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A review of the global burden, new diagnostics and current therapeutics for amebiasis

A review of the global burden, new diagnostics and current therapeutics for amebiasis 1 2 3 2 Debbie-Ann T. Shirley , Laura Farr , Koji Watanabe and Shannon Moonah Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA Department of Medicine, University of Virginia School of Medicine Charlottesville, VA, USA AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan Keywords: amebiasis, diarrhea, colitis, burden, PCR, HIV, MSM Corresponding author contact information: Shannon Moonah, MD, ScM Division of Infectious Diseases Department of Medicine University of Virginia Health System 345 Crispell Drive, MR-6 1st floor, Room 1709 Charlottesville, VA 22908 sm5fe@virginia.edu 434-924-8189 (phone) © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Alternate author contact information: Debbie-Ann Shirley, MD, MPH Division of Pediatric Infectious Diseases Department of Pediatrics University of Virginia P.O. Box 800386 Charlottesville, VA 22908 ds3ru@virginia.edu 434-924-9141 (phone) 434-982-4246 (fax) Author Contributions: SM and DAS developed the concept and design of the project. DAS prepared the first draft of the manuscript. SM, LF, KW, and DAS revised the manuscript. Summary: Amebiasis remains an important cause of diarrhea worldwide. Here we review the most recent data regarding the global burden, diagnosis, treatment and prevention of amebiasis. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Abstract Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea globally. Largely an infection of impoverished communities in developing countries, amebiasis has emerged as an important infection among returning travelers, immigrants, and men who have sex with men residing in developed countries. Severe cases can be associated with high case fatality. PCR-based diagnosis is increasingly available but remains underutilized. Nitroimidazoles are currently recommended for treatment, but new drug development to treat parasitic agents is a high priority. Amebiasis should be considered prior to corticosteroid therapy to decrease complications. There is no effective vaccine, so prevention focuses on sanitation and access to clean water. Further understanding of parasite biology and pathogenesis will advance future targeted therapeutic and preventative strategies. Abbreviations EhMIF: Entamoeba histolytica macrophage migration inhibitory factor GEMS: Global Enteric Multi-Center Study HIV: Human immunodeficiency virus IBD: Inflammatory bowel disease NIAID: National Institute of Allergy and Infectious Diseases NIH: National Institutes of Health MMPs: matrix metalloproteinases MSM: Men who have sex with men PCR: polymerase chain reaction Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Introduction Amebiasis is caused by infection with the pseudopod-forming, non-flagellated protozoan parasite Entamoeba histolytica. Amebiasis can be asymptomatic or can lead to the development of severe infection with amebic colitis and amebic liver abscess. The significance of amebiasis is exemplified in several ways. Amebic colitis is a leading cause of severe diarrhea worldwide and is listed among the top 15 causes of diarrhea in the first two years of life in children living in the developing world, where diarrhea remains the third leading cause of death, accounting for 1-3 9% of all deaths in children under the age of 5 years. Fulminant amebic colitis is an uncommon complication of amebiasis, but associated with high mortality, and on average more than 50% die with severe colitis. E. histolytica is classified as a category B priority biodefense pathogen by the National Institute of Allergy and Infectious Diseases (NIAID) because of its low infectious dose, chlorine resistance and environmental stability, properties which can pose a threat of easy dissemination through contamination of food and water supplies. Even in low incidence settings, these properties of the parasite lend to outbreaks among military and 5-7 general populations. In addition, E. histolytica is one of the most common causes of infectious diarrhea among travelers returning from endemic areas. Advances in molecular diagnostic methodologies have improved our understanding and led to the recognition and separation of E. histolytica from non-pathogenic species of Entamoeba. Of the many Entamoeba species that infect humans, three species are morphologically indistinguishable from E. histolytica. Of these three, E. moshkovskii may cause diarrhea, while E. dispar and the newly described E. bangladeshi are considered non-pathogenic. Earlier descriptions of amebiasis relying solely on microscopy may have been obscured by these non- pathogenic strains. There is no vaccine to prevent amebiasis. Nitroimidazoles are the mainstay treatment for invasive amebiasis. Given the toxicity that can be associated with this class and potential concerns for development of resistance, as has already been reported for some Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript anaerobic pathogens, new therapies are needed. In addition, the NIAID has set priorities for drug development for treatment of category B pathogens. For these many reasons, improved understanding of amebiasis pathogenesis is needed as a way forward towards enhanced treatment and prevention. This report reviews recent literature expanding our knowledge of the epidemiology, clinical presentation and management of amebiasis, while providing important new insights into the diagnostic evaluation and prevention. Epidemiology Global burden The global significance of amebiasis is wide spread, with the highest burden of amebiasis borne by those residing in developing countries particularly of the tropics and subtropics, when there is inadequate hygiene and access to sanitation. Millions of people are infected with E. histolytica making amebic colitis a leading cause of diarrhea, estimated to kill more than 55, 000 people each year. Amebiasis is endemic in developing parts of Central and South America, Africa and Asia. In the United States, the incidence of amebiasis is low, though amebiasis-related deaths still routinely occur, accounting for at least five deaths per year. Amebiasis in the US is seen mostly in returning travelers or immigrants from endemic countries. Data from the GeoSentinel Surveillance Network, a large international surveillance and monitoring system, has shown that E. histolytica is the third most frequently isolated pathogen among returning travelers with infectious gastrointestinal disease. Amebiasis accounts for 12.5% of all microbiologically confirmed cases, with an estimated rate of affecting 14 in every 1000 returned travelers. Travelers to South Asia, the Middle East and South America appear to have the highest risk, in particular those volunteering as missionary workers or other volunteering work. Even travel of household or sexual contacts to an endemic area may pose a risk of infection. Other industrialized countries including parts of Asia, Europe, North America and Australia have Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript highlighted gay, bisexual and other men who have sex with men (MSM) as a population at higher risk of acquiring amebiasis than the general population. Recent reports from Taiwan and 14,15 Japan, for example, have shown high rates of invasive amebiasis in HIV-infected MSM. In developing countries, the exact burden of amebiasis is difficult to quantify and reports can be affected by geographic region, study design, sample size, incubation, symptom severity and the sensitivity of diagnostic modality used (Table 1). In addition, diagnostic capacities and surveillance are often limited in areas where E. histolytica is endemic. Recent reports however, show that the seroprevalence of E. histolytica in some rural communities of Mexico remains as high as 42%. In an urban slum of Dhaka, Bangladesh, 11% of children had an episode of amebic diarrhea in the first year of life. By cross-sectional survey, E. histolytica was detected using PCR in 13.7% of fecal samples in Northeast states of India. E. histolytica seropositivity was found to be 11% among seven provinces of China, and was as high as 41% among MSM 19,20 in the two provinces of Beijing and Tianjin. A re-emergence of E. histolytica infection was described in Jeddah, Saudi Arabia among children under the age of 16 years presenting to hospital with acute gastroenteritis. Using fecal antigen detection, E. histolytica was found to be the most prevalent enteropathogen associated with diarrhea, with a prevalence of 20%. The epidemiology on incidence and prevalence of amebiasis in Africa is particularly limited, but appears widespread, as exemplified in a cross-sectional study of patients attending gastroenterology clinics in South Africa where E. histolytica was detected by PCR in 8.5% of fecal samples. In the large Global Enteric Multi-Center Study (GEMS), E. histolytica was one of the top ten causative agents of moderate-to-severe diarrhea in children under the age of five years in two of their seven study sites across sub-Saharan Africa and South Asia. In addition, E. histolytica diarrhea was associated with a relatively greater risk of death across all GEMS sites and was the enteric pathogen with the highest hazard ratio for death in the second year of life. