A disproportionate burden of helminthiases in human populations occurs in marginalised, low-income, and resource-constrained regions of the world, with over 1 billion people in developing areas of sub-Saharan Africa, Asia, and the Americas infected with one or more helminth species. The morbidity caused by such infections imposes a substantial burden of disease, contributing to a vicious circle of infection, poverty, decreased productivity, and inadequate socioeconomic development. Furthermore, helminth infection accentuates the morbidity of malaria and HIV/AIDS, and impairs vaccine efficacy. Polyparasitism is the norm in these populations, and infections tend to be persistent. Hence, there is a great need to reduce morbidity caused by helminth infections. However, major deficiencies exist in diagnostics and interventions, including vector control, drugs, and vaccines. Overcoming these deficiencies is hampered by major gaps in knowledge of helminth biology and transmission dynamics, platforms from which to help develop such tools. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, we provide an overview of the forces driving the persistence of helminthiases as a public health problem despite the many control initiatives that have been put in place; identify the main obstacles that impede progress towards their control and elimination; and discuss recent advances, opportunities, and challenges for the understanding of the biology, epidemiology, and control of these infections. The helminth infections that will be discussed include: onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, food-borne trematodiases, and taeniasis/cysticercosis.
Citation: Lustigman S, Prichard RK, Gazzinelli A, Grant WN, Boatin BA, McCarthy JS, et al. (2012) A Research Agenda for Helminth Diseases of Humans: The Problem of Helminthiases. PLoS Negl Trop Dis 6(4): e1582. https://doi.org/10.1371/journal.pntd.0001582
Editor: Charles D. Mackenzie, Michigan State University, United States of America
Published: April 24, 2012
Copyright: © 2012 Lustigman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: SL received intramural funding from the New York Blood Center and a research grant from the NIAID/NIH (R01AI078314). Research by RKP and BAB, at the Institute of Parasitology, McGill University, is supported by a Regroupement Stratégique grant from FQRNT, Quebec to the Centre for Host-Parasite Interactions. AG receives financial support from CNPq, INCT ( http://www.cnpq.br ) and FAPEMIG ( http://www.fapemig.br ). JSMC is funded by an NHMRC Practitioner Fellowship and by a Government of Queensland Health Research Fellowship. M-GB is funded by the Wellcome Trust, http://www.wellcome.ac.uk (Grants 085133/Z/08/Z and 092677/Z/10/Z) and the Royal Society-Leverhulme Trust ( http://www.royalsociety.org ), for a Capacity Building Africa Award. The Special Programme for Research and Training in Tropical Diseases (TDR) provided both technical and financial support to the Disease Reference Group on Helminth Infections (DRG4), and the European Commission provided financial support under Agreement PP-AP/2008/160-163. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Since the publication by Norman Stoll in 1947 of “This Wormy World” Leather Sneakers Alexander White Size Alexander 36 Woman Wang Wang N185ETt  , where the intolerable burden of intestinal nematode infections was highlighted, several global efforts have been made to address the health effects of human parasitism by helminths. Helminths (roundworm and flatworm parasites) are among the most widespread infectious agents of human populations. Today, they disproportionately affect marginalised, low-income, and resource-constrained regions of the world. It is estimated that over 1 billion people in developing regions areas of sub-Saharan Africa (SSA), Asia, and the Americas are infected with one or more species of helminths  ,  . The morbidity associated with most of the helminthic diseases we focus on in this report and in the other reviews in this issue are closely linked to poverty; they result from poverty and markedly contribute to further poverty by, among others, impairing agricultural and economic productivity, and they exert a detrimental impact on cognitive development and educational outcomes, thereby hampering socioeconomic development. Moreover, the infections themselves may accentuate the effect of other significant pathogens such as malaria and HIV, and attenuate the response to a range of vaccines.
