada, 91 percent of healthy children had detectable serum antibodies to D. fragilis, suggesting that mild or subclinical infections were common during childhood (though cross-reactivity is possible) [62].
DIFFERENTIAL DIAGNOSIS
●Gastrointestinal symptoms – Other protozoal parasites including giardiasis and Blastocystis can cause similar symptoms of abdominal pain, diarrhea, and anorexia. These are distinguished from D. fragilis via stool microscopy, immunoassay, or polymerase chain reaction. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis" and "Blastocystis species".)
●Gastrointestinal symptoms and eosinophilia – Other causes of gastrointestinal symptoms and eosinophilia include isosporiasis, strongyloidiasis, ascariasis, and hookworm. Coinfection can occur; the diagnoses are distinguished by stool microscopy. (See "Strongyloidiasis" and "Ascariasis" and "Hookworm infection".)
●Irritable bowel syndrome – Clinical manifestations of irritable bowel syndrome include chronic abdominal pain and altered bowel habits, including diarrhea or constipation. The diagnosis is established based on clinical criteria. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults".)
TREATMENT
Clinical approach — While identification of D. fragilis in an asymptomatic individual requires no treatment, infections with D. fragilis should be treated when the organism is found as a sole potential pathogen in stool samples from patients with abdominal pain or diarrhea lasting for more than one week.
No large-scale randomized controlled trials have been performed to assess the effect of various antimicrobial agents in patients infected with D. fragilis [63]. Moreover, the increasing applications of nucleic acid amplification test (NAAT) polymerase chain reaction (PCR)-based diagnostic fecal testing for D. fragilis are revealing that therapies often fail to eradicate fecal excretion of the organism. There are several regimens that may be used to treat symptomatic D. fragilis infections, including [39,48,64,65]:
●Paromomycin (25 to 35 mg/kg per day in three divided doses for seven days)
●Metronidazole (500 to 750 mg three times a day for 10 days)
●Tetracycline (500 mg [10 mg/kg] orally four times daily for 10 days) or doxycycline (100 mg [2 mg/kg] orally twice daily for 10 days)
In a study evaluating the in vitro susceptibility of D. fragilis to several antiparasitic agents, 5-nitroimidazole derivatives were found to be the most active compounds (including ornidazole, tinidazole, metronidazole, and secnidazole), followed by nitazoxanide, tetracyclines, furazolidone, paromomycin, and diloxanide furoate [66]. Benzimidazoles (albendazole, mebendazole) have no activity in vitro against D. fragilis [67].
A randomized, double-blinded study in Denmark evaluated 96 children with D. fragilis infection and chronic gastrointestinal symptoms (abdominal pain and/or diarrhea lasting greater than four weeks) treated with a 10-day course of either metronidazole or placebo [68]. Metronidazole did not significantly reduce gastrointestinal symptoms compared to placebo. Eradication of D. fragilis was significantly greater in the metronidazole group as assessed by PCR 14 days after completion of therapy, although PCR positivity rebounded by eight weeks after completion of therapy to levels comparable with those seen in placebo recipients [68]. Since the role of D. fragilis as the sole etiologic agent of the chronic gastrointestinal disease in these children remained uncertain, it is unclear whether the failure of metronidazole to lead to clinical improvement indicates its lack of efficacy against D. fragilis.
For colonic infections, paromomycin, a nonabsorbable aminoglycoside has higher intra-colonic concentrations than oral metronidazole that is well taken up in the proximal gastrointestinal tract to act systemically. Data suggest paromomycin is efficacious despite relatively weak in vitro susceptibility data as well as a lack of randomized controlled trial data [41,69]. One retrospective study utilizing fecal microscopy reported eradication rates of 98 percent for paromomycin versus 57 percent for metronidazole and 41 percent for no treatment [70]. In one study from Italy including 85 patients, the rate of clinical improvement was higher among those treated with paromomycin compared with metronidazole (100 versus 53 percent) [42].
Other agents — In addition to metronidazole, other nitroimidazole agents with potential efficacy include secnidazole, ornidazole, and tinidazole.
Secnidazole was evaluated in a study of 35 Turkish patients with D. fragilis infection; in all but one patient, the organism was eradicated, as judged by fecal microscopy, with a single dose of secnidazole, suggesting that secnidazole is effective in achieving parasitological and clinical cure [36].
Ornidazole (30 mg/kg single dose for children and 2 g single dose for adults) was superior to metronidazole in a randomized trial of 112 Turkish patients with respect to parasitologic cure (92.9 versus 69.6 percent, p = 0.001) and clinical cure (96.4 versus 76.8 percent, p = 0.001) [71].
Tinidazole (2 g single dose) is more widely available than the above agents and is better tolerated than metronidazole; use of this agent is reasonable although data are limited. It may be effective in combination with paromomycin or other agents; further study is needed [41,69].
PREVENTION — Since the mechanism of transmission of fecally derived D. fragilis is not fully understood, there are no specific guidelines on measures to prevent acquisition of infection with this organism. Screening of household members of D. fragilis patients has been suggested [49,72], especially in cases of relapsed infection. (See 'Transmission' above.)
SUMMARY AND RECOMMENDATIONS
●Microbiology – Dientamoeba fragilis is an anaerobic intestinal protozoan parasite. It is a flagellate that produces trophozoites as well as cysts. Infection may be symptomatic or asymptomatic. (See 'Introduction' above and 'Microbiology' above.)
●Epidemiology – Infection is transmitted by the fecal-oral route. D. fragilis is distributed globally. Since many diagnostic laboratories lack the requisite procedures for detection, the prevalence is probably underestimated. (See 'Transmission' above and 'Epidemiology' above.)
●Clinical manifestations – The incubation period and proportion of asymptomatic infected individuals are unknown. The parasite localizes in the colon and can cause colitis. Common symptoms include abdominal pain and acute and recurrent diarrhea. D. fragilis may present with peripheral eosinophilia and/or eosinophilic colitis. (See 'Clinical manifestations' above.)
●Diagnosis – The diagnosis is made via detection of D. fragilis trophozoites in microscopic examinations of appropriately fixed and stained stool samples or by polymerase chain reaction (PCR)–based nucleic acid amplification test (NAAT) techniques and real-time PCR have significantly higher sensitivity and specificity than microscopy. (See 'Diagnosis' above.)
●Treatment – Treatment is warranted when the organism is found as a sole potential pathogen in stool samples in the setting of abdominal pain or diarrhea lasting more than one week. The optimal therapy is uncertain; we suggest treatment with metronidazole or paromomycin (Grade 2C). (See 'Treatment' above.)
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