REVIEW URRENT C OPINION
Global progress towards eliminating gastrointestinal helminth infections Thomas R. McCarty , Joshua A. Turkeltaub , and Peter J. Hotez
Purpose of review To highlight the gastrointestinal helminths in the context of renewed global commitment to control or eliminate neglected tropical diseases in the coming decade. Recent findings Two key documents, namely the 2012 London Declaration for Neglected Tropical Diseases and the 2013 World Health Assembly resolution, emphasize the importance of mass drug administration (MDA) for controlling several key neglected tropical diseases. These documents, together with the Global Burden of Disease Study 2010, establish the major gastrointestinal helminth infections, including the soil-transmitted helminthiases – ascariasis, trichuriasis, hookworm, and strongyloidiasis – in addition to the intestinal and liver fluke infections, as some of the most important gastrointestinal infections of humankind. Current MDA approaches using single-dose albendazole or mebendazole are effective for ascariasis, less so for other soil-transmitted helminth infections. Expanded use of albendazole in combination with ivermectin would ensure improved drug efficacies against trichuriasis and strongyloidiasis. There is no effective elimination strategy for targeting hookworm and liver and intestinal fluke infections through current MDA approaches. Summary The global community must expand current MDA efforts, while simultaneously developing additional drugs, diagnostics, and vaccines alongside better utilizing transmission dynamics and modeling, if it is to successfully meet the goals and targets established by policymakers. Keywords food-borne trematode, liver fluke infection, mass drug administration, neglected tropical diseases, soil-transmitted helminth
INTRODUCTION Recently, two important global health policies (and linked documents) regarding neglected tropical diseases (NTDs) were launched, each affirming a global commitment to control or eliminate these conditions. The first is the 2012 London Declaration for NTDs that sets control and elimination targets in the coming decade, with parallel commitments from the major multinational pharmaceutical companies as well as foundations and other nonprofits to provide essential medicines for mass drug administration (MDA) [1 ]. Another is the 2013 World Health Assembly resolution (WHA 66.12) urging the disease-endemic countries to assume ownership of their major NTDs through MDA, health system strengthening, and provision of safe drinking water and sanitation [2 ]. The NTDs are a group of chronic parasitic and related infectious diseases that disable pediatric and adult populations in developing countries through &&
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their effects on child development and productive capacity, respectively [3]. The WHO currently recognizes 17 major NTDs [4 ], including several helminthic diseases affecting the gastrointestinal tract, such as the three major soil-transmitted helminth (STH) infections, that is, ascariasis, trichuriasis, and hookworm infection. Strongyloidiasis is a fourth major STH infection. Beyond the STH infections, food-borne trematode infections caused by &&
National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, USA Correspondence to Peter J. Hotez, MD, PhD, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Tel: +1 713 798 1199; e-mail: [email protected] Thomas R. McCarty and Joshua A. Turkeltaub are medical students at Baylor College of Medicine and contributed equally to the writing of the manuscript.
Curr Opin Gastroenterol 2014, 30:18–24 DOI:10.1097/MOG.0000000000000025 Volume 30 Number 1 January 2014
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Eliminating gastrointestinal helminth infections globally McCarty et al.
KEY POINTS MDA currently reaches 30% of children at risk for acquiring the STH infections: ascariasis, trichuriasis, and hookworm infection, using single-dose albendazole or mebendazole. Even as global coverage increases under the auspices of the 2012 London Declaration and the 2013 WHA resolution 66.12, this approach alone may not be effective for controlling STH infections beyond ascariasis. Adding ivermectin globally will facilitate reductions or control of trichuriasis and strongyloidiasis, whereas adding tribendimidine to praziquantel may improve the control of relevant liver flukes. There is a need for better use of helminth transmission dynamics in order to model optimal use of existing drugs and to develop improved and field-ready drugs and diagnostics for gastrointestinal helminthiases. Anthelminthic vaccines that target hookworm or several STH infections simultaneously would be a major advance in global gastrointestinal helminthiases, control and elimination.
selected intestinal flukes and liver flukes affecting the bile ducts, that is, clonorchiasis and opisthorchiasis, have also emerged as leading gastrointestinal helminthiases. Today, each of these gastrointestinal helminth infections can be targeted for control through MDA with a benzimidazole anthelminthic (e.g. albendazole or mebendazole) for ascariasis, trichuriasis, and hookworm infection; ivermectin for strongyloidiasis; and praziquantel for clonorchiasis and opisthorchiasis [5], together with environmental control through sanitation and clean drinking water. Thus, it is expected that impoverished populations affected by gastrointestinal helminthiases would benefit from the renewed global commitments contained in the London Declaration and WHA 66.12. However, these measures alone may not be sufficient to achieve elimination, so that new biotechnologies, that is, additional drugs, diagnostics, and even vaccines, may need to be developed [6]. Here, we review progress on global efforts to control or eliminate the major gastrointestinal helminth infections listed above since we last reviewed them in 2009 [5], as well as newly published information from the Global Burden of Disease (GBD) Study 2010 [7 –9 ]. Specific progress on the leading pediatric NTDs, which include STH infections in both preschool and school-aged children as well as schistosomiasis, lymphatic filariasis, onchocerciasis, and trachoma, with an emphasis on the policy framework for these activities, was also just reviewed [10 ]. &
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THE MAJOR GASTROINTESTINAL HELMINTH INFECTIONS: SPECIFIC EFFECTS ON THE GASTROINTESTINAL TRACT AND DISEASE BURDEN &