In response to growing evidence demonstrating the devastating impact of these neglected tropical diseases (NTDs) on the bottom billion of the world population through their effects on health, education, and socioeconomic development, the World Health Assembly (WHA) has adopted several resolutions calling for the control or elimination of these diseases, and for the implementation of a number of large-scale control and elimination programmes. These have been aimed at the parasites themselves and/or the agents (vectors and intermediate hosts) responsible for their transmission. In 1974, WHA resolution WHA27.52 was passed, calling upon the World Health Organization (WHO) to intensify research on major parasitic diseases. This led in 1975 to the creation of the Special Programme for Training and Research in Tropical Diseases (TDR). That year also saw the commencement of antivectorial operations by the Onchocerciasis Control Programme (OCP) in West Africa. In 1993 and 1995, respectively, the Onchocerciasis Elimination Program for the Americas (OEPA) and the African Programme for Onchocerciasis Control (APOC) were initiated. In 1997, resolution WHA50.29 was passed, which urged the WHO and member states to eliminate lymphatic filariasis (LF). This led to the formation of the Global Programme to Eliminate Lymphatic Filariasis (GPELF), which is supported by the Global Alliance to Eliminate Lymphatic Filariasis (GAELF), a public–private partnership that was launched in 2000 to support the GPELF in fundraising, advocacy, communications, resource mobilisation, and programme implementation. In 2001, resolution WHA54.19 was passed, setting the global target of treating by the year 2010 at least 75% of all school-age children at risk of morbidity from soil-transmitted helminthiases (STHs) and schistosomiasis. This resolution led to the establishment of Partners for Parasite Control (PPC) by the WHO. More recently, the global public health community has been invigorated by the articulation of the Millennium Development Goals (MDGs), which are: MDG1: Eradicate extreme poverty and hunger; MDG2: Achieve universal primary education; MDG3: Promote gender equality and empower women; MDG4: Reduce child mortality; MDG5: Improve maternal health; MDG6: Combat HIV/AIDS, malaria and other diseases; MDG7: Ensure environmental sustainability; and MDG8: Develop a global partnership for development
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. Several new initiatives have been also been established, most notably the Schistosomiasis Control Initiative (SCI) in 2002 and the Global Network for Neglected Tropical Disease Control (GNNTDC) in 2006.
However, despite such WHA/WHO resolutions, the initiatives described above, and the many scientific advances in our understanding of the biology and epidemiology of helminth infections, obstacles remain that challenge the global public health community in their efforts to attain the aims of controlling morbidity and eliminating infection. Some of the identified obstacles include the current scarcity of tools for: 1) updated disease mapping (particularly as interventions progress); 2) new anthelmintics and vaccines that would provide higher levels of control and greater sustainability than currently available to the present control measures; 3) improved, more sensitive diagnostics that are required for specific activities, such as in elimination settings; 4) monitoring the progress of control interventions and quantifying changes in incidence of infection and disease; 5) assessing the efficacy of drug and interventions to control vectors/intermediate hosts (e.g., insecticides) and promptly detecting possible development of resistance to these; 6) determining programme end points (for elimination of the public health burden and/or the infection reservoir) and deciding when interventions could be safely stopped; and 7) implementing post-control surveillance. Research gaps in these and other areas, as well as inclusion of a research and development agenda for human helminthiases for each of the topics covered (interventions, diagnostics, basic biology, mathematical modelling, social and environmental determinants, and capacity building) have been the subject of deliberation by the Disease Reference Group on Helminth Infections (DRG4), established in 2009 by TDR, and will be further discussed in detail in the following reviews within this PLoS Neglected Tropical Diseases collection. Box 1 lists the abbreviations used in this paper.
Alexander Woman Leather Size Wang White Wang Sneakers 36 Alexander 0YUtR Box 1. List of Abbreviations
ADLA , acute dermatolymphangioadenitis
DALY , disability-adjusted life year
DRG4 , Disease Reference Group on Helminth Infections
EST , expressed sequence tag
GIS , geographical information systems
GAELF , Global Alliance to Eliminate Lymphatic Filariasis
GNNTDC , Global Network for Neglected Tropical Disease Control
GPELF , Global Programme to Eliminate Lymphatic Filariasis
LF , lymphatic filariasis
Alexander Wang Size Woman Alexander Sneakers Wang White Leather 36 vkYy059k MDGs , Millennium Development Goals
MSAT , mass screen and treat
NCC , neurocysticercosis
NTDs , neglected tropical diseases
OCP , Onchocerciasis Control Programme in West Africa
M&E , monitoring and evaluation
OEPA , Onchocerciasis Elimination Program for the Americas
OSD , onchocercal skin disease
PPC , Partners for Parasite Control
REA , rapid epidemiological assessment
RNAi , RNA interference
RS , remote sensing
SCI , Schistosomiasis Control Initiative
STHs , soil-transmitted helminthiases
SSA , sub-Saharan Africa
TDR , Special Programme for Research and Training in Tropical Diseases
WHA , World Health Assembly
WHO , World Health Organization
Human Helminthiases, Populations at Risk, and Resulting Diseases
Helminth parasites are parasitic worms from the phyla Nematoda (roundworms) and Platyhelminthes (flatworms). Together, they comprise the most common infectious agents of humans in developing countries. The most common helminthiases of humans are those caused by intestinal infection with STHs, namely
, and hookworms (
), followed by schistosomiasis and lymphatic filariasis (LF). In
the estimated number of people infected (although estimates are given separately, there is a significant amount of co-infection), the burden of disease (in terms of disability-adjusted life years [DALYs]), and the estimated number of annual deaths attributable to each disease, are summarised for each condition. The collective burden of the common helminth diseases rivals that of the main high-mortality conditions such as HIV/AIDS or malaria; 85% of the NTD burden for the poorest 500 million people living in SSA results from helminth infections. Of the 580 million people in Latin America and the Caribbean, 241 million live in areas where at least one of the NTDs is endemic
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. Since the remit of the series of these review papers is centered on the issues of identifying research priorities for the improvement of helminth control programmes, the infections described below are ordered not in terms of their abundance but in terms of their history of intervention, with the OCP in West Africa (1975–2002) being the first large-scale programme to have been implemented (originally based on vector control).