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Recent re-analysis of specimens from GEMS, to reassess estimates of pathogen-specific diarrhea exclusively using PCR diagnostics, showed that E. histolytica was one of the top seven pathogens causing dysentery, with the most frequent cause of dysentery led by the combined group of Shigella species and enteroinvasive Escherichia coli. In summary, the global impact of amebic infection remains significant, though challenging to quantify with precision given several methodologic and epidemiologic complexities, but prevalence estimates remain as high as 40% in some populations (Table 1). Transmission The life cycle of E. histolytica is simple, with only two stages, existing as either an infectious cyst or invasive trophozoite (Figure 1). Transmission occurs after the ingestion of the infectious cyst. This most commonly arises from fecally contaminated hands, food or water, but there is a new appreciation that exposure to fecal matter may occur during sexual contact, in particular among MSM groups. Following ingestion, excystation to trophozoites occurs, and the released trophozoites migrate to the large intestine, multiplying by binary fission to produce more cysts. The trophozoite may invade the intestinal epithelium and even pass to extra-intestinal sites such as the liver via the hepatic portal circulation or disseminate further to distant sites such as the brain and lungs hematogenously. Symptoms may occur within weeks after ingestion but may also develop years after infection. Cysts and trophozoites are passed in stools. Several properties of the cyst help it to remain hardy in the environment for weeks at a time, while trophozoites do not survive. For example, cysts are resistant to gastric acidity and are also relatively resistant to chlorine. The low 5,6 infectious dose and environmental stability can predispose to the development of outbreaks. Cysts can be killed by boiling. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Pathogenesis E. histolytica pathogenesis can be characterized by three events: host cell death, inflammation and parasite invasion. Contact with host cells is required for parasite-induced death. Adherence is mediated through the parasite Gal/GalNAc lectin adhesion molecule. Trophozoites are able to kill host cells by several different mechanisms, which include inducing programmed cell death, phagocytosis, and trogocytosis. E. histolytica causes inflammation of the colon, termed amebic colitis. The intestinal epithelium is the point of first contact for E. histolytica. Prior to cell adherence, trophozoites secrete immune modulators that stimulate epithelial cells resulting in cytokine production and 26,27 subsequent mucosal inflammatory cell infiltration. E. histolytica, like several pathogenic protozoa, secretes a protein homolog of the proinflammatory cytokine macrophage migration inhibitory factor (EhMIF). A positive correlation was recently found between EhMIF levels and intestinal inflammation in persons with amebic colitis. It would seem counterintuitive for parasites to produce such a molecule like EhMIF, however E. histolytica has developed a number of mechanisms to evade the immune response and persist in the host. Also, E. histolytica exploits the inflammatory response to promote its own invasion. EhMIF-induced inflammation results in increased production in matrix metalloproteinases (MMPs). MMPs break down the extracellular matrix in the gut to promote cell migration, and 29,30 are overexpressed in all infections with protozoan parasites, including amebiasis. In a recent study, MMPs were shown to be necessary for E. histolytica tissue invasion. It appears that EhMIF is a parasite virulence factor that triggers inflammation, resulting in increased expression of MMPs which promotes invasion of the host. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Immune Response Various host immune mechanisms are elicited in response to amebiasis in an attempt to clear or prevent infection. Interferon gamma (IFN-Ɣ) appears to provide protection from amebiasis, as children with higher IFN-Ɣ had a significantly lower incidence of future E. histolytica diarrhea. Also, protection from amebiasis includes acquired immunity from antibodies against amebic antigens Gal/GalNAc lectin and EhMIF. Infected children develop antibodies against EhMIF, 28,33 which are associated with protection from reinfection. Although the immune response is normally protective, it can also produce undesirable effects when the response is excessive. For example, higher TNF-α production was shown to correlate with E. histolytica diarrhea in children. Another cytokine produced during infection is Interleukin-8 (IL-8), a potent neutrophil chemoattractant. In response to IL-8, neutrophils infiltrate the intestinal tract as the first cells of 27,30 an innate immune response to amebic invasion. Patients with severe amebic colitis have higher colonic tissue levels of IL-8 and neutrophils, suggesting that neutrophils might be 34-36 responsible for collateral tissue damage during inflammation at the site of invasion. Clinical Manifestations The majority of E. histolytica infections are asymptomatic, only about 10-20 % progress to develop symptomatic infection. The reasons for this are poorly understood but result from an interplay of several factors related to parasite, host and environment. Recently, it was found that the gut microbiome is enriched in Prevotella copri in people with amebic diarrhea indicating that dysbiosis may in part contribute to susceptibility to the development of colitis. Intraluminal amebiasis. Asymptomatic infection is referred to as luminal amebiasis. Screening for asymptomatic infection should be considered in those with a personal history of travel to/ immigration from an endemic area or a history of this in either a household or sexual contact. A Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript gender difference in amebiasis is not seen in children, but interestingly, in the adult population, invasive disease is more common in males than females, particularly for amebic liver abscess. Amebic colitis. Symptomatic intestinal infection can have a wide spectrum of manifestations (Table 2). Diarrhea is the hallmark of amebic colitis, which may be watery, or bloody and present with abdominal cramps, pain/ tenderness and weight loss. Presentation may be acute or more gradual, and amebic colitis may also present similarly to inflammatory bowel disease (IBD). It may not be possible to distinguish amebic colitis from IBD even by imaging, inflammatory markers or endoscopy, and the colon may appear friable, with diffuse ulceration by gross examination (Figure 1). Disease may be limited to the ascending colon or cecum. Life- threatening manifestations of amebic colitis include fulminant infection, which can result in massive areas of colonic involvement with perforation and peritonitis, bowel necrosis or toxic megacolon. Corticosteroid use has been described as a risk factor for the development of fulminant forms of amebic colitis. Patients may be toxic in appearance, febrile, hypotensive, with profuse bloody diarrhea, abdominal pain, distension and signs of peritonism. Case fatality of fulminant amebic colitis ranges from 40-89%. Toxic megacolon has been described in a patient with amebic colitis and heavy use of the anti-motility agent, loperamide Other implicated risk factors for fulminant disease include diabetes mellitus, alcoholism, malignancy/ chemotherapy, and pregnancy. Amebic colitis may also present as acute appendicitis (Figure 2). Appendicitis was noted in up to 15% of Japanese HIV-infected patients presenting with appendicitis and undergoing appendectomy. The only distinguishing features was a higher median neutrophil count in those with amebic infection, compared to those without in this series. Ameboma, the development of tumor like granulation tissue in the colonic lumen, can mimic colonic cancer. The differential diagnosis of amebic colitis includes bacterial enteric infection, such as Salmonella spp., Shigella spp., Campylobacter spp., enterohemorrhagic E. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript coli, enteroinvasive E. coli, Clostridium difficile infection, IBD and other non-infectious causes of colitis. The aid of stool PCR and culture can help to distinguish several of these differentials. Disseminated amebic disease. Amebic liver abscess, which is the most common extra-intestinal manifestation develops when trophozoites disseminate to the liver. For poorly understood reasons, amebic liver abscesses are 10 times more common in men than women, often presenting between the ages of 20 and 40 years. Onset can be acute, subacute or subtle. Hepatic amebiasis has been reported over 20 years after the last visit to an endemic area, so any travel history may be important in this diagnosis. The majority will present with fever, and right upper quadrant pain, typically without concurrent dysentery or gastrointestinal symptoms (Table 2). Hepatomegaly with point tenderness over the liver can often be detected. Cough and respiratory symptoms, including pleuritic right sided chest pain may occur or even referred pain to the shoulder. Elevated alkaline phosphatase and peripheral leukocytosis, usually in the range of 12,000- 20,000/ mm is seen, though usually without eosinophilia. Imaging more often reveals right lobe lesions, usually solitary, but left lobe or multiple lesions may be less commonly seen (Table 2). Amebic liver abscess may be difficult to clinically distinguish from pyogenic liver abscess. Echinococcal cysts of the liver are another important differential, but tend to appear as multiple clustered fluid collections without surrounding enhancement on imaging. Peripheral eosinophilia is rare with amebic liver abscess, and is more commonly associated with echinococcosis and hepatic fascioliasis (liver fluke). Detection of bacteremia by blood culture, stool studies and serology will also help to narrow the differential. Occasionally, diagnostic or therapeutic aspiration is required. Aspiration of the amebic liver abscess reveals “anchovy paste” chocolate colored fluid consisting of necrotic hepatocytes. Pleuropulmonary amebiasis can occur as a complication of ruptured amebic liver abscess, presenting with pneumonitis or lung abscess. Intraperitoneal rupture is rare but can be life- Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript threatening if there is pericardial involvement. Trophozoites may also on occasion disseminate hematogenously to the central nervous system and other extra-intestinal sites. Laboratory Diagnosis A number of diagnostic modalities are available to assist with diagnosis, including microscopy, antigen detection, molecular tests, and serology (Table 3). Often a combination of tests is required to establish diagnosis. Traditionally, microscopy has been the most widely used, but has limited diagnostic utility and is no longer recommended as a reliable way to diagnose amebiasis. Most cases of extra-intestinal abscess occur without concurrent intestinal infection, resulting in lower sensitivity of stool studies for the diagnosis of amebic liver abscess. Stool microscopy. Cysts and trophozoites can be visualized by an experienced eye, sometimes with evidence of hemophagocytosis. Fresh stools increase the recovery of both trophozoites and cysts and can be prepared as either wet mounts or stained preparations. Mature cysts have 4 nuclei measuring about 12-15 µm in diameter. Trophozoites have a single nucleus and are slightly larger measuring about 15-20 µm. Microscopy should not be used when other modalities are accessible. Stool antigen detection. Antigen detection tests have helped to overcome some of the limitations of stool microscopy, and are easy to use, but in practice have variable sensitivity and specificity, particularly in low endemic areas. While several EIA kits are commercially available, they are not as widely available in resource-limited settings. The Techlab E. histolytica II test (Blacksburg, VA, USA) which detects E. histolytica-derived Gal/GalNAc- specific lectin, can exclude non-pathogenic E. dispar, as can the Cellabs CELISA Path (Brookvale, Australia). A false-negative EIA test was reported from Spain, possibly from interference, as the result turned positive with subsequent testing. Recently, an E. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript HISTOLYTICA QUIK CHEK immunochromatographic (IC) assay which is simple to perform, with a quick turnaround time was approved by the US Food and Drug Administration (FDA). Stool molecular studies. Stool PCR is extremely sensitive. It is considered the gold standard for diagnosis of amebiasis and is becoming readily available through FDA-cleared gastrointestinal panels which simultaneously detect multiple enteropathogens, such as the BD Max Enteric TM Parasite Panel (Becton, Dickinson and Company, USA), the Luminex xTAG Gastrointestinal Pathogen Panel® (Luminex Corporation, Toronto, Canada) and the Biofire FilmArray Gastrointestinal Panel® (BioFire Diagnostics, Salt Lake City, UT). The use of PCR is also endorsed by the World Health Organization, but the expense and requirement for technical expertise may limit use in resource-limited settings. Purulent fluid aspirated from liver abscess can also be tested. Serology. Serology is a useful adjunct to stool studies. Several EIA kits for antibody detection are commercially available, including indirect fluorescence, immunoelectrophoresis and immunosorbent assays, but the indirect hemagglutination test has been replaced by EIA. Antibody detection is particularly helpful in the diagnosis of extra-intestinal disease, when stool studies may be negative. False-positive results have been reported. Antibodies remain detectable for years after successful treatment, so cannot reliably distinguish between active and past infection. Other diagnostic methods. Amebic ulcers most often develop in the cecum. Histology obtained by diagnostic endoscopic biopsy or surgical resection may show the characteristic flask-shaped ulcer (Figure 1). Trophozoites may be identified at the edge of the ulcer or within the tissue, using periodic acid-Schiff staining or immunoperoxidase staining with specific anti-E. histolytica antibodies (Figure 2). Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Imaging. Ultrasonography, abdominal computed tomography and magnetic resonance imaging are all good modalities to detect liver abscess. By ultrasound, a cystic intrahepatic hypoechoic lesion can be found. By CT an abscess with non-enhancing center, surrounded by a rim of inflammation can be seen following contrast administration. The detection of a space-occupying lesion in the liver and positive amebic serology supports the diagnosis of amebic liver abscess. Therapy All patients with amebiasis should be treated (Table 4). Patients with clinical disease require treatment with two drugs: an amebicidal tissue-active agent as well as a luminal cysticidal agent. Those with asymptomatic amebiasis need only be treated with a luminal cysticidal agent to prevent invasion and transmission. The amebicidal agents include metronidazole and tinidazole, which are both nitroimidazole agents. They are highly effective at eliminating invading trophozoites and remain the recommended therapy for amebic colitis and amebic liver disease. Tinidazole has a longer half- life and is better tolerated, but metronidazole is as effective at clearing parasites. Side effects of metronidazole include nausea, headache, anorexia, metallic taste, peripheral neuropathy and disulfiram-like reaction with alcohol. The nitroimidazoles do not effectively eradicate luminal cysts and must be followed by a luminal agent. The thiazolide agent, nitazoxanide, with reputed broad spectrum antimicrobial properties, was shown in a small, single center trial from Egypt to have clinical and microbiologic response in patients treated for hepatic and intestinal amebiasis of over 90%. However, the unexpectedly high response rate in the placebo group of 40-50% raises methodologic concerns. The aminoglycoside paromomycin, is a luminal cysticidal agent. As it may cause diarrhea, paromomycin should not be administered at the same time as the nitroimidazole agent. Diloxanide and iodoquinol are alternatives, but neither are available in the US. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Patients with fulminant amebic colitis will additionally require fluid resuscitation, broad spectrum antimicrobial therapy for peritonitis, intensive supportive care and surgical intervention for bowel perforation and bowel necrosis. Occasionally colectomy has been necessitated by the development of toxic megacolon or extensive bowel necrosis. In patients who are unable to tolerate or absorb oral metronidazole, then intravenous metronidazole should be used. Drainage of liver abscess, either by image-guided or open aspiration, may occasionally be required in addition to anti-parasitic therapy. Drainage is typically reserved for those who do not show prompt clinical response to anti-parasitic therapy by about 72 hours; or those at high risk for impending abscess rupture, typically defined as a cavity with diameter > 5-10 cm or by left lobe abscess which could rupture into the pericardium. Serial imaging may show that it takes months following appropriate therapy for the abscess cavity to resolve. Auranofin, a gold compound that has been used to treat selective cases of rheumatoid arthritis has entered into early clinical drug development as an anti-parasitic agent, but further study is needed to determine if it will be effective treatment of amebiasis and whether known safety concerns such as diarrhea, rash and bone marrow suppression will limit its use. Prevention There is no vaccine to prevent amebiasis. The focus of primary preventative efforts, therefore, remains food and water safety, attention to hand hygiene and avoidance of fecal-oral exposure, including through sexual practices. Prior to travel to endemic areas such as Asia, Mexico, South America and sub-Saharan Africa, patients should be advised on food safety to prevent enteric illness. Patients, especially MSM, should also be advised to avoid sexual practices that may lead to fecal-oral transmission. Patients should be asked about prior travel and screened appropriately for secondary prevention. Even a remote travel history is important, as amebic liver abscess and fulminant amebic colitis could occur years after travel. Household contacts of Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript patients with amebiasis should be screened, as amebiasis may spread among family and household contact. Patients with a new diagnosis of IBD that have traveled to an endemic area should be screened as well, as fulminant amebic colitis may ensue if patients are administered corticosteroid or other immunosuppressive therapy with misdiagnosis. Use of loperamide should be avoided in amebic colitis. Conclusion Amebiasis remains one of the most significant enteropathogens worldwide. Advances in molecular epidemiology and pathogenesis have advanced our understanding of this parasite, however many gaps in knowledge remain. In addition, while efforts are ongoing, there is no vaccine and only a single effective drug class. Prevention remains challenging, highlighting the need for improved awareness of this infection as well as novel therapeutic and preventative strategies. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Funding This work was supported by the National Institutes of Health (NIH) R01AI026649-S1, K08AI119181, and the Robert Wood Johnson Foundation–Harold Amos Medical Faculty Development Program Award (to SM). Emerging Infectious Diseases Project of Japan from the Japan Agency for Medical Research and Development (AMED), and the Grant for National Center for Global Health and Medicine (29-2013) (to KW). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Acknowledgements We acknowledge Dr. William A. Petri, Jr. for helpful advice. We apologize to all colleagues we were unable to cite due to space limitations. 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Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 15. Watanabe K, Gatanaga H, Escueta-de Cadiz A, Tanuma J, Nozaki T, Oka S. Amebiasis in HIV-1-infected Japanese men: Clinical features and response to therapy. PLoS Negl Trop Dis. 2011;5(9):e1318. doi: 10.1371/journal.pntd.0001318 [doi]. 