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Listed in Table 1 [7 –9 ,11–13] are the major gastrointestinal helminthiases, their causes, and the most recently available data for their prevalence and disease burden measured in years lost from disability (YLDs) and disability-adjusted life years (DALYs) [7 –9 ,11,12]. Ascariasis is the most common gastrointestinal helminth infection, followed by the three other STH infections. Together, these helminthiases may represent the most common infections of humans. The liver fluke and intestinal fluke infections are less prevalent globally, although they are highly prevalent in East Asia [11]. With the exception of ascariasis, which can cause a significant global number of deaths from acute obstruction in young children, all of the DALYs are attributed to YLDs resulting from heavy infections, wasting, and abdominopelvic problems, in addition to anemia in the case of hookworm infection [9 ]. The GBD Study 2010 estimates that almost 6 million DALYs are lost annually from the major gastrointestinal helminth infections (no estimates for strongyloidiasis were obtained). This value exceeds the global disease burden resulting from better-known gastrointestinal conditions such as noninfective inflammatory bowel disease, appendicitis, gastritis, or pancreatitis [8 ]. Overall, the GBD Study 2010 likely underestimates the true disease burden from gastrointestinal helminth infections since it does not attribute any deaths to hookworm anemia, or to bile duct cancer from clonorchiasis or opisthorchiasis, even though thousands of people may die annually from these conditions. &
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GLOBAL CONTROL AND ELIMINATION World Health Assembly resolution 66.12 calls on member states to assume greater ownership of their NTD control programs, most of which include MDA efforts for gastrointestinal helminth infections [2 ]. Currently, most gastrointestinal helminth control programs are focused on targeting pediatric populations (preschool children and school-aged children) affected by ascariasis, trichuriasis, and hookworm infection with annual doses of albendazole or mebendazole [5,10 ]. In areas of very heavy intensity, sometimes twice-annual or even threetimes annual MDA is required because of rapid re-infection. This approach, while focusing on one of the most vulnerable populations, often leaves out adults with hookworm infection, especially pregnant women. Moreover, populations in Asia affected by high rates of liver and intestinal fluke
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Gastrointestinal infections Table 1. The major gastrointestinal helminth infections Global burden of disease: disease and parasite
Specific manifestations
Estimated prevalence
Estimated disease burden 2010 (YLDs)
Estimated disease burden 2010 (DALYs)
Reference
Ascariasis: Ascaris lumbricoides
Malabsorption, bowel obstruction, intussusception, volvulus, cholecystitis, pancreatitis, cholangitis
807–1221 million
1 111 000
1 315 000
[7 –9 ,11]
Trichuriasis: Trichuris trichiura
Colitis, anemia, impaired growth, chronic dysentery, rectal prolapse
604–795 million
638 000
638 000
[7 –9 ,11]
Hookworm: Necator americanus, Ancylostoma duodenale
Iron deficiency anemia, hypoproteinemia, anasarca
576–740 million
3 231 000
3 231 000
[7 –9 ,11]
Strongyloidiasis: Strongyloides stercoralis
Nausea, vomiting, constipation, diarrhea, hyperinfection, disseminated infection, ileus, intestinal obstruction, sepsis Epigastric pain, diarrhea, jaundice, gallstones, pyogenic cholangitis, hepatomegaly, cholangiocarcinoma
30–100 million
ND
ND
[7 –9 ,11]
1.7 million total; clonorchiasis 15.3 million, opisthorchiasis 8.4 million
356 000; clonorchiasis 296 000, opisthorchiasis 60 000
356 000
[7 –9 ,12]
Diarrhea, constipation, colic, edema, intestinal erosion, ulceration, hemorrhage
6.7 million
106 000
106 000
[7 –9 ,12,13]
>1 billion
5.4 million
5.6 million
Liver fluke infections – clonorchiasis and opisthorchiasis: Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus Intestinal fluke infections: Fasciolopsis buski and several other species Total
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DALYs, disability-adjusted life years; ND, not determined; YLDs, years lost from disability.
infections frequently do not receive praziquantel in large-scale control programs, and, globally, strongyloidiasis is not generally targeted for MDA even though ivermectin may present an attractive agent for that purpose. Both the WHA and the WHO use the term ‘preventive chemotherapy’ to describe MDA for gastrointestinal helminthiases using single-dose albendazole or mebendazole, which in many African countries is integrated with MDA for schistosomiasis using praziquantel; lymphatic filariasis and onchocerciasis using ivermectin; and trachoma using azithromycin [3,4 ,5,10 ]. There are safety data available to justify combining albendazole, praziquantel, and ivermectin (reviewed in [5]). In many Asian countries, MDA is often integrated with diethylcarbamazine (DEC) for simultaneous gastrointestinal helminth and lymphatic filariasis control and elimination [5]. Liver fluke and intestinal fluke infections are not yet typically targeted in these efforts by adding praziquantel despite widespread &&
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endemicity in parts of China and Southeast Asia [14]. Furthermore, ivermectin is not commonly added for strongyloidiasis control. In Latin America and the Caribbean, deworming using either albendazole or mebendazole is commonly carried out with DEC added in a few areas where lymphatic filariasis occurs [15]. To our knowledge, ivermectin is not yet widely distributed for strongyloidiasis control in affected areas of Latin America, such as in northern Argentina or Brazil.
Disease mapping Prior to implementing MDA efforts, detailed maps are often generated for each disease-endemic area. Efforts to obtain up-to-date, accurate data are sometimes complicated by depleted health systems infrastructures, remoteness, and conflict. In August 2010, the Global Atlas of Helminth Infections (GAHI) was launched as an open-access knowledge management platform to determine the prevalence Volume 30 Number 1 January 2014
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Eliminating gastrointestinal helminth infections globally McCarty et al.