Onchocerciasis (caused by infection with Wang Woman Leather Alexander 36 Alexander White Size Wang Sneakers 0U21g Onchocerca volvulus ) affects, according to recent estimates  , 37 million people in 34 countries and is the second cause of infectious blindness after trachoma, with 99% of the cases in SSA. In Latin America, onchocerciasis has been endemic in six countries (namely, Mexico, Guatemala, Colombia, Ecuador, Venezuela, and Brazil), with 13 focal areas originally described, and 510,000 individuals estimated to have been at risk of infection  . However, in eight of these focal areas, there is encouraging evidence of interruption of transmission after the implementation of the regional strategy adopted by the OEPA  ,  . Notably, most of these foci are small and circumscribed, with probably not much genetic diversity in the parasite population at any single focus, some (though not all) of the blackfly vectors are less efficient than their African counterparts, and treatment with ivermectin has been more frequent (biannually instead of yearly, and in some localities up to four times per year) and has achieved a high coverage  .
In onchocerciasis, morbidity is manifested as ocular involvement including blindness, dermal involvement including skin disease and palpable nodules, neuro-hormonal involvement including associations with epilepsy and hypo-sexual dwarfism (Nakalanga syndrome), and lymphatic involvement including lymphadenopathy, hanging groin, and lymphoedema. Although onchocercal ocular disease and blindness are more prominent in African savannah regions, onchodermatitis or onchocercal skin disease (OSD) has a higher prevalence in forest areas, possibly because of differences in parasite strains. The importance of OSD as a contributor to the disease burden of onchocerciasis has been recognised relatively recently  . In 1995, the year APOC was implemented (and 25 years after the commencement of the OCP), the burden of disease was estimated to amount to 1.99 million DALYs lost because of onchocerciasis. In 2003, on the basis of updated mapping and treatment coverage data, and assumed decreases in attributable morbidity due to skin and eye disease, the DALYs due to onchocerciasis were re-estimated to have reduced to 1.49 million  .
LF is endemic in 83 countries and territories. It is estimated that 1.3 billion people are at risk for developing the disease, with some 120 million people being infected
. Over 40 million people are seriously incapacitated and disfigured by the disease. Of these, 95% are infected with
, and the remainder with
. The infection, usually acquired in early childhood, causes considerable morbidity and social stigma because of the deformities it produces. LF provokes acute dermatolymphangioadenitis (ADLA) and lymphoedema. Major chronic manifestations include hydrocoele and lymphoedema of limbs, as well as chyluria, lymphoedema of the scrotum, adenopathy, haematuria, and tropical pulmonary eosinophilia. The disease causes permanent and long-term disability, and damages and deforms the limbs, breasts, and genitals, resulting in serious psychosocial consequences. Worldwide, 5 million DALYs are lost annually due to LF
. The Southeast Asia region accounts for about 57% of the total global burden. India's economic losses due to LF have been estimated at ∼US$ 1 billion per year
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The STHs are intestinal nematode infections and are among the most common and persistent parasitic infections worldwide. According to the latest estimates, 1221–1472 million people are infected with roundworm (
), 795–1050 million with whipworm (
), and 740–1300 million with hookworm (
. Although not mentioned further in this report, it is worth noting that an unknown, but estimated 30–100 million people are infected with threadworm (
. The morbidity attributable to this lifelong infection is poorly studied but the serious morbidity and mortality it causes in immuno-suppressed individuals continues to be reported in the medical literature
. In Latin America and the Caribbean, STHs are present in all countries with an estimated 26.3 million school-age children at risk of infection. In 13 of the 14 countries in this region, many areas have an infection prevalence higher than 20%
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. Globally, approximately 300 million people suffer from severe morbidity that results in 10,000–135,000 deaths annually. However, their greatest impact is through the impairment of physical and mental development in children, which ultimately retards educational advancement and economic productivity. The relationship between hookworm infection and anaemia is well recognised, with numerous intervention trials showing a direct effect of cure of infection with reduction in prevalence and intensity of iron deficiency anaemia. However, for A. lumbricoides and T. trichiura infection, the relationship between infection and specific morbidity measures is less well established. The uncommon, but potentially severe, adverse clinical outcomes of rectal prolapse due to