16. Alvarado-Esquivel C, Hernandez-Tinoco J, Sanchez-Anguiano LF. Seroepidemiology of Entamoeba histolytica infection in general population in rural Durango, Mexico. J Clin Med Res. 2015;7(6):435-439. doi: 10.14740/jocmr2131w [doi]. 17. Mondal D, Minak J, Alam M, et al. Contribution of enteric infection, altered intestinal barrier function, and maternal malnutrition to infant malnutrition in Bangladesh. Clin Infect Dis. 2012;54(2):185-192. doi: 10.1093/cid/cir807 [doi]. 18. Nath J, Ghosh SK, Singha B, Paul J. 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Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 29. Geurts N, Opdenakker G, Van den Steen PE. Matrix metalloproteinases as therapeutic targets in protozoan parasitic infections. Pharmacol Ther. 2012;133(3):257-279. doi: 10.1016/j.pharmthera.2011.11.008 [doi]. 30. Peterson KM, Guo X, Elkahloun AG, et al. The expression of REG 1A and REG 1B is increased during acute amebic colitis. Parasitol Int. 2011;60(3):296-300. doi: 10.1016/j.parint.2011.04.005 [doi]. 31. Thibeaux R, Ave P, Bernier M, et al. The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue. Nat Commun. 2014;5:5142. doi: 10.1038/ncomms6142 [doi]. 32. Haque R, Mondal D, Shu J, et al. Correlation of interferon-gamma production by peripheral blood mononuclear cells with childhood malnutrition and susceptibility to amebiasis. 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Polymorphonuclear neutrophil infiltration intensity as consequence of Entamoeba histolytica density in amebic colitis. Surg Infect (Larchmt). 2009;10(2):91-97. doi: 10.1089/sur.2008.011 [doi]. 37. McGregor A, Brown M, Thway K, Wright SG. Fulminant amoebic colitis following loperamide use. J Travel Med. 2007;14(1):61-62. doi: JTM96 [pii]. 38. Kobayashi T, Watanabe K, Yano H, et al. Underestimated amoebic appendicitis among HIV- 1-infected individuals in Japan. J Clin Microbiol. 2016;55(1):313-320. doi: 10.1128/JCM.01757- 16 [doi]. 39. Moonah S, Petri W. Free-living and parasitic amebic infections. In: Scheld W, Whitley R, Marra C, eds. Infections of the central nervous system. 4th ed. Lippincott Williams & Wilkins; 2014:770-775. 40. Stark D, van Hal S, Fotedar R, et al. Comparison of stool antigen detection kits to PCR for diagnosis of amebiasis. J Clin Microbiol. 2008;46(5):1678-1681. doi: 10.1128/JCM.02261-07 [doi]. 41. Prim N, Escamilla P, Sole R, Llovet T, Soriano G, Munoz C. 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Nitazoxanide in the treatment of amoebiasis. Trans R Soc Trop Med Hyg. 2007;101(10):1025-1031. doi: S0035-9203(07)00102- 2 [pii]. 46. Kimura M, Nakamura T, Nawa Y. Experience with intravenous metronidazole to treat moderate-to-severe amebiasis in Japan. Am J Trop Med Hyg. 2007;77(2):381-385. doi: 77/2/381 [pii]. 47. Capparelli EV, Bricker-Ford R, Rogers MJ, McKerrow JH, Reed SL. Phase I clinical trial results of auranofin, a novel antiparasitic agent. Antimicrob Agents Chemother. 2016;61(1):10.1128/AAC.01947-16. Print 2017 Jan. doi: e01947-16 [pii]. 48. Alvarado-Esquivel C, Hernandez-Tinoco J, Francisco Sanchez-Anguiano L, Ramos-Nevarez A, Margarita Cerrillo-Soto S, Alberto Guido-Arreola C. Serosurvey of Entamoeba histolytica exposure among Tepehuanos population in Durango, Mexico. Int J Biomed Sci. 2015;11(2):61- 49. Alam MA, Maqbool A, Nazir MM, et al. 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Pathogen-specific burdens of community diarrhoea in developing countries: A multisite birth cohort study (MAL-ED). Lancet Glob Health. 2015;3(9):e564-75. doi: 10.1016/S2214-109X(15)00151-5 [doi]. 53. Ozin Y, Kilic MZ, Nadir I, et al. Presence and diagnosis of amebic infestation in Turkish patients with active ulcerative colitis. Eur J Intern Med. 2009;20(5):545-547. doi: 10.1016/j.ejim.2009.05.014 [doi]. 54. Al-Areeqi MA, Sady H, Al-Mekhlafi HM, et al. First molecular epidemiology of Entamoeba histolytica, E. dispar and E. moshkovskii infections in Yemen: Different species-specific associated risk factors. Trop Med Int Health. 2017;22(4):493-504. doi: 10.1111/tmi.12848 [doi]. 55. Abd-Alla MD, Ravdin JI. Diagnosis of amoebic colitis by antigen capture ELISA in patients presenting with acute diarrhoea in Cairo, Egypt. Trop Med Int Health. 2002;7(4):365-370. doi: 862 [pii]. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 56. Samie A, Barrett LJ, Bessong PO, et al. Seroprevalence of Entamoeba histolytica in the context of HIV and AIDS: The case of Vhembe district, in South Africa’s Limpopo province. Ann Trop Med Parasitol. 2010;104(1):55-63. doi: 10.1179/136485910X12607012373911 [doi]. 57. Abramowicz J, ed. Drugs for parasitic infections. 2nd ed. New Rochelle, New York: The Medical Letter; 2010. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Tables Table 1. Recent prevalence estimates of Entamoeba histolytica infection by world regions Country f (%) Method Study characteristics Ref. Latin America and Caribbean 16,48 Durango, Mexico 42 AB Cross-sectional serosurvey among rural communities Asia-Pacific Beijing and Tianjin, China 41 AB Cross-sectional serosurvey of men who have sex with men CCDC, China 11 AB Cross-sectional serosurvey of the general population Lahore, Pakistan 17 AG Cross-sectional survey among 3 different socioeconomic strata Northeast, India 14 PCR Cross-sectional survey Dhaka, Bangladesh 11 PCR Prospective birth cohort study of infants followed for 1 year Selangor, Malaysia 8 PCR Cross-sectional survey of selected ethnic groups Sydney, Australia 5 AB Retrospective study of HIV infected men who have sex with men Mirzapur, Bangladesh 3 AG Multinational case-control study of children <5 years with MSD Vellore, India 1* AG Multinational prospective birth cohort study of children followed for 2 years to determine the adjusted attributable fraction of diarrhea and Naushahro Feroze, Pakistan Europe Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Turkey 32 AG Prevalence study among patients presenting with ulcerative colitis Middle East Jeddah, Saudi Arabia 20 AG Cross-sectional study of children hospitalized with acute diarrhea Yemen 20 PCR Community based cross-sectional survey Africa Cairo, Egypt 38 AG Case-control study of patients presenting with acute diarrhea Vhembe, South Africa 34 AB Cross-sectional serosurvey Giyani and Soshanguve, South Africa 9 PCR Cross-sectional study of patients attending Gastroenterology clinic AB, serology; AG, stool antigen detection; CCDC, Chinese Center of Disease Control and Prevention (seven provinces of China including Guangxi, Qinghai, Guizhou, Shanghai, Sichuan, Sinkiang and Beijing); f, frequency; MSD, moderate-to- severe diarrhea; PCR, stool detection by polymerase chain reaction; * in year two of life Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 2. Clinical findings in amebic colitis and amebic liver abscess Characteristic Amebic colitis Amebic liver abscess Migration from or travel to an endemic area ++++ ++++ Diarrhea ++++ ++ Heme-positive stools +++ - Abdominal pain ++++ ++++ Hepatomegaly - ++ Weight loss ++ ++ Fever > 38 ˚ C + ++++ Cough - ++ Leukocytosis +/- ++++ Elevated Alkaline phosphatasec - ++++ Sigmoidoscopy/ colonoscopy Friable colonic mucosa - with discrete ulcers Abdominal imaging (ultrasound, CT or MRI) Colonic inflammation Intrahepatic lesion and bowel wall typically right lobe, thickening often solitary ++++, ≥75%, +++ 50-74%, ++ 25-50%, + < 25%, +/- variable. Pain is located in the right upper b c quadrant in amebic liver abscess; typically without eosinophilia; Transaminase enzymes may also be elevated in amebic liver abscess Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 3. Comparison of laboratory diagnostic tests for Amebiasis. Method Sensitivity,% Specificity,% Advantages Disadvantages [Reference] [Reference] Microscopy <60% [ ] - Widely available Poor sensitivity and specificity; Cannot differentiate from other Entamoeba spp. Screens for other parasites Multiple stools need to be submitted Minimal equipment and reagents Skilled observer required; time consuming required 16 16 Serology 65-92% [ ] >90% [ ] High sensitivity and specificity, useful Serology remains positive for years after adjunct to stool studies resolution of infection, so less helpful in endemic areas; more useful in travelers Rapid turnaround Antibody response is often detectable by the time of presentation but may need to be repeated in 7-10 days if initially negative 42 42 Stool Antigen 0-88% [ ] >80% [ ] May have high sensitivity in endemic Poor sensitivity for amebic liver abscess detection areas, but reduced sensitivity in non- endemic areas Simple to perform, rapid turnaround Requires fresh, not fixative preserved time and commercially available stool for analysis combined tests exist to detect several enteroparasites 42 42 PCR 92-100% [ ] 89-100% [ ] Gold standard. High sensitivity and More expensive, cost may limit use in specificity for colitis and liver abscess resource-limited settings with increasing availability Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Rapid turnaround; automated systems Requires analysis instruments, kits and reduce technician time and risk of skilled technician contamination Can be combined with multiplex panels to detect multiple enteric pathogens at a time Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 4. Anti-parasitic therapy for Entamoeba histolytica infection Drug of Daily dose Duration, Alternatives choice days Tissue-active agent Amebic colitis Metronidazole 750 mg po TID (35- 5-10 Nitazoxanide^ or 50 mg/ kg/ d divided TID) Tinidazole 2 g po once daily 3-5 (50 mg/kg/once daily) Amebic liver Metronidazole 750 mg po TID (35- 10 - abscess and 50 mg/ kg/ d divided or disseminated TID) amebic disease* Tinidazole 2 g po once daily 5 (50 mg/ kg/ once daily) Luminal agent Asymptomatic Paromomycin 25-35 mg/ kg/ d by 7 Iodoquinol/ carriage or mouth divided TID diiodohydroxyquin following tissue- Diloxanide active agent furoate Severe disease or unable to tolerate oral therapy, use metronidazole 1500 mg IV divided TID (7.5-30 mg/ kg/ day divided TID) ; ^, limited data, 500 mg po BID (≥12 years), 200 mg BID (age 4-11 years) or 100 mg BID (age 1-3 years) for 3 days; Iodoquinol 650 mg po TID (30-40 mg/kg/day po divided TID for children) for 20 days, after meals (optic neuritis and peripheral neuropathy have been reported), diloxanide furoate 500 mg po TID (20 mg/kg/day po divided TID for children) for 10 days. d, day; BID, twice daily; g, grams; IV, intravenous; kg, kilogram; mg, milligram; TID three times daily. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure Legends Figure 1. Entamoeba histolytica in stool and pathological features of intestinal amebiasis. (A) Cyst of E. histolytica/E. dispar stained with trichrome. Note the chromatoid body with blunt ends (red arrow). (B) Trophozoite of E. histolytica with ingested erythrocytes stained with trichrome. The ingested erythrocytes appear as dark inclusions (red arrow). The parasite shows nuclei that have the typical small, centrally located karyosome, and thin, uniform peripheral chromatin. (C) Intestinal tissue from a patient with amebic colitis showing multiple ulcers. (D) Classic flask- shaped ulcer of amebiasis. (Courtesy of the Centers for Disease Control and Prevention) Figure 2. Amebic colitis. Immunohistochemical staining of trophozoites (brown) using specific anti-Entamoeba histolytica MIF antibodies in a patient with amebic appendicitis Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 2. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

A review of the global burden, new diagnostics and current therapeutics for amebiasis

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Abstract

1 2 3 2 Debbie-Ann T. Shirley , Laura Farr , Koji Watanabe and Shannon Moonah Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA Department of Medicine, University of Virginia School of Medicine Charlottesville, VA, USA AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan Keywords: amebiasis, diarrhea, colitis, burden, PCR, HIV, MSM Corresponding author contact information: Shannon Moonah, MD, ScM Division of Infectious Diseases Department of Medicine University of Virginia Health System 345 Crispell Drive, MR-6 1st floor, Room 1709 Charlottesville, VA 22908 sm5fe@virginia.edu 434-924-8189 (phone) © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Alternate author contact information: Debbie-Ann Shirley, MD, MPH Division of Pediatric Infectious Diseases Department of Pediatrics University of Virginia P.O. Box 800386 Charlottesville, VA 22908 ds3ru@virginia.edu 434-924-9141 (phone) 434-982-4246 (fax) Author Contributions: SM and DAS developed the concept and design of the project. DAS prepared the first draft of the manuscript. SM, LF, KW, and DAS revised the manuscript. Summary: Amebiasis remains an important cause of diarrhea worldwide. Here we review the most recent data regarding the global burden, diagnosis, treatment and prevention of amebiasis. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Abstract Amebiasis, due to the pathogenic parasite Entamoeba histolytica, is a leading cause of diarrhea globally. Largely an infection of impoverished communities in developing countries, amebiasis has emerged as an important infection among returning travelers, immigrants, and men who have sex with men residing in developed countries. Severe cases can be associated with high case fatality. PCR-based diagnosis is increasingly available but remains underutilized. Nitroimidazoles are currently recommended for treatment, but new drug development to treat parasitic agents is a high priority. Amebiasis should be considered prior to corticosteroid therapy to decrease complications. There is no effective vaccine, so prevention focuses on sanitation and access to clean water. Further understanding of parasite biology and pathogenesis will advance future targeted therapeutic and preventative strategies. Abbreviations EhMIF: Entamoeba histolytica macrophage migration inhibitory factor GEMS: Global Enteric Multi-Center Study HIV: Human immunodeficiency virus IBD: Inflammatory bowel disease NIAID: National Institute of Allergy and Infectious Diseases NIH: National Institutes of Health MMPs: matrix metalloproteinases MSM: Men who have sex with men PCR: polymerase chain reaction Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Introduction Amebiasis is caused by infection with the pseudopod-forming, non-flagellated protozoan parasite Entamoeba histolytica. Amebiasis can be asymptomatic or can lead to the development of severe infection with amebic colitis and amebic liver abscess. The significance of amebiasis is exemplified in several ways. Amebic colitis is a leading cause of severe diarrhea worldwide and is listed among the top 15 causes of diarrhea in the first two years of life in children living in the developing world, where diarrhea remains the third leading cause of death, accounting for 1-3 9% of all deaths in children under the age of 5 years. Fulminant amebic colitis is an uncommon complication of amebiasis, but associated with high mortality, and on average more than 50% die with severe colitis. E. histolytica is classified as a category B priority biodefense pathogen by the National Institute of Allergy and Infectious Diseases (NIAID) because of its low infectious dose, chlorine resistance and environmental stability, properties which can pose a threat of easy dissemination through contamination of food and water supplies. Even in low incidence settings, these properties of the parasite lend to outbreaks among military and 5-7 general populations. In addition, E. histolytica is one of the most common causes of infectious diarrhea among travelers returning from endemic areas. Advances in molecular diagnostic methodologies have improved our understanding and led to the recognition and separation of E. histolytica from non-pathogenic species of Entamoeba. Of the many Entamoeba species that infect humans, three species are morphologically indistinguishable from E. histolytica. Of these three, E. moshkovskii may cause diarrhea, while E. dispar and the newly described E. bangladeshi are considered non-pathogenic. Earlier descriptions of amebiasis relying solely on microscopy may have been obscured by these non- pathogenic strains. There is no vaccine to prevent amebiasis. Nitroimidazoles are the mainstay treatment for invasive amebiasis. Given the toxicity that can be associated with this class and potential concerns for development of resistance, as has already been reported for some Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript anaerobic pathogens, new therapies are needed. In addition, the NIAID has set priorities for drug development for treatment of category B pathogens. For these many reasons, improved understanding of amebiasis pathogenesis is needed as a way forward towards enhanced treatment and prevention. This report reviews recent literature expanding our knowledge of the epidemiology, clinical presentation and management of amebiasis, while providing important new insights into the diagnostic evaluation and prevention. Epidemiology Global burden The global significance of amebiasis is wide spread, with the highest burden of amebiasis borne by those residing in developing countries particularly of the tropics and subtropics, when there is inadequate hygiene and access to sanitation. Millions of people are infected with E. histolytica making amebic colitis a leading cause of diarrhea, estimated to kill more than 55, 000 people each year. Amebiasis is endemic in developing parts of Central and South America, Africa and Asia. In the United States, the incidence of amebiasis is low, though amebiasis-related deaths still routinely occur, accounting for at least five deaths per year. Amebiasis in the US is seen mostly in returning travelers or immigrants from endemic countries. Data from the GeoSentinel Surveillance Network, a large international surveillance and monitoring system, has shown that E. histolytica is the third most frequently isolated pathogen among returning travelers with infectious gastrointestinal disease. Amebiasis accounts for 12.5% of all microbiologically confirmed cases, with an estimated rate of affecting 14 in every 1000 returned travelers. Travelers to South Asia, the Middle East and South America appear to have the highest risk, in particular those volunteering as missionary workers or other volunteering work. Even travel of household or sexual contacts to an endemic area may pose a risk of infection. Other industrialized countries including parts of Asia, Europe, North America and Australia have Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript highlighted gay, bisexual and other men who have sex with men (MSM) as a population at higher risk of acquiring amebiasis than the general population. Recent reports from Taiwan and 14,15 Japan, for example, have shown high rates of invasive amebiasis in HIV-infected MSM. In developing countries, the exact burden of amebiasis is difficult to quantify and reports can be affected by geographic region, study design, sample size, incubation, symptom severity and the sensitivity of diagnostic modality used (Table 1). In addition, diagnostic capacities and surveillance are often limited in areas where E. histolytica is endemic. Recent reports however, show that the seroprevalence of E. histolytica in some rural communities of Mexico remains as high as 42%. In an urban slum of Dhaka, Bangladesh, 11% of children had an episode of amebic diarrhea in the first year of life. By cross-sectional survey, E. histolytica was detected using PCR in 13.7% of fecal samples in Northeast states of India. E. histolytica seropositivity was found to be 11% among seven provinces of China, and was as high as 41% among MSM 19,20 in the two provinces of Beijing and Tianjin. A re-emergence of E. histolytica infection was described in Jeddah, Saudi Arabia among children under the age of 16 years presenting to hospital with acute gastroenteritis. Using fecal antigen detection, E. histolytica was found to be the most prevalent enteropathogen associated with diarrhea, with a prevalence of 20%. The epidemiology on incidence and prevalence of amebiasis in Africa is particularly limited, but appears widespread, as exemplified in a cross-sectional study of patients attending gastroenterology clinics in South Africa where E. histolytica was detected by PCR in 8.5% of fecal samples. In the large Global Enteric Multi-Center Study (GEMS), E. histolytica was one of the top ten causative agents of moderate-to-severe diarrhea in children under the age of five years in two of their seven study sites across sub-Saharan Africa and South Asia. In addition, E. histolytica diarrhea was associated with a relatively greater risk of death across all GEMS sites and was the enteric pathogen with the highest hazard ratio for death in the second year of life. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Recent re-analysis of specimens from GEMS, to reassess estimates of pathogen-specific diarrhea exclusively using PCR diagnostics, showed that E. histolytica was one of the top seven pathogens causing dysentery, with the most frequent cause of dysentery led by the combined group of Shigella species and enteroinvasive Escherichia coli. In summary, the global impact of amebic infection remains significant, though challenging to quantify with precision given several methodologic and epidemiologic complexities, but prevalence estimates remain as high as 40% in some populations (Table 1). Transmission The life cycle of E. histolytica is simple, with only two stages, existing as either an infectious cyst or invasive trophozoite (Figure 1). Transmission occurs after the ingestion of the infectious cyst. This most commonly arises from fecally contaminated hands, food or water, but there is a new appreciation that exposure to fecal matter may occur during sexual contact, in particular among MSM groups. Following ingestion, excystation to trophozoites occurs, and the released trophozoites migrate to the large intestine, multiplying by binary fission to produce more cysts. The trophozoite may invade the intestinal epithelium and even pass to extra-intestinal sites such as the liver via the hepatic portal circulation or disseminate further to distant sites such as the brain and lungs hematogenously. Symptoms may occur within weeks after ingestion but may also develop years after infection. Cysts and trophozoites are passed in stools. Several properties of the cyst help it to remain hardy in the environment for weeks at a time, while trophozoites do not survive. For example, cysts are resistant to gastric acidity and are also relatively resistant to chlorine. The low 5,6 infectious dose and environmental stability can predispose to the development of outbreaks. Cysts can be killed by boiling. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Pathogenesis E. histolytica pathogenesis can be characterized by three events: host cell death, inflammation and parasite invasion. Contact with host cells is required for parasite-induced death. Adherence is mediated through the parasite Gal/GalNAc lectin adhesion molecule. Trophozoites are able to kill host cells by several different mechanisms, which include inducing programmed cell death, phagocytosis, and trogocytosis. E. histolytica causes inflammation of the colon, termed amebic colitis. The intestinal epithelium is the point of first contact for E. histolytica. Prior to cell adherence, trophozoites secrete immune modulators that stimulate epithelial cells resulting in cytokine production and 26,27 subsequent mucosal inflammatory cell infiltration. E. histolytica, like several pathogenic protozoa, secretes a protein homolog of the proinflammatory cytokine macrophage migration inhibitory factor (EhMIF). A positive correlation was recently found between EhMIF levels and intestinal inflammation in persons with amebic colitis. It would seem counterintuitive for parasites to produce such a molecule like EhMIF, however E. histolytica has developed a number of mechanisms to evade the immune response and persist in the host. Also, E. histolytica exploits the inflammatory response to promote its own invasion. EhMIF-induced inflammation results in increased production in matrix metalloproteinases (MMPs). MMPs break down the extracellular matrix in the gut to promote cell migration, and 29,30 are overexpressed in all infections with protozoan parasites, including amebiasis. In a recent study, MMPs were shown to be necessary for E. histolytica tissue invasion. It appears that EhMIF is a parasite virulence factor that triggers inflammation, resulting in increased expression of MMPs which promotes invasion of the host. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Immune Response Various host immune mechanisms are elicited in response to amebiasis in an attempt to clear or prevent infection. Interferon gamma (IFN-Ɣ) appears to provide protection from amebiasis, as children with higher IFN-Ɣ had a significantly lower incidence of future E. histolytica diarrhea. Also, protection from amebiasis includes acquired immunity from antibodies against amebic antigens Gal/GalNAc lectin and EhMIF. Infected children develop antibodies against EhMIF, 28,33 which are associated with protection from reinfection. Although the immune response is normally protective, it can also produce undesirable effects when the response is excessive. For example, higher TNF-α production was shown to correlate with E. histolytica diarrhea in children. Another cytokine produced during infection is Interleukin-8 (IL-8), a potent neutrophil chemoattractant. In response to IL-8, neutrophils infiltrate the intestinal tract as the first cells of 27,30 an innate immune response to amebic invasion. Patients with severe amebic colitis have higher colonic tissue levels of IL-8 and neutrophils, suggesting that neutrophils might be 34-36 responsible for collateral tissue damage during inflammation at the site of invasion. Clinical Manifestations The majority of E. histolytica infections are asymptomatic, only about 10-20 % progress to develop symptomatic infection. The reasons for this are poorly understood but result from an interplay of several factors related to parasite, host and environment. Recently, it was found that the gut microbiome is enriched in Prevotella copri in people with amebic diarrhea indicating that dysbiosis may in part contribute to susceptibility to the development of colitis. Intraluminal amebiasis. Asymptomatic infection is referred to as luminal amebiasis. Screening for asymptomatic infection should be considered in those with a personal history of travel to/ immigration from an endemic area or a history of this in either a household or sexual contact. A Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript gender difference in amebiasis is not seen in children, but interestingly, in the adult population, invasive disease is more common in males than females, particularly for amebic liver abscess. Amebic colitis. Symptomatic intestinal infection can have a wide spectrum of manifestations (Table 2). Diarrhea is the hallmark of amebic colitis, which may be watery, or bloody and present with abdominal cramps, pain/ tenderness and weight loss. Presentation may be acute or more gradual, and amebic colitis may also present similarly to inflammatory bowel disease (IBD). It may not be possible to distinguish amebic colitis from IBD even by imaging, inflammatory markers or endoscopy, and the colon may appear friable, with diffuse ulceration by gross examination (Figure 1). Disease may be limited to the ascending colon or cecum. Life- threatening manifestations of amebic colitis include fulminant infection, which can result in massive areas of colonic involvement with perforation and peritonitis, bowel necrosis or toxic megacolon. Corticosteroid use has been described as a risk factor for the development of fulminant forms of amebic colitis. Patients may be toxic in appearance, febrile, hypotensive, with profuse bloody diarrhea, abdominal pain, distension and signs of peritonism. Case fatality of fulminant amebic colitis ranges from 40-89%. Toxic megacolon has been described in a patient with amebic colitis and heavy use of the anti-motility agent, loperamide Other implicated risk factors for fulminant disease include diabetes mellitus, alcoholism, malignancy/ chemotherapy, and pregnancy. Amebic colitis may also present as acute appendicitis (Figure 2). Appendicitis was noted in up to 15% of Japanese HIV-infected patients presenting with appendicitis and undergoing appendectomy. The only distinguishing features was a higher median neutrophil count in those with amebic infection, compared to those without in this series. Ameboma, the development of tumor like granulation tissue in the colonic lumen, can mimic colonic cancer. The differential diagnosis of amebic colitis includes bacterial enteric infection, such as Salmonella spp., Shigella spp., Campylobacter spp., enterohemorrhagic E. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript coli, enteroinvasive E. coli, Clostridium difficile infection, IBD and other non-infectious causes of colitis. The aid of stool PCR and culture can help to distinguish several of these differentials. Disseminated amebic disease. Amebic liver abscess, which is the most common extra-intestinal manifestation develops when trophozoites disseminate to the liver. For poorly understood reasons, amebic liver abscesses are 10 times more common in men than women, often presenting between the ages of 20 and 40 years. Onset can be acute, subacute or subtle. Hepatic amebiasis has been reported over 20 years after the last visit to an endemic area, so any travel history may be important in this diagnosis. The majority will present with fever, and right upper quadrant pain, typically without concurrent dysentery or gastrointestinal symptoms (Table 2). Hepatomegaly with point tenderness over the liver can often be detected. Cough and respiratory symptoms, including pleuritic right sided chest pain may occur or even referred pain to the shoulder. Elevated alkaline phosphatase and peripheral leukocytosis, usually in the range of 12,000- 20,000/ mm is seen, though usually without eosinophilia. Imaging more often reveals right lobe lesions, usually solitary, but left lobe or multiple lesions may be less commonly seen (Table 2). Amebic liver abscess may be difficult to clinically distinguish from pyogenic liver abscess. Echinococcal cysts of the liver are another important differential, but tend to appear as multiple clustered fluid collections without surrounding enhancement on imaging. Peripheral eosinophilia is rare with amebic liver abscess, and is more commonly associated with echinococcosis and hepatic fascioliasis (liver fluke). Detection of bacteremia by blood culture, stool studies and serology will also help to narrow the differential. Occasionally, diagnostic or therapeutic aspiration is required. Aspiration of the amebic liver abscess reveals “anchovy paste” chocolate colored fluid consisting of necrotic hepatocytes. Pleuropulmonary amebiasis can occur as a complication of ruptured amebic liver abscess, presenting with pneumonitis or lung abscess. Intraperitoneal rupture is rare but can be life- Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript threatening if there is pericardial involvement. Trophozoites may also on occasion disseminate hematogenously to the central nervous system and other extra-intestinal sites. Laboratory Diagnosis A number of diagnostic modalities are available to assist with diagnosis, including microscopy, antigen detection, molecular tests, and serology (Table 3). Often a combination of tests is required to establish diagnosis. Traditionally, microscopy has been the most widely used, but has limited diagnostic utility and is no longer recommended as a reliable way to diagnose amebiasis. Most cases of extra-intestinal abscess occur without concurrent intestinal infection, resulting in lower sensitivity of stool studies for the diagnosis of amebic liver abscess. Stool microscopy. Cysts and trophozoites can be visualized by an experienced eye, sometimes with evidence of hemophagocytosis. Fresh stools increase the recovery of both trophozoites and cysts and can be prepared as either wet mounts or stained preparations. Mature cysts have 4 nuclei measuring about 12-15 µm in diameter. Trophozoites have a single nucleus and are slightly larger measuring about 15-20 µm. Microscopy should not be used when other modalities are accessible. Stool antigen detection. Antigen detection tests have helped to overcome some of the limitations of stool microscopy, and are easy to use, but in practice have variable sensitivity and specificity, particularly in low endemic areas. While several EIA kits are commercially available, they are not as widely available in resource-limited settings. The Techlab E. histolytica II test (Blacksburg, VA, USA) which detects E. histolytica-derived Gal/GalNAc- specific lectin, can exclude non-pathogenic E. dispar, as can the Cellabs CELISA Path (Brookvale, Australia). A false-negative EIA test was reported from Spain, possibly from interference, as the result turned positive with subsequent testing. Recently, an E. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript HISTOLYTICA QUIK CHEK immunochromatographic (IC) assay which is simple to perform, with a quick turnaround time was approved by the US Food and Drug Administration (FDA). Stool molecular studies. Stool PCR is extremely sensitive. It is considered the gold standard for diagnosis of amebiasis and is becoming readily available through FDA-cleared gastrointestinal panels which simultaneously detect multiple enteropathogens, such as the BD Max Enteric TM Parasite Panel (Becton, Dickinson and Company, USA), the Luminex xTAG Gastrointestinal Pathogen Panel® (Luminex Corporation, Toronto, Canada) and the Biofire FilmArray Gastrointestinal Panel® (BioFire Diagnostics, Salt Lake City, UT). The use of PCR is also endorsed by the World Health Organization, but the expense and requirement for technical expertise may limit use in resource-limited settings. Purulent fluid aspirated from liver abscess can also be tested. Serology. Serology is a useful adjunct to stool studies. Several EIA kits for antibody detection are commercially available, including indirect fluorescence, immunoelectrophoresis and immunosorbent assays, but the indirect hemagglutination test has been replaced by EIA. Antibody detection is particularly helpful in the diagnosis of extra-intestinal disease, when stool studies may be negative. False-positive results have been reported. Antibodies remain detectable for years after successful treatment, so cannot reliably distinguish between active and past infection. Other diagnostic methods. Amebic ulcers most often develop in the cecum. Histology obtained by diagnostic endoscopic biopsy or surgical resection may show the characteristic flask-shaped ulcer (Figure 1). Trophozoites may be identified at the edge of the ulcer or within the tissue, using periodic acid-Schiff staining or immunoperoxidase staining with specific anti-E. histolytica antibodies (Figure 2). Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Imaging. Ultrasonography, abdominal computed tomography and magnetic resonance imaging are all good modalities to detect liver abscess. By ultrasound, a cystic intrahepatic hypoechoic lesion can be found. By CT an abscess with non-enhancing center, surrounded by a rim of inflammation can be seen following contrast administration. The detection of a space-occupying lesion in the liver and positive amebic serology supports the diagnosis of amebic liver abscess. Therapy All patients with amebiasis should be treated (Table 4). Patients with clinical disease require treatment with two drugs: an amebicidal tissue-active agent as well as a luminal cysticidal agent. Those with asymptomatic amebiasis need only be treated with a luminal cysticidal agent to prevent invasion and transmission. The amebicidal agents include metronidazole and tinidazole, which are both nitroimidazole agents. They are highly effective at eliminating invading trophozoites and remain the recommended therapy for amebic colitis and amebic liver disease. Tinidazole has a longer half- life and is better tolerated, but metronidazole is as effective at clearing parasites. Side effects of metronidazole include nausea, headache, anorexia, metallic taste, peripheral neuropathy and disulfiram-like reaction with alcohol. The nitroimidazoles do not effectively eradicate luminal cysts and must be followed by a luminal agent. The thiazolide agent, nitazoxanide, with reputed broad spectrum antimicrobial properties, was shown in a small, single center trial from Egypt to have clinical and microbiologic response in patients treated for hepatic and intestinal amebiasis of over 90%. However, the unexpectedly high response rate in the placebo group of 40-50% raises methodologic concerns. The aminoglycoside paromomycin, is a luminal cysticidal agent. As it may cause diarrhea, paromomycin should not be administered at the same time as the nitroimidazole agent. Diloxanide and iodoquinol are alternatives, but neither are available in the US. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Patients with fulminant amebic colitis will additionally require fluid resuscitation, broad spectrum antimicrobial therapy for peritonitis, intensive supportive care and surgical intervention for bowel perforation and bowel necrosis. Occasionally colectomy has been necessitated by the development of toxic megacolon or extensive bowel necrosis. In patients who are unable to tolerate or absorb oral metronidazole, then intravenous metronidazole should be used. Drainage of liver abscess, either by image-guided or open aspiration, may occasionally be required in addition to anti-parasitic therapy. Drainage is typically reserved for those who do not show prompt clinical response to anti-parasitic therapy by about 72 hours; or those at high risk for impending abscess rupture, typically defined as a cavity with diameter > 5-10 cm or by left lobe abscess which could rupture into the pericardium. Serial imaging may show that it takes months following appropriate therapy for the abscess cavity to resolve. Auranofin, a gold compound that has been used to treat selective cases of rheumatoid arthritis has entered into early clinical drug development as an anti-parasitic agent, but further study is needed to determine if it will be effective treatment of amebiasis and whether known safety concerns such as diarrhea, rash and bone marrow suppression will limit its use. Prevention There is no vaccine to prevent amebiasis. The focus of primary preventative efforts, therefore, remains food and water safety, attention to hand hygiene and avoidance of fecal-oral exposure, including through sexual practices. Prior to travel to endemic areas such as Asia, Mexico, South America and sub-Saharan Africa, patients should be advised on food safety to prevent enteric illness. Patients, especially MSM, should also be advised to avoid sexual practices that may lead to fecal-oral transmission. Patients should be asked about prior travel and screened appropriately for secondary prevention. Even a remote travel history is important, as amebic liver abscess and fulminant amebic colitis could occur years after travel. Household contacts of Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript patients with amebiasis should be screened, as amebiasis may spread among family and household contact. Patients with a new diagnosis of IBD that have traveled to an endemic area should be screened as well, as fulminant amebic colitis may ensue if patients are administered corticosteroid or other immunosuppressive therapy with misdiagnosis. Use of loperamide should be avoided in amebic colitis. Conclusion Amebiasis remains one of the most significant enteropathogens worldwide. Advances in molecular epidemiology and pathogenesis have advanced our understanding of this parasite, however many gaps in knowledge remain. In addition, while efforts are ongoing, there is no vaccine and only a single effective drug class. Prevention remains challenging, highlighting the need for improved awareness of this infection as well as novel therapeutic and preventative strategies. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Funding This work was supported by the National Institutes of Health (NIH) R01AI026649-S1, K08AI119181, and the Robert Wood Johnson Foundation–Harold Amos Medical Faculty Development Program Award (to SM). Emerging Infectious Diseases Project of Japan from the Japan Agency for Medical Research and Development (AMED), and the Grant for National Center for Global Health and Medicine (29-2013) (to KW). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Acknowledgements We acknowledge Dr. William A. Petri, Jr. for helpful advice. We apologize to all colleagues we were unable to cite due to space limitations. 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Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 29. Geurts N, Opdenakker G, Van den Steen PE. Matrix metalloproteinases as therapeutic targets in protozoan parasitic infections. Pharmacol Ther. 2012;133(3):257-279. doi: 10.1016/j.pharmthera.2011.11.008 [doi]. 30. Peterson KM, Guo X, Elkahloun AG, et al. The expression of REG 1A and REG 1B is increased during acute amebic colitis. Parasitol Int. 2011;60(3):296-300. doi: 10.1016/j.parint.2011.04.005 [doi]. 31. Thibeaux R, Ave P, Bernier M, et al. The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue. Nat Commun. 2014;5:5142. doi: 10.1038/ncomms6142 [doi]. 32. Haque R, Mondal D, Shu J, et al. Correlation of interferon-gamma production by peripheral blood mononuclear cells with childhood malnutrition and susceptibility to amebiasis. 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Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript 56. Samie A, Barrett LJ, Bessong PO, et al. Seroprevalence of Entamoeba histolytica in the context of HIV and AIDS: The case of Vhembe district, in South Africa’s Limpopo province. Ann Trop Med Parasitol. 2010;104(1):55-63. doi: 10.1179/136485910X12607012373911 [doi]. 57. Abramowicz J, ed. Drugs for parasitic infections. 2nd ed. New Rochelle, New York: The Medical Letter; 2010. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Tables Table 1. Recent prevalence estimates of Entamoeba histolytica infection by world regions Country f (%) Method Study characteristics Ref. Latin America and Caribbean 16,48 Durango, Mexico 42 AB Cross-sectional serosurvey among rural communities Asia-Pacific Beijing and Tianjin, China 41 AB Cross-sectional serosurvey of men who have sex with men CCDC, China 11 AB Cross-sectional serosurvey of the general population Lahore, Pakistan 17 AG Cross-sectional survey among 3 different socioeconomic strata Northeast, India 14 PCR Cross-sectional survey Dhaka, Bangladesh 11 PCR Prospective birth cohort study of infants followed for 1 year Selangor, Malaysia 8 PCR Cross-sectional survey of selected ethnic groups Sydney, Australia 5 AB Retrospective study of HIV infected men who have sex with men Mirzapur, Bangladesh 3 AG Multinational case-control study of children <5 years with MSD Vellore, India 1* AG Multinational prospective birth cohort study of children followed for 2 years to determine the adjusted attributable fraction of diarrhea and Naushahro Feroze, Pakistan Europe Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Turkey 32 AG Prevalence study among patients presenting with ulcerative colitis Middle East Jeddah, Saudi Arabia 20 AG Cross-sectional study of children hospitalized with acute diarrhea Yemen 20 PCR Community based cross-sectional survey Africa Cairo, Egypt 38 AG Case-control study of patients presenting with acute diarrhea Vhembe, South Africa 34 AB Cross-sectional serosurvey Giyani and Soshanguve, South Africa 9 PCR Cross-sectional study of patients attending Gastroenterology clinic AB, serology; AG, stool antigen detection; CCDC, Chinese Center of Disease Control and Prevention (seven provinces of China including Guangxi, Qinghai, Guizhou, Shanghai, Sichuan, Sinkiang and Beijing); f, frequency; MSD, moderate-to- severe diarrhea; PCR, stool detection by polymerase chain reaction; * in year two of life Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 2. Clinical findings in amebic colitis and amebic liver abscess Characteristic Amebic colitis Amebic liver abscess Migration from or travel to an endemic area ++++ ++++ Diarrhea ++++ ++ Heme-positive stools +++ - Abdominal pain ++++ ++++ Hepatomegaly - ++ Weight loss ++ ++ Fever > 38 ˚ C + ++++ Cough - ++ Leukocytosis +/- ++++ Elevated Alkaline phosphatasec - ++++ Sigmoidoscopy/ colonoscopy Friable colonic mucosa - with discrete ulcers Abdominal imaging (ultrasound, CT or MRI) Colonic inflammation Intrahepatic lesion and bowel wall typically right lobe, thickening often solitary ++++, ≥75%, +++ 50-74%, ++ 25-50%, + < 25%, +/- variable. Pain is located in the right upper b c quadrant in amebic liver abscess; typically without eosinophilia; Transaminase enzymes may also be elevated in amebic liver abscess Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 3. Comparison of laboratory diagnostic tests for Amebiasis. Method Sensitivity,% Specificity,% Advantages Disadvantages [Reference] [Reference] Microscopy <60% [ ] - Widely available Poor sensitivity and specificity; Cannot differentiate from other Entamoeba spp. Screens for other parasites Multiple stools need to be submitted Minimal equipment and reagents Skilled observer required; time consuming required 16 16 Serology 65-92% [ ] >90% [ ] High sensitivity and specificity, useful Serology remains positive for years after adjunct to stool studies resolution of infection, so less helpful in endemic areas; more useful in travelers Rapid turnaround Antibody response is often detectable by the time of presentation but may need to be repeated in 7-10 days if initially negative 42 42 Stool Antigen 0-88% [ ] >80% [ ] May have high sensitivity in endemic Poor sensitivity for amebic liver abscess detection areas, but reduced sensitivity in non- endemic areas Simple to perform, rapid turnaround Requires fresh, not fixative preserved time and commercially available stool for analysis combined tests exist to detect several enteroparasites 42 42 PCR 92-100% [ ] 89-100% [ ] Gold standard. High sensitivity and More expensive, cost may limit use in specificity for colitis and liver abscess resource-limited settings with increasing availability Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Rapid turnaround; automated systems Requires analysis instruments, kits and reduce technician time and risk of skilled technician contamination Can be combined with multiplex panels to detect multiple enteric pathogens at a time Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Table 4. Anti-parasitic therapy for Entamoeba histolytica infection Drug of Daily dose Duration, Alternatives choice days Tissue-active agent Amebic colitis Metronidazole 750 mg po TID (35- 5-10 Nitazoxanide^ or 50 mg/ kg/ d divided TID) Tinidazole 2 g po once daily 3-5 (50 mg/kg/once daily) Amebic liver Metronidazole 750 mg po TID (35- 10 - abscess and 50 mg/ kg/ d divided or disseminated TID) amebic disease* Tinidazole 2 g po once daily 5 (50 mg/ kg/ once daily) Luminal agent Asymptomatic Paromomycin 25-35 mg/ kg/ d by 7 Iodoquinol/ carriage or mouth divided TID diiodohydroxyquin following tissue- Diloxanide active agent furoate Severe disease or unable to tolerate oral therapy, use metronidazole 1500 mg IV divided TID (7.5-30 mg/ kg/ day divided TID) ; ^, limited data, 500 mg po BID (≥12 years), 200 mg BID (age 4-11 years) or 100 mg BID (age 1-3 years) for 3 days; Iodoquinol 650 mg po TID (30-40 mg/kg/day po divided TID for children) for 20 days, after meals (optic neuritis and peripheral neuropathy have been reported), diloxanide furoate 500 mg po TID (20 mg/kg/day po divided TID for children) for 10 days. d, day; BID, twice daily; g, grams; IV, intravenous; kg, kilogram; mg, milligram; TID three times daily. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure Legends Figure 1. Entamoeba histolytica in stool and pathological features of intestinal amebiasis. (A) Cyst of E. histolytica/E. dispar stained with trichrome. Note the chromatoid body with blunt ends (red arrow). (B) Trophozoite of E. histolytica with ingested erythrocytes stained with trichrome. The ingested erythrocytes appear as dark inclusions (red arrow). The parasite shows nuclei that have the typical small, centrally located karyosome, and thin, uniform peripheral chromatin. (C) Intestinal tissue from a patient with amebic colitis showing multiple ulcers. (D) Classic flask- shaped ulcer of amebiasis. (Courtesy of the Centers for Disease Control and Prevention) Figure 2. Amebic colitis. Immunohistochemical staining of trophozoites (brown) using specific anti-Entamoeba histolytica MIF antibodies in a patient with amebic appendicitis Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 1. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript Figure 2. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofy161/5049601 by Ed 'DeepDyve' Gillespie user on 17 July 2018 Accepted Manuscript

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Jul 5, 2018

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