of several key STH infections and schistosomiasis [16]. The atlas encompasses maps for every country showing the prevalence based on survey data, illustrating which districts require MDA treatment, or where further surveys would be helpful in defining risk [16]. In addition, the WHO established a Preventive Chemotherapy and Transmission Control (PCT) Databank, creating a database that can be constantly updated based on new publications and reports, as well as field data provided by contributors [17 ]. Moreover, this allows detailed geostatistical analyses of disease distribution in space and time [18]. Both resources have enhanced our ability to identify disease burden and accurately plan interventions and strategies for change. &
Mass drug administration: achievements to date The WHO estimates that almost 900 million children are at risk for acquiring STH infections and require annual preventive chemotherapy [4 ,10 ]. MDA focuses on the use of single-dose albendazole or mebendazole, although the WHO also endorses use of levamisole and pyrantel when available. WHA resolution 66.12 builds on an earlier 2001 resolution (WHA 54.19) for reaching at least 75% and up to 100% of children at risk of morbidity [10 ,19]. To date, however, global coverage of the medicines used to prevent these during 2009 has reached only 30–40% of those in need [10 ]. In association with the London Declaration, MDA coverage is expected to improve, with 600 million free tablets of albendazole or mebendazole becoming available annually to treat school-aged children in endemic countries, which began in 2012 [20]. Yet, the projected number of anthelminthics needed for all countries to reach 75 and 100% national coverage by 2020 would need to be increased significantly [21 ]. Even if the global target to reach 75–100% is achieved, its impact on ultimately controlling pediatric STH infections worldwide has some uncertainties. Single-dose albendazole or mebendazole results in greater than a 90% cure rate for ascariasis, but significantly lower cure rates for hookworm and trichuriasis [5,22,23]. For instance, single-dose mebendazole for human hookworm infection results in only 15% cure and between 0 and 68% intensity reduction [23]. Infections with Necator americanus, the most predominant hookworm species, are particularly recalcitrant to the effects of single-dose mebendazole, the basis of which remains unknown [23,24]. For trichuriasis, the efficacy of albendazole or mebendazole to cure infection increases substantially when it is combined with ivermectin in programs for integrated NTD &&
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control [4 ,25]. For instance, mebendazole/ ivermectin combination showed a 55% Trichuris trichiura cure rate, significantly improved from mebendazole alone (19%) with egg reduction of 97% in combination therapy [26]. The safety data on adding ivermectin to benzimidazole anthelminthics have been reviewed previously [5], and therefore we believe that both anthelminthics could be employed for global deworming. However, given that ivermectin is not highly effective against N. americanus hookworms, it remains unclear whether this medicine in combination with the benzimidazoles will substantially improve cure rates for this particular STH infection.
IMPROVING MASS DRUG ADMINISTRATION FOR GASTROINTESTINAL HELMINTH INFECTIONS If the goal is to target both trichuriasis and strongyloidiasis in addition to current approaches that successfully treat ascariasis, expansion of deworming efforts with benzimidazole anthelminthics in combination with ivermectin might represent an essential step for advancing global helminth control. However, this approach may not be effective for hookworm infection when mebendazole is used, nor does it have an impact on liver or intestinal fluke infections. Therefore, we advocate for developing additional interventions.
Improved drugs and modeling The basis for single-dose mebendazole drug failure in hookworm is unknown. A genetic polymorphism in b-tubulin linked to benzimidazole resistance in livestock gastrointestinal helminths has not yet been conclusively identified for N. americanus [27]. However, given the rapidity by which resistance develops in livestock gastrointestinal helminths, it is prudent to promote drug discovery efforts for human STH infections. Along those lines, tribendimidine, an L-type nicotinic acetylcholine receptor approved by China since 2004 [28], has superior-to-equivalent cure rates against Ascaris lumbricoides (90.1–95.0%) and moderate-to-high cure rates against hookworm (82.0–88.4%). However, a single oral dose of tribendimidine showed lower cure rates against Strongyloides stercoralis (53.3%) and T. trichiura (23.9–36.8%). Tribendimidine may also prove to be an alternative anthelminthic drug for liver flukes, as it showed a cure rate for Opisthorchis viverrini (70.0%) and Clonorchis sinensis (40%) [29]. When combined with praziquantel, egg reduction rates were 99.3 and 98.4%,
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Gastrointestinal infections
respectively [30]. Monepantel and moxidectin are additional anthelminthic drugs, but do not appear to have a role in treating human STH infections at this time. Moxidectin is under development for systemic helminths such as onchocerciasis [31], and the efficacy of monepantel, a potential drug development candidate for human STH infections and a current veterinary drug, has been shown in animal models to have low activities against several of the major geohelminths [32]. Still another exciting new agent is a Bacillus thuringiensis-derived Cry5B crystal protein with in-vivo anthelminthic activity against Ascaris suum and hookworms [33,34]. Equally important is the need to expand use of transmission dynamics models in order to assess and optimize the impact of these anthelminthics. For instance, it has been suggested that targeting pediatric populations may be sufficient to interrupt transmission of ascariasis and trichuriasis because children harbor the highest-intensity infections [35], whereas it may not be expected to have an effect on hookworm transmission because adults harbor significant worm burdens [36 ]. &
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are 81, 54.4, and 14.3%, respectively [43 ], future generations, improved mobile phone image quality, and further testing may rapidly improve the diagnostic yield [44]. With improvements, the device could emerge as a simple, inexpensive, hand-held diagnostic tool to enhance helminth detection rates in the most rural of areas. Food-borne trematodiases remain a diagnostic challenge. Direct parasitological diagnosis, immunodiagnosis, and molecular diagnosis are the three main methods currently, each with shortcomings [45–48]. Molecular diagnosis using PCR has not yet translated widely to mass testing in rural areas.
Anthelminthic vaccines Although MDA and deworming programs together with improved sanitation and access to clean water are the mainstays of control, vaccines on the horizon could facilitate global elimination efforts. The Sabin Vaccine Institute Product Development Partnership is developing a bivalent human hookworm vaccine (HHV) consisting of two antigens: N. americanus GST-1 (Na-GST-1) and N. americanus APR-1 (M74) (Na-APR-1) [10 ,49 ]. The rationale and basis for antigen selection and approach to developing the HHV was recently reviewed [49 ]. Currently, the Na-GST-1 antigen is undergoing clinical testing in field trials in Brazil, while the Na-APR-1 antigen is expected to enter the clinic soon. It might also be possible to expand the valency of the HHV in order to develop a ‘pan-anthelminthic vaccine’ that simultaneously targets hookworm infection as well as ascariasis and trichuriasis. The two major antigens that compose the HHV exhibit considerable amino acid homology to ascaris antigens, whereas several other candidate antigens have been proposed [50,51,52 ]. Similarly, the feasibility of a trichuriasis vaccine in mice has been demonstrated using adult excretory–secretory products [53]. &&
Improved diagnostics Traditionally, stool microscopy has been utilized for the diagnosis of the various gastrointestinal helminth infections. However, the requirement for trained (and expensive) microscopists for such traditional diagnostic approaches has in some cases slowed global control efforts. There is a need to develop improved and field-ready diagnostics for most of the gastrointestinal helminthiases. The development of a quantitative multiparallel realtime PCR (qPCR) has shown increased detection rates and significantly increased specificity for A. lumbricoides, N. americanus, T. trichiura, and S. stercoralis [37 ]. qPCR also affords an increased ability to detect parasitic co-infections compared with microscopy [37 ]. FLOTAC is a novel technique examining fecal samples for the presence and count of parasitic elements (eggs, larvae, oocysts, and cysts). Previous studies have shown the FLOTAC technique is more sensitive than the Kato-Katz method for the diagnosis of STH infections [38–41]. However, recently, a study showed improved sensitivities for only T. trichiura and A. lumbricoides, not hookworm [42]. Another potential and highly innovative alternative to conventional microscopy is mobile phone microscopy. This diagnostic innovation involves an iPhone 4S, roughly US $250, and US $5 modification. Whereas sensitivity of STH infections of A. lumbricoides, T. trichiura, and hookworm &
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CONCLUSION Beyond ascariasis, current approaches using singledose albendazole and mebendazole for global deworming may not be adequate as a ‘one-sizefits-all’ approach for achieving London Declaration and WHA 66.12 targets. It may become necessary to add ivermectin for simultaneously targeting trichuriasis and strongyloidiasis [5], and possibly tribendimidine to praziquantel for selected food-borne trematode infections caused by liver and intestinal flukes. Greater application of helminth transmission dynamics might further optimize the use Volume 30 Number 1 January 2014
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Eliminating gastrointestinal helminth infections globally McCarty et al.