T. trichiura infection and bile duct or intestinal obstruction due to A. lumbricoides infection are well recognised in the medical literature. However, there is a lack of epidemiological data defining the prevalence of these complications, and relating them to community prevalence and infection intensity  –  . Less easily measured parameters such as hypoproteinemia have been attributed to heavy infection with these parasites, but likewise there is a dearth of quality epidemiological data. Studies have been undertaken to relate school, cognitive, and athletic performance to infection, largely through chemotherapy interventions. While there appears to be some effect, distinguishing this from other coexisting confounding variables such as micro- and macronutrient deficiency is not straightforward.
Schistosomiasis is endemic in 76 countries and territories in the tropics and subtropics. Schistosoma mansoni is endemic in 54 countries and S. haematobium in 55  . Infection by S. japonicum remains an important public health burden in the Philippines, China, and parts of Indonesia, despite continued efforts by ongoing control programmes  . Worldwide, almost 800 million individuals are at risk; about 200 million people are estimated to be infected, and over half of these have various degrees of morbidity  –  . Of the 200 million people infected with Wang Alexander 36 Wang Leather White Alexander Size Woman Sneakers 9kNnrpI Schistosoma spp. in the world, 160 live in SSA, where approximately 110 million are infected with S. haematobium  . Schistosomiasis causes 15,000–280,000 deaths annually in SSA alone  and severe disability in approximately 20 million people. In its chronic stage, the disease is associated with liver and bladder cancer.
Infection with S. haematobium is particularly burdensome, causing a large number of cases of hydronephrosis, renal failure, and bladder cancer. Women with urinary/genital schistosomiasis are at an increased risk of acquiring HIV infection  . Over 80% of the schistosomiasis burden is concentrated in SSA. In Latin America and the Caribbean, S. mansoni infection is prevalent in four countries: Brazil, Saint Lucia, Suriname, and Venezuela, with 25 million people at risk of infection and 1–3 million people infected. The figures presented in Table 1 (corresponding to the Global Burden of Disease estimates for 2000 and updated in 2004) are thought to considerably underestimate the true burden of schistosomiasis  ,  . As for almost all helminth infections, schistosome infection is not equivalent to schistosomiasis disease. Likewise, there is a paucity of validated direct and indirect indicators of schistosome-related morbidity  –  . In urinary schistosomiasis, macroscopic haematuria is an obvious early sign of morbidity. However, for S. mansoni and S. japonicum , assessment of morbidity is more difficult. Furthermore, few, if any, of the clinical manifestations of schistosomiasis are specific and overlap with other causes, including other helminth infections, malaria, and viral hepatitis, which often are co-endemic with schistosomiasis.
Food-borne trematodiases, including liver flukes ( Opisthorchis viverrini , Op. felineus , and Clonorchis sinensis ) and lung flukes ( Paragonimus spp.), remain important public health problems, particularly in Asia. Chronic infections with Op. viverrini and C. sinensis have long been associated with cholangiocarcinoma (bile duct cancer). C. sinensis is widespread in China, Korea, and Vietnam, while Op. viverrini is endemic in Southeast Asia, including Thailand, Lao People's Democratic Republic (Lao PDR), Cambodia, and central Vietnam. Recent reports suggest that about 35 million people globally are infected with C. sinensis , with up to 15 million human infections in China alone and another 10 million individuals infected with Op. viverrini in Thailand and Lao PDR. In a recent review it was estimated that 80 million people in Thailand, Lao PDR, Cambodia, Vietnam, and Eastern Europe are at risk for infection with Op. viverrini and Op. felineus . Over 45 million people are infected by both liver flukes Op. viverrini and C. sinensis . More than 600 million people, mainly in Asia, including China, Korea, Taiwan, and Vietnam, are at risk of infection  . The infections are associated with hepatobiliary diseases including hepatomegaly, cholangitis, fibrosis of the periportal system, cholecystitis, gallstone disease, and, importantly, are major precipitants of cholangiocarcinoma. The liver fluke–endemic area of Khon Kaen in northeast Thailand has reported the highest incidence of this liver cancer in the world  . Indeed, liver and bile duct cancers, end-stage consequences of liver fluke disease, rank number five in Thai males and number six in females among all diseases in terms of DALYs in 2005. About 56.2 million people were infected with food-borne trematodes in 2005, 7.9 million had severe sequelae, and 7,158 died, mostly from cholangiocarcinoma and cerebral infection. Taken together, the global burden of food-borne trematodiasis was estimated at 665,352 DALYs (ranging from 479,496 to 859,051)  .
