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Helminthic Diseases: Intestinal Nematode Infections☆
Helminthic Diseases: Intestinal Nematode Infections☆ L Savioli, AF Gabrielli, and A Montresor, World Health Organization, Geneva, Switzerland ã 2015 Elsevier Inc. All rights reserved.
Introduction Biology Distribution Transmission Epidemiology Pathogenesis, Morbidity and Burden of Disease Diagnosis Therapy Public Health Control: Rationale Public Health Control: Implementation Deworming for Health and Development
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Introduction Intestinal nematode infections are a group of helminth (worm) infections in which the adult worm lives in the intestine of the human final host. The main group of intestinal nematode infections is represented by the soil-transmitted helminth (STH) infections, so called because they are all acquired through direct contact with the soil, where the infective stage of the worm undergoes development. The three most common STH infections are: ascariasis (caused by the roundworm, Ascaris lumbricoides), trichuriasis (caused by the whipworm, Trichuris trichiura), and hookworm infections (ancylostomiasis, caused by Ancylostoma duodenale and necatoriasis, caused by Necator americanus). A fourth STH infection is strongyloidiasis (caused by the threadworm, Strongyloides stercoralis). Another common intestinal nematode infection that cannot be considered a STH infection as it does not require soil for transmission is enterobiasis (caused by the pinworm, Enterobius vermicularis).
Biology Nematodes are whitish/yellowish/greyish/pinkish worms, grossly cylindrical in shape and tapering at both ends. They are dioecious, that is, they have separate sexes, with individuals having female reproductive organs, and other individuals having male reproductive organs; as such, they undergo sexual reproduction. The length of the adult worm varies according to the species: 2.0–2.7 mm (S. stercoralis), 2–13 mm (E. vermicularis), 7–11 mm (N. americanus), 8–13 mm (A. duodenale), 30–50 mm (T. trichiura), 150–400 mm (A. lumbricoides). Female worms are morphologically distinguishable from male worms, and in all species they are larger and longer than the males. Female worms produce eggs that are characteristic in shape and morphology (length: between 50 and 90 mm according to the species).
Distribution Intestinal nematode infections are among the most common infections worldwide. STH infections are cosmopolitan and widespread in tropical, subtropical and temperate climates. Estimates suggest that A. lumbricoides infects over 1.2 billion individuals, T. trichiura approximately 800 million and hookworms approximately 750 million. Among hookworm infections, ancylostomiasis is typical of the Mediterranean basin, the Middle East, and the eastern coast of Africa, while necatoriasis is common to western coasts of Africa and the Americas. However, areas of overlap are not infrequent, especially in southern and eastern Asia where both species coexist. Strongyloidiasis is also cosmopolitan but less prevalent with estimates ranging between 30 and 370 million human cases. Enterobiasis is very abundant, especially in temperate climates, with over 1 billion estimated cases worldwide.
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Change History: October 2014. L Savioli, A Montresor, and AF Gabrielli updated the text of all sections and the list of references. The sections on public health control were reorganized and expanded. Current Tables 1 and 2 were added.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.03106-8
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Helminthic Diseases: Intestinal Nematode Infections
Transmission The common characteristic of STH infections is that they are transmitted to humans through contact with soil contaminated with feces containing infective worm eggs or larvae. The mechanism of infection can be:
• •
ingestion of the parasite embryonated eggs adhering to soil, food, fingers and water (A. lumbricoides and T. trichiura), or transcutaneous penetration of parasite larvae present in the soil (A. duodenale, N. americanus and S. stercoralis). Penetration site is usually between the toes or fingers, however oral infection by salad vegetables contaminated with larvae has also been described, especially in the case of A. duodenale.