of these drugs in public health campaigns. Investments will also be required for low-cost disease mapping and simple rapid diagnostics in addition to MDA. Ultimately, the global control and elimination of gastrointestinal helminthiases must be conducted in parallel with a program of research and development for new anthelminthic drugs, diagnostics, and vaccines [54,55 ,56]. &
Acknowledgements P.J.H. is supported for work to develop a human hookworm vaccine by grants from the Bill & Melinda Gates Foundation, the Dutch Ministry of Foreign Affairs, and the European Commission FP-7 Program. Conflicts of interest P.J.H. is principal investigator and patent holder on vaccines in development against hookworm and schistosomiasis. For T.R.J. and J.A.T. there are no conflicts of interest to declare.
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Olliaro P, Seiler J, Kuesel A, et al. Potential drug development candidates for human soil-transmitted helminthiases. PLoS Negl Trop Dis 2011; 5:e1138. 32. Tritten L, Silbereisen A, Keiser J. In vitro and in vivo efficacy of Monepantel (AAD 1566) against laboratory models of human intestinal nematode infections. PLoS Negl Trop Dis 2011; 5:e1457. 33. Hu Y, Zhan B, Keegan B, et al. Mechanistic and single-dose in vivo therapeutic studies of Cry5B anthelmintic action against hookworms. PLoS Negl Trop Dis 2012; 6:e1900. 34. Urban JF Jr, Hu Y, Miller MM, et al. Bacillus thuringiensis-derived Cry5B has potent anthelmintic activity against Ascaris suum. PLoS Negl Trop Dis 2013; 7:e2263. 35. Thein H, Than S, Htay Htay A, et al. Epidemiology and transmission dynamics of Ascaris lumbricoides in Okpo village, rural Burma. Transactions of the Royal Society of Tropical Medicine and Hygiene 1984; 78:497–504. 36. Anderson RM, Truscott JE, Pullan RL, et al. How effective is school-based & deworming for the community-wide control of soil-transmitted helminths? PLoS Negl Trop Dis 2013; 7:e2027. New study illustrating how helminth transmission dynamics could be employed to optimize the use of anthelminthic drugs and why current MDA approaches focused on children will not eliminate hookworm.
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Gastrointestinal infections 37. Mejia R, Vicuna Y, Broncano N, et al. A novel, multiparallel, real-time polymerase chain reaction approach for eight gastrointestinal parasites provides improved diagnostic capabilities to resource-limited at-risk populations. Am J Trop Med Hyg 2013; 88:1041–1047. New PCR biotechnology for the diagnosis of STH infections. 38. Glinz D, Silue KD, Knopp S, et al. Comparing diagnostic accuracy of KatoKatz, Koga agar plate, ether-concentration, and FLOTAC for Schistosoma mansoni and soil-transmitted helminths. PLoS Negl Trop Dis 2010; 4:e754. 39. Knopp S, Glinz D, Rinaldi L, et al. FLOTAC: a promising technique for detecting helminth eggs in human faeces. Trans R Soc Trop Med Hyg 2009; 103:1190–1194. 40. Knopp S, Rinaldi L, Khamis IS, et al. A single FLOTAC is more sensitive than triplicate Kato-Katz for the diagnosis of low-intensity soil-transmitted helminth infections. Trans R Soc Trop Med Hyg 2009; 103:347–354. 41. Utzinger J, Rinaldi L, Lohourignon LK, et al. FLOTAC: a new sensitive technique for the diagnosis of hookworm infections in humans. Trans R Soc Trop Med Hyg 2008; 102:84–90. 42. Speich B, Knopp S, Mohammed KA, et al. Comparative cost assessment of the Kato-Katz and FLOTAC techniques for soil-transmitted helminth diagnosis in epidemiological surveys. Parasit Vectors 2010; 3:71. 43. Bogoch II, Andrews JR, Speich B, et al. Mobile phone microscopy for the & diagnosis of soil-transmitted helminth infections: a proof-of-concept study. Am J Trop Med Hyg 2013; 88:626–629. The use of a modified mobile phone as a potential alternative diagnostic modality to conventional microscopy for helminth infections. 44. Breslauer DN, Maamari RN, Switz NA, et al. Mobile phone based clinical microscopy for global health applications. PloS One 2009; 4:e6320. 45. Chai JY. Food-borne parasitic zoonoses: Fish and plant-borne parasites. World Class Parasites. Intestinal flukes 2007; 11:53–115. 46. Sripa B, Kaewkes S, Intapan PM, et al. Food-borne trematodiases in Southeast Asia epidemiology, pathology, clinical manifestation and control. Adv Parasitol 2010; 72:305–350. &
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47. Sithithaworn PYP, Tesana S, Pairojkul C. Liver flukes. Food-borne parasitic zoonoses, fish and plant-borne parasites. World Class Parasites 2007; 11:3–52. 48. Furst T, Sayasone S, Odermatt P, et al. Manifestation, diagnosis, and management of food-borne trematodiasis. BMJ 2012; 344:e4093. 49. Hotez PJ, Diemert D, Bacon KM, et al. The human hookworm vaccine. Vaccine && 2013; 31 (Suppl 2):B227–B232. New review on current progress of the human hookworm vaccine. 50. Tsuji N, Suzuki K, Kasuga-Aoki H, et al. Mice intranasally immunized with a recombinant 16-kilodalton antigen from roundworm Ascaris parasites are protected against larval migration of Ascaris suum. Infect Immun 2003; 71:5314–5323. 51. Tsuji N, Suzuki K, Kasuga-Aoki H, et al. Intranasal immunization with recombinant Ascaris suum 14-kilodalton antigen coupled with cholera toxin B subunit induces protective immunity to A. suum infection in mice. Infect Immun 2001; 69:7285–7292. 52. Chen N, Yuan ZG, Xu MJ, et al. Ascaris suum enolase is a potential vaccine & candidate against ascariasis. Vaccine 2012; 30:3478–3482. Potential vaccine candidate against ascariasis. 53. Dixon H, Johnston CE, Else KJ. Antigen selection for future anti-Trichuris vaccines: a comparison of cytokine and antibody responses to larval and adult antigen in a primary infection. Parasite Immunol 2008; 30:454–461. 54. Bergquist R, Lustigman S. Control of important helminthic infections vaccine development as part of the solution. Adv Parasitol 2010; 73:297– 326. 55. Lustigman S, Geldhof P, Grant WN, et al. A research agenda for helminth & diseases of humans: basic research and enabling technologies to support control and elimination of helminthiases. PLoS Negl Trop Dis 2012; 6:e1445. Summary of WHO expert review group on helminth infections. 56. Hotez P. Enlarging the ‘Audacious Goal’: elimination of the world’s high prevalence neglected tropical diseases. Vaccine 2011; 29 (Suppl 4):D104– D110.