Taeniasis/CysticercosisWhite Wang Leather Alexander Wang Sneakers 36 Size Alexander Woman 3vnbgRaY
Human infections with the cestode parasite Taenia solium are endemic in Latin America, most parts of Asia (including China and the Indian subcontinent), Eastern Europe, and most of Africa. Imported cases occur in most developed countries due to immigration from and tourism to endemic regions. T. solium infection, which causes intestinal taeniasis and tissue cysticercosis, represent two different life stages and clinical entities in the human host. Intestinal taeniasis with the adult tapeworm (when humans act as definitive hosts) causes low morbidity by itself, but represents the sole source of the more pathogenic tissue infection, designated cysticercosis, that affects both humans and pigs. Cysticercosis, the infection with the larval stage of the parasite or cysticercus (when humans act as “intermediate hosts”), is a major cause of seizure disorders worldwide (human neurocysticercosis or NCC), and also causes economic losses due to infected pork (porcine cysticercosis). The most consistent indicator of the prevalence of neurocysticercosis is that of seizure disorders. In several endemic areas of Latin America, the attributed fraction for NCC is around 30% of all seizure disorders, with this estimate also being consistent among people with epilepsy worldwide  . Subarachnoid NCC is also associated with intracranial hypertension and mortality.Lands Jersey Cap Womens End BLUE Midi Sleeve 1416 Print Dress 8FW1q
–  as well as in industrialised countries such as the United States where it is becoming a better recognised and possibly an increasing problem, the latter because of immigration of tapeworm carriers from endemic areas. As the estimate for the proportion of NCC among people with epilepsy is very robust  , it could be used, in conjunction with estimates of the prevalence and incidence of epilepsy, to estimate this component of the burden of NCC in endemic areas.
Distribution and Co-Occurrence
Epidemiologically, human helminthiases are characterised by long-lasting infection with one or, more often, more than one of the helminth species referred to above. This phenomenon, known as polyparasitism, is the result of commonalities in ecological and environmental requirements, infection routes, host exposures, and susceptibility, as well as behavioural, sociological, and economic factors that enable co-occurrence of a multiplicity of parasite–host systems in time and space. In Figure 1 , the geographical distribution of co-occurrence of helminth species (LF, onchocerciasis, schistosomiasis, and STHs) at country level is presented.Asos Contrast Embroidered Contrast multi Kaftan Maxi Statement Black Statement qt8Zptnr
The helminth infections include: lymphatic filariasis (LF), onchocerciasis (Oncho), schistosomiasis (SCH), and soil-transmitted helminthiases (STH). The different colors represent the following co-infections: STH+SCH+Oncho+LF; STH+SCH+LF; STH+SCH+Oncho; STH+Oncho; STH+SCH; STH+LF; and only STH. The information is based on reference  .
As studies have demonstrated that individuals infected with multiple helminth species may also have the most intense infections  –  , polyparasitism may have a greater impact on morbidity than the sum of single-species infections. In addition, multiple species infections may increase susceptibility to other infections, such as malaria or HIV  ,  , particularly given the often detrimental immunomodulatory effect of helminth infections. Consequently, efforts have been made to better understand the consequences of the co-existence of parasites within the same host on the immunological responses to each species and, more importantly, whether such interactions affect resistance, susceptibility, or clinical outcome  . Co-infections are also shifting some of the prevention and control measures of helminth infections from single-drug treatments to integrated approaches that can simultaneously target as many as four of the helminth NTDs, including onchocerciasis, LF, STHs, and schistosomiasis—a mission undertaken by the GNNTDC and the WHO  ,  .