Once in the human body, worms undergo subsequent developmental stages that may entail a passage through the lungs until full maturation (adulthood) is reached. Adult worms live in the intestine of the host, usually the small intestine except T. trichiura (and E. vermicularis, see following discussion), which live in the large intestine and in the cecum. Female worms produce large numbers of eggs (T. trichiura: 3000–5000 eggs per worm per day; N. americanus: 6000–20 000; A. duodenale: 25 000–30 000; A. lumbricoides: over 200 000) that are shed with feces, thus contaminating the soil and closing the life cycle. There is no risk of direct person-to-person transmission or auto-infection from fresh feces because eggs passed in feces need 2–3 weeks in the soil where they undergo subsequent developmental stages before they become infective. In the case of S. stercoralis, however, eggs hatch before being shed with feces and release larvae that can develop into infective stages before leaving the body. When larvae are deposited with faecal matter on the perianal skin, they might penetrate it and re-infect the individual. This explains why some individuals are still infected after having left endemic areas many years prior. In the case of E. vermicularis, human-to-human transmission does not require contact with soil. It mainly takes place indoors, involves ingestion of the parasite eggs and is typically mediated by contaminated bedclothes, nightclothes and dust. Autoreinfection through ingestion of eggs deposited by gravid female worms on the perianal and perineal skin is also a very common event in enterobiasis, and is the result of intense itching and consequent scratching. Even if some animal species have been found to be infected with N. americanus, T. trichiura, S. stercoralis and E. vermicularis, and species similar to A. lumbricoides and A. duodenale (Ascaris suum and Ancylostoma caninum) have been found in pigs and dogs, respectively, the overall importance of animals as reservoir hosts is considered negligible. The lifespan of adult worms in the human host is about 1 month for E. vermicularis, 1 year for A. lumbricoides, T. trichiura, and A. duodenale, and 3–5 years or more for N. americanus. Human hosts can remain infected from S. stercoralis for decades due to autoreinfection. Table 1 summarizes the main features related to transmission of intestinal nematodes.
Epidemiology STH infections show a characteristic age-related pattern of prevalence of infection (proportion of individuals infected in a given population) and intensity of infection (usually expressed as eggs per gram of feces as a proxy for number of adult worms harbored in the intestine of the human host). Prevalence of infection with A. lumbricoides and T. trichiura typically peaks in childhood and subsequently reaches a plateau that is maintained into adulthood. Hookworm infections and strongyloidiasis have a more delayed pattern whereby peak and plateau are reached in adolescence and early adulthood. With regards to intensity of infection, in ascariasis and trichuriasis the peak of intensity typically coincides temporally with peak of prevalence (i.e. in childhood), but radically decreases in adolescence and adulthood. In hookworm infections and Table 1
Main features related to transmission of intestinal nematodes
( ) Once a person is infected with S. stercoralis, auto-reinfection by infective larvae deposited with fecal matter on the perianal skin is possible; in this case contact with soil is no further required for transmission.
Helminthic Diseases: Intestinal Nematode Infections
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strongyloidiasis, intensity of infection gradually rises throughout childhood and adolescence, reaches its maximum in early adulthood, and is maintained throughout adulthood. For those STHs that do not replicate in the human host, the number of worms in a given individual only increases through subsequent re-infections. The pattern of intensity of infection therefore reflects the age-dependent adoption of behaviors likely to increase or decrease risk of infection or reinfection. Rates of reinfection with STHs depend on prevalences in the community; however they are typically among the highest of all helminth infections; individuals living in highly endemic areas therefore reacquire infection within months after treatment with anti-helminthic drugs, which justifies more than one treatment per year in such areas (see sections titled ‘Public health control’). A group infection pattern has been described in enterobiasis, which typically involves children and frequently clusters in families and in institutions such as boarding schools, hospitals, psychiatric institutions, and orphanages.