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Global progress towards eliminating gastrointestinal helminth infections Thomas R. McCarty , Joshua A. Turkeltaub , and Peter J. Hotez
Purpose of review To highlight the gastrointestinal helminths in the context of renewed global commitment to control or eliminate neglected tropical diseases in the coming decade. Recent findings Two key documents, namely the 2012 London Declaration for Neglected Tropical Diseases and the 2013 World Health Assembly resolution, emphasize the importance of mass drug administration (MDA) for controlling several key neglected tropical diseases. These documents, together with the Global Burden of Disease Study 2010, establish the major gastrointestinal helminth infections, including the soil-transmitted helminthiases – ascariasis, trichuriasis, hookworm, and strongyloidiasis – in addition to the intestinal and liver fluke infections, as some of the most important gastrointestinal infections of humankind. Current MDA approaches using single-dose albendazole or mebendazole are effective for ascariasis, less so for other soil-transmitted helminth infections. Expanded use of albendazole in combination with ivermectin would ensure improved drug efficacies against trichuriasis and strongyloidiasis. There is no effective elimination strategy for targeting hookworm and liver and intestinal fluke infections through current MDA approaches. Summary The global community must expand current MDA efforts, while simultaneously developing additional drugs, diagnostics, and vaccines alongside better utilizing transmission dynamics and modeling, if it is to successfully meet the goals and targets established by policymakers. Keywords food-borne trematode, liver fluke infection, mass drug administration, neglected tropical diseases, soil-transmitted helminth
INTRODUCTION Recently, two important global health policies (and linked documents) regarding neglected tropical diseases (NTDs) were launched, each affirming a global commitment to control or eliminate these conditions. The first is the 2012 London Declaration for NTDs that sets control and elimination targets in the coming decade, with parallel commitments from the major multinational pharmaceutical companies as well as foundations and other nonprofits to provide essential medicines for mass drug administration (MDA) [1 ]. Another is the 2013 World Health Assembly resolution (WHA 66.12) urging the disease-endemic countries to assume ownership of their major NTDs through MDA, health system strengthening, and provision of safe drinking water and sanitation [2 ]. The NTDs are a group of chronic parasitic and related infectious diseases that disable pediatric and adult populations in developing countries through &&
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their effects on child development and productive capacity, respectively [3]. The WHO currently recognizes 17 major NTDs [4 ], including several helminthic diseases affecting the gastrointestinal tract, such as the three major soil-transmitted helminth (STH) infections, that is, ascariasis, trichuriasis, and hookworm infection. Strongyloidiasis is a fourth major STH infection. Beyond the STH infections, food-borne trematode infections caused by &&
National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, USA Correspondence to Peter J. Hotez, MD, PhD, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Tel: +1 713 798 1199; e-mail: [email protected] Thomas R. McCarty and Joshua A. Turkeltaub are medical students at Baylor College of Medicine and contributed equally to the writing of the manuscript.
Curr Opin Gastroenterol 2014, 30:18–24 DOI:10.1097/MOG.0000000000000025 Volume 30 Number 1 January 2014
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Eliminating gastrointestinal helminth infections globally McCarty et al.
KEY POINTS MDA currently reaches 30% of children at risk for acquiring the STH infections: ascariasis, trichuriasis, and hookworm infection, using single-dose albendazole or mebendazole. Even as global coverage increases under the auspices of the 2012 London Declaration and the 2013 WHA resolution 66.12, this approach alone may not be effective for controlling STH infections beyond ascariasis. Adding ivermectin globally will facilitate reductions or control of trichuriasis and strongyloidiasis, whereas adding tribendimidine to praziquantel may improve the control of relevant liver flukes. There is a need for better use of helminth transmission dynamics in order to model optimal use of existing drugs and to develop improved and field-ready drugs and diagnostics for gastrointestinal helminthiases. Anthelminthic vaccines that target hookworm or several STH infections simultaneously would be a major advance in global gastrointestinal helminthiases, control and elimination.
selected intestinal flukes and liver flukes affecting the bile ducts, that is, clonorchiasis and opisthorchiasis, have also emerged as leading gastrointestinal helminthiases. Today, each of these gastrointestinal helminth infections can be targeted for control through MDA with a benzimidazole anthelminthic (e.g. albendazole or mebendazole) for ascariasis, trichuriasis, and hookworm infection; ivermectin for strongyloidiasis; and praziquantel for clonorchiasis and opisthorchiasis [5], together with environmental control through sanitation and clean drinking water. Thus, it is expected that impoverished populations affected by gastrointestinal helminthiases would benefit from the renewed global commitments contained in the London Declaration and WHA 66.12. However, these measures alone may not be sufficient to achieve elimination, so that new biotechnologies, that is, additional drugs, diagnostics, and even vaccines, may need to be developed [6]. Here, we review progress on global efforts to control or eliminate the major gastrointestinal helminth infections listed above since we last reviewed them in 2009 [5], as well as newly published information from the Global Burden of Disease (GBD) Study 2010 [7 –9 ]. Specific progress on the leading pediatric NTDs, which include STH infections in both preschool and school-aged children as well as schistosomiasis, lymphatic filariasis, onchocerciasis, and trachoma, with an emphasis on the policy framework for these activities, was also just reviewed [10 ]. &
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THE MAJOR GASTROINTESTINAL HELMINTH INFECTIONS: SPECIFIC EFFECTS ON THE GASTROINTESTINAL TRACT AND DISEASE BURDEN &
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Listed in Table 1 [7 –9 ,11–13] are the major gastrointestinal helminthiases, their causes, and the most recently available data for their prevalence and disease burden measured in years lost from disability (YLDs) and disability-adjusted life years (DALYs) [7 –9 ,11,12]. Ascariasis is the most common gastrointestinal helminth infection, followed by the three other STH infections. Together, these helminthiases may represent the most common infections of humans. The liver fluke and intestinal fluke infections are less prevalent globally, although they are highly prevalent in East Asia [11]. With the exception of ascariasis, which can cause a significant global number of deaths from acute obstruction in young children, all of the DALYs are attributed to YLDs resulting from heavy infections, wasting, and abdominopelvic problems, in addition to anemia in the case of hookworm infection [9 ]. The GBD Study 2010 estimates that almost 6 million DALYs are lost annually from the major gastrointestinal helminth infections (no estimates for strongyloidiasis were obtained). This value exceeds the global disease burden resulting from better-known gastrointestinal conditions such as noninfective inflammatory bowel disease, appendicitis, gastritis, or pancreatitis [8 ]. Overall, the GBD Study 2010 likely underestimates the true disease burden from gastrointestinal helminth infections since it does not attribute any deaths to hookworm anemia, or to bile duct cancer from clonorchiasis or opisthorchiasis, even though thousands of people may die annually from these conditions. &
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GLOBAL CONTROL AND ELIMINATION World Health Assembly resolution 66.12 calls on member states to assume greater ownership of their NTD control programs, most of which include MDA efforts for gastrointestinal helminth infections [2 ]. Currently, most gastrointestinal helminth control programs are focused on targeting pediatric populations (preschool children and school-aged children) affected by ascariasis, trichuriasis, and hookworm infection with annual doses of albendazole or mebendazole [5,10 ]. In areas of very heavy intensity, sometimes twice-annual or even threetimes annual MDA is required because of rapid re-infection. This approach, while focusing on one of the most vulnerable populations, often leaves out adults with hookworm infection, especially pregnant women. Moreover, populations in Asia affected by high rates of liver and intestinal fluke
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Gastrointestinal infections Table 1. The major gastrointestinal helminth infections Global burden of disease: disease and parasite
Specific manifestations
Estimated prevalence
Estimated disease burden 2010 (YLDs)
Estimated disease burden 2010 (DALYs)
Reference
Ascariasis: Ascaris lumbricoides
Malabsorption, bowel obstruction, intussusception, volvulus, cholecystitis, pancreatitis, cholangitis
807–1221 million
1 111 000
1 315 000
[7 –9 ,11]
Trichuriasis: Trichuris trichiura
Colitis, anemia, impaired growth, chronic dysentery, rectal prolapse
604–795 million
638 000
638 000
[7 –9 ,11]
Hookworm: Necator americanus, Ancylostoma duodenale
Iron deficiency anemia, hypoproteinemia, anasarca
576–740 million
3 231 000
3 231 000
[7 –9 ,11]
Strongyloidiasis: Strongyloides stercoralis
Nausea, vomiting, constipation, diarrhea, hyperinfection, disseminated infection, ileus, intestinal obstruction, sepsis Epigastric pain, diarrhea, jaundice, gallstones, pyogenic cholangitis, hepatomegaly, cholangiocarcinoma
30–100 million
ND
ND
[7 –9 ,11]
1.7 million total; clonorchiasis 15.3 million, opisthorchiasis 8.4 million
356 000; clonorchiasis 296 000, opisthorchiasis 60 000
356 000
[7 –9 ,12]
Diarrhea, constipation, colic, edema, intestinal erosion, ulceration, hemorrhage
6.7 million
106 000
106 000
[7 –9 ,12,13]
>1 billion
5.4 million
5.6 million
Liver fluke infections – clonorchiasis and opisthorchiasis: Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus Intestinal fluke infections: Fasciolopsis buski and several other species Total
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DALYs, disability-adjusted life years; ND, not determined; YLDs, years lost from disability.
infections frequently do not receive praziquantel in large-scale control programs, and, globally, strongyloidiasis is not generally targeted for MDA even though ivermectin may present an attractive agent for that purpose. Both the WHA and the WHO use the term ‘preventive chemotherapy’ to describe MDA for gastrointestinal helminthiases using single-dose albendazole or mebendazole, which in many African countries is integrated with MDA for schistosomiasis using praziquantel; lymphatic filariasis and onchocerciasis using ivermectin; and trachoma using azithromycin [3,4 ,5,10 ]. There are safety data available to justify combining albendazole, praziquantel, and ivermectin (reviewed in [5]). In many Asian countries, MDA is often integrated with diethylcarbamazine (DEC) for simultaneous gastrointestinal helminth and lymphatic filariasis control and elimination [5]. Liver fluke and intestinal fluke infections are not yet typically targeted in these efforts by adding praziquantel despite widespread &&
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endemicity in parts of China and Southeast Asia [14]. Furthermore, ivermectin is not commonly added for strongyloidiasis control. In Latin America and the Caribbean, deworming using either albendazole or mebendazole is commonly carried out with DEC added in a few areas where lymphatic filariasis occurs [15]. To our knowledge, ivermectin is not yet widely distributed for strongyloidiasis control in affected areas of Latin America, such as in northern Argentina or Brazil.
Disease mapping Prior to implementing MDA efforts, detailed maps are often generated for each disease-endemic area. Efforts to obtain up-to-date, accurate data are sometimes complicated by depleted health systems infrastructures, remoteness, and conflict. In August 2010, the Global Atlas of Helminth Infections (GAHI) was launched as an open-access knowledge management platform to determine the prevalence Volume 30 Number 1 January 2014
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Eliminating gastrointestinal helminth infections globally McCarty et al.
of several key STH infections and schistosomiasis [16]. The atlas encompasses maps for every country showing the prevalence based on survey data, illustrating which districts require MDA treatment, or where further surveys would be helpful in defining risk [16]. In addition, the WHO established a Preventive Chemotherapy and Transmission Control (PCT) Databank, creating a database that can be constantly updated based on new publications and reports, as well as field data provided by contributors [17 ]. Moreover, this allows detailed geostatistical analyses of disease distribution in space and time [18]. Both resources have enhanced our ability to identify disease burden and accurately plan interventions and strategies for change. &
Mass drug administration: achievements to date The WHO estimates that almost 900 million children are at risk for acquiring STH infections and require annual preventive chemotherapy [4 ,10 ]. MDA focuses on the use of single-dose albendazole or mebendazole, although the WHO also endorses use of levamisole and pyrantel when available. WHA resolution 66.12 builds on an earlier 2001 resolution (WHA 54.19) for reaching at least 75% and up to 100% of children at risk of morbidity [10 ,19]. To date, however, global coverage of the medicines used to prevent these during 2009 has reached only 30–40% of those in need [10 ]. In association with the London Declaration, MDA coverage is expected to improve, with 600 million free tablets of albendazole or mebendazole becoming available annually to treat school-aged children in endemic countries, which began in 2012 [20]. Yet, the projected number of anthelminthics needed for all countries to reach 75 and 100% national coverage by 2020 would need to be increased significantly [21 ]. Even if the global target to reach 75–100% is achieved, its impact on ultimately controlling pediatric STH infections worldwide has some uncertainties. Single-dose albendazole or mebendazole results in greater than a 90% cure rate for ascariasis, but significantly lower cure rates for hookworm and trichuriasis [5,22,23]. For instance, single-dose mebendazole for human hookworm infection results in only 15% cure and between 0 and 68% intensity reduction [23]. Infections with Necator americanus, the most predominant hookworm species, are particularly recalcitrant to the effects of single-dose mebendazole, the basis of which remains unknown [23,24]. For trichuriasis, the efficacy of albendazole or mebendazole to cure infection increases substantially when it is combined with ivermectin in programs for integrated NTD &&
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control [4 ,25]. For instance, mebendazole/ ivermectin combination showed a 55% Trichuris trichiura cure rate, significantly improved from mebendazole alone (19%) with egg reduction of 97% in combination therapy [26]. The safety data on adding ivermectin to benzimidazole anthelminthics have been reviewed previously [5], and therefore we believe that both anthelminthics could be employed for global deworming. However, given that ivermectin is not highly effective against N. americanus hookworms, it remains unclear whether this medicine in combination with the benzimidazoles will substantially improve cure rates for this particular STH infection.
IMPROVING MASS DRUG ADMINISTRATION FOR GASTROINTESTINAL HELMINTH INFECTIONS If the goal is to target both trichuriasis and strongyloidiasis in addition to current approaches that successfully treat ascariasis, expansion of deworming efforts with benzimidazole anthelminthics in combination with ivermectin might represent an essential step for advancing global helminth control. However, this approach may not be effective for hookworm infection when mebendazole is used, nor does it have an impact on liver or intestinal fluke infections. Therefore, we advocate for developing additional interventions.
Improved drugs and modeling The basis for single-dose mebendazole drug failure in hookworm is unknown. A genetic polymorphism in b-tubulin linked to benzimidazole resistance in livestock gastrointestinal helminths has not yet been conclusively identified for N. americanus [27]. However, given the rapidity by which resistance develops in livestock gastrointestinal helminths, it is prudent to promote drug discovery efforts for human STH infections. Along those lines, tribendimidine, an L-type nicotinic acetylcholine receptor approved by China since 2004 [28], has superior-to-equivalent cure rates against Ascaris lumbricoides (90.1–95.0%) and moderate-to-high cure rates against hookworm (82.0–88.4%). However, a single oral dose of tribendimidine showed lower cure rates against Strongyloides stercoralis (53.3%) and T. trichiura (23.9–36.8%). Tribendimidine may also prove to be an alternative anthelminthic drug for liver flukes, as it showed a cure rate for Opisthorchis viverrini (70.0%) and Clonorchis sinensis (40%) [29]. When combined with praziquantel, egg reduction rates were 99.3 and 98.4%,
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Gastrointestinal infections
respectively [30]. Monepantel and moxidectin are additional anthelminthic drugs, but do not appear to have a role in treating human STH infections at this time. Moxidectin is under development for systemic helminths such as onchocerciasis [31], and the efficacy of monepantel, a potential drug development candidate for human STH infections and a current veterinary drug, has been shown in animal models to have low activities against several of the major geohelminths [32]. Still another exciting new agent is a Bacillus thuringiensis-derived Cry5B crystal protein with in-vivo anthelminthic activity against Ascaris suum and hookworms [33,34]. Equally important is the need to expand use of transmission dynamics models in order to assess and optimize the impact of these anthelminthics. For instance, it has been suggested that targeting pediatric populations may be sufficient to interrupt transmission of ascariasis and trichuriasis because children harbor the highest-intensity infections [35], whereas it may not be expected to have an effect on hookworm transmission because adults harbor significant worm burdens [36 ]. &
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are 81, 54.4, and 14.3%, respectively [43 ], future generations, improved mobile phone image quality, and further testing may rapidly improve the diagnostic yield [44]. With improvements, the device could emerge as a simple, inexpensive, hand-held diagnostic tool to enhance helminth detection rates in the most rural of areas. Food-borne trematodiases remain a diagnostic challenge. Direct parasitological diagnosis, immunodiagnosis, and molecular diagnosis are the three main methods currently, each with shortcomings [45–48]. Molecular diagnosis using PCR has not yet translated widely to mass testing in rural areas.