Pathogenesis, Morbidity and Burden of Disease Acute clinical manifestations might include itching and burning (‘ground itch’) at the larval site of entry in infections transmitted by transcutaneous penetration (hookworm infections and strongyloidiasis); and cough due to bronchitis or pneumonitis in infections characterized by larval migration through the lungs (ascariasis, hookworm infections and strongyloidiasis). Once the adult worms reach the intestine, symptoms are usually mild and nonspecific; as such, many recently established intestinal nematode infections go unnoticed. The most common symptoms include diarrhea associated with other gastrointestinal disorders such as vomiting, nausea and loss of appetite. In strongyloidiasis, urticaria and the itchy, visible rapid movements of the worms’ larvae under the skin (larva currens) are typical findings, as is severe itching in the perianal and perineal region (pruritus ani) in enterobiasis. The chronic phase of infection is the one typically associated with the most severe morbidity. In this phase, the severity of symptoms and signs experienced by an infected individual is associated with the number of adult worms harbored in the intestine (i.e. with intensity of infection). A correlation between intensity of infection and associated morbidity has been established, such that morbidity is present when intensity reaches moderate or high levels, while it is negligible when intensity is light. For ascariasis, trichuriasis and hookworm infections, classes of intensity have been established and are summarized in Table 2. Intestinal nematodes induce reduced intake (by decreased appetite) and absorption (by chronic intestinal inflammation) of nutrients and micronutrients. The consequence is an overall lowered energy intake and deficiencies in protein, fat, iodine, vitamin A, folate, B12, iodine and iron metabolisms. In addition, hookworm infections and trichuriasis are responsible for significant loss of blood resulting in iron-deficiency anemia, attributable to both blood feeding (mainly in hookworms) and haemorrhage (mainly in trichuriasis, in which the whiplike anterior part of each worm becomes embedded in the host’s mucosa causing inflammation and lacerations). Blood loss (and the resulting anaemia) caused by an equivalent number of worms is more severe in infections caused by A. duodenale (0.14–0.25 ml per worm per day), followed by N. americanus (0.03–0.05 ml per worm per day), and by T. trichiura (0.005 ml per worm per day). The main outcome of chronic intestinal nematode infections as a whole is the reduced physical and cognitive development of affected individuals, resulting in poor educational and societal outcomes. Such disturbances are at most appreciable in infected school-age children in which school performance and physical growth are significantly compromised, and absenteeism and stunting are frequent findings. Adults are also affected with decreased fitness and the consequential reduced work capacity and productivity. Furthermore, anaemia in pregnancy is associated with increased maternal and fetal morbidity and mortality due to a higher risk of complications in pregnancy, resulting in premature delivery and reduced birth weight. In addition to such chronic illness, intestinal nematode infections can be associated with acute complications during the chronic phase. Such acute complications account for most deaths attributable to intestinal nematodes. Intestinal obstruction due to a knotted bolus of worms is a possible outcome of infections with A. lumbricoides - the risk being proportional to the number of worms in the intestine and inversely correlated with the size of the lumen, hence the higher risk in younger children; biliary obstruction is another described event. Heavy-intensity trichuriasis can result in severe colitis with diffuse edema and ulcerations. This picture is frequently complicated by severe dysentery (bloody diarrhea) resulting in the so-called Trichuris dysentery syndrome (TDS), which can also be further complicated by prolapse of the rectum, especially in children.
Table 2
Classes of intensity for ascariasis, trichuriasis and hookworm infections, by stool examination, expressed as eggs per gram of feces (epg)
Organism
Light-intensity infections
Moderate-intensity infections
Heavy-intensity infections
A. lumbricoides T. trichiura Hookworms (A. duodenale and N. americanus)
1–4999 1–999 1–1999
5000–49 999 1000–9999 2000–3999
50 000 10 000 4000
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Helminthic Diseases: Intestinal Nematode Infections
Individuals with an impaired immune system may experience – as a result of accelerated auto-reinfection - a complicated and often fatal form of strongyloidiasis associated with invasion of several tissues (especially the gastrointestinal tract, the lungs, and the central nervous system) by large numbers of worms. Severe inflammation of the mucosa and submucosa of the intestine might be further complicated by ulcerative and fibrotic processes with extensive haemorrhage and paralytic ileus. It is difficult to estimate the number of infected people who are actually suffering morbidity or dying from intestinal nematode infections because of the nonspecificity of the symptoms and signs they provoke, and of the frequent coinfection with other parasitic and non-parasitic diseases. Conservative estimates regarding two of the most common STH infections, ascariasis and hookworm infections, suggest that individuals showing morbidity are 200 million and 90–130 million, respectively, while deaths per year are 60–100 000 and 65 000, respectively.
Diagnosis The cellophane faecal thick-smear (Kato-Katz technique) for parasite eggs (or larvae in the case of S. stercoralis) remains the best option for diagnosis of STH infections. Since it is carried out on a fixed amount of feces, the Kato-Katz technique allows for a quantification of the intensity of infection by calculating the number of eggs per gram of feces (e.p.g.). Due to its quantitative technique and its easy logistics, the Kato-Katz is recommended by the World Health Organization (WHO) for population-based assessments of prevalence and intensity of infection in endemic areas and for monitoring and evaluating the impact of control programs among targeted communities. Cellophane faecal thick smear slides can be prepared in the field and stored for subsequent readings, since eggs remain visible in slides for months (with the exception of hookworm eggs which are no longer visible 2 h after preparation). If the slide is prepared 24 h or more after collection of feces, differentiation is needed between larvae of hookworms (possibly hatched from eggs) and those of S. stercoralis. Different egg size and shape allow for differentiation between worm species, however eggs of A. duodenale and N. americanus are indistinguishable. Because of the small quantity of feces examined, the Kato-Katz technique might miss light infections. In clinical practice it is therefore recommended to prepare several slides from different stool samples of the same individual so as to decrease the possibility of a false-negative diagnosis. Alternatively, if STH infection is still suspected despite negative Kato-Katz, a concentration technique using the formalin-ether (or formalin-ethyl acetate) method might be employed. Such technique, however, does not allow an easy measurement and comparison of intensity of infection in a field setting because of the inconsistent quantity of feces analyzed. However, the Kato-Katz technique is not very sensitive for the diagnoses of strongyloidiasis and the best laboratory method for this parasite are the Baermann funnel technique or the Koga agar plate. Since eggs of E. vermicularis are not usually found in faecal samples, a swab technique using adhesive tape is the recommended diagnostic procedure. The sticky side of a transparent adhesive tape is rubbed over the anal region and subsequently stuck to a slide. The swab technique is simple but not very sensitive and should be repeated for several days before a negative diagnosis is made.
Therapy Four antihelminthic drugs are currently recommended by WHO for treatment of ascariasis, trichuriasis and hookworm infections: albendazole, mebendazole (both benzimidazoles), levamisole and pyrantel. Dosages and recommendations applicable to both clinical practice and public health interventions are summarized in Table 3. Albendazole and mebendazole have excellent safety profiles and are effective against both larval and adult stages of all STH species when administered in single dose, both in terms of cure rate (proportion of treated individuals that are cured) and egg reduction rate (posttreatment decrease in egg per gram of feces, expressed as a percentage of the pretreatment count). The same can be said of levamisole and pyrantel with the proviso that they have only a limited effect on trichuriasis. Ivermectin 200 mg kg 1 or 200 mg kg 1 per day on two consecutive days is the treatment of choice for strongyloidiasis. Alternatively albendazole 400 mg once or twice daily for 3 days can be used. Enterobiasis can be treated with albendazole 400 mg, mebendazole 500 mg or pyrantel 10 mg kg 1. Such drugs given at single dose achieve excellent cure rates; however, in order to tackle auto-reinfection episodes occurring between administration of drugs and clearance of eggs in anal and perianal region, at least one further dose should be administered 2–4 weeks after the first dose. When an individual is diagnosed with enterobiasis, it is advisable to treat the entire family or group (e.g. school or other institution), otherwise re-