Anthelminthic vaccines Although MDA and deworming programs together with improved sanitation and access to clean water are the mainstays of control, vaccines on the horizon could facilitate global elimination efforts. The Sabin Vaccine Institute Product Development Partnership is developing a bivalent human hookworm vaccine (HHV) consisting of two antigens: N. americanus GST-1 (Na-GST-1) and N. americanus APR-1 (M74) (Na-APR-1) [10 ,49 ]. The rationale and basis for antigen selection and approach to developing the HHV was recently reviewed [49 ]. Currently, the Na-GST-1 antigen is undergoing clinical testing in field trials in Brazil, while the Na-APR-1 antigen is expected to enter the clinic soon. It might also be possible to expand the valency of the HHV in order to develop a ‘pan-anthelminthic vaccine’ that simultaneously targets hookworm infection as well as ascariasis and trichuriasis. The two major antigens that compose the HHV exhibit considerable amino acid homology to ascaris antigens, whereas several other candidate antigens have been proposed [50,51,52 ]. Similarly, the feasibility of a trichuriasis vaccine in mice has been demonstrated using adult excretory–secretory products [53]. &&
Improved diagnostics Traditionally, stool microscopy has been utilized for the diagnosis of the various gastrointestinal helminth infections. However, the requirement for trained (and expensive) microscopists for such traditional diagnostic approaches has in some cases slowed global control efforts. There is a need to develop improved and field-ready diagnostics for most of the gastrointestinal helminthiases. The development of a quantitative multiparallel realtime PCR (qPCR) has shown increased detection rates and significantly increased specificity for A. lumbricoides, N. americanus, T. trichiura, and S. stercoralis [37 ]. qPCR also affords an increased ability to detect parasitic co-infections compared with microscopy [37 ]. FLOTAC is a novel technique examining fecal samples for the presence and count of parasitic elements (eggs, larvae, oocysts, and cysts). Previous studies have shown the FLOTAC technique is more sensitive than the Kato-Katz method for the diagnosis of STH infections [38–41]. However, recently, a study showed improved sensitivities for only T. trichiura and A. lumbricoides, not hookworm [42]. Another potential and highly innovative alternative to conventional microscopy is mobile phone microscopy. This diagnostic innovation involves an iPhone 4S, roughly US $250, and US $5 modification. Whereas sensitivity of STH infections of A. lumbricoides, T. trichiura, and hookworm &
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CONCLUSION Beyond ascariasis, current approaches using singledose albendazole and mebendazole for global deworming may not be adequate as a ‘one-sizefits-all’ approach for achieving London Declaration and WHA 66.12 targets. It may become necessary to add ivermectin for simultaneously targeting trichuriasis and strongyloidiasis [5], and possibly tribendimidine to praziquantel for selected food-borne trematode infections caused by liver and intestinal flukes. Greater application of helminth transmission dynamics might further optimize the use Volume 30 Number 1 January 2014
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Eliminating gastrointestinal helminth infections globally McCarty et al.
of these drugs in public health campaigns. Investments will also be required for low-cost disease mapping and simple rapid diagnostics in addition to MDA. Ultimately, the global control and elimination of gastrointestinal helminthiases must be conducted in parallel with a program of research and development for new anthelminthic drugs, diagnostics, and vaccines [54,55 ,56]. &
Acknowledgements P.J.H. is supported for work to develop a human hookworm vaccine by grants from the Bill & Melinda Gates Foundation, the Dutch Ministry of Foreign Affairs, and the European Commission FP-7 Program. Conflicts of interest P.J.H. is principal investigator and patent holder on vaccines in development against hookworm and schistosomiasis. For T.R.J. and J.A.T. there are no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. London Declaration of Neglected Tropical Diseases. London; January 2013. Uniting to combat NTDs. http://unitingtocombatntds.org/downloads/ press/ntd_event_london_declaration_on_ntds.pdf. [Accessed 14 July 2013] The first annual report on the London Declaration on NTDs bringing together a group of partners in the NTD community in line with targets set by the WHO. 2. WHA 66.12. Sixty-Sixth World Health Assembly. Geneva; 27 May 2013. && http://www.who.int/neglected_diseases/mediacentre/WHA_66.12_Eng.pdf. [Accessed 16 June 2013] A World Health Assembly resolution addressing and encouraging both diseaseendemic countries and WHO’s international partners towards the goal of overcoming neglected tropical diseases. 3. Hotez PJ, Molyneux DH, Fenwick A, et al. Control of neglected tropical diseases. N Engl J Med 2007; 357:1018–1027. 4. WHO. Accelerating work to overcome the global impact of neglected tropical && diseases: a roadmap for implementation. Geneva; 2012. http://whqlibdoc. who.int/hq/2012/WHO_HTM_NTD_2012.1_eng.pdf. [Accessed 16 June 2013]. A roadmap aimed at guiding the implementation of policies and strategies for combating neglected tropical diseases. It addresses current interventions, shortcomings, costs, financing, and milestones in hopes of achieving the eradication and elimination of neglected tropical diseases. 5. Hotez PJ. Mass drug administration and integrated control for the world’s high-prevalence neglected tropical diseases. Clin Pharmacol Therapeut 2009; 85:659–664. 6. Hotez PJ, Pecoul B. ‘Manifesto’ for advancing the control and elimination of neglected tropical diseases. PLoS Negl Trop Dis 2010; 4:e718. 7. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from & 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study. Lancet 2012; 380:2095– 2128. An analysis on global and regional causes of death in 1990 and 2010. 8. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for & 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2197– 2223. Recently released summary of the Global Burden of Disease Study 2010. 9. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for & 1160 sequelae of 289 diseases and injuries 1999–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2163–2196. GBD Study 2010 that identifies the clinical sequelae used in calculated years lived with disability from gastrointestinal helminth infections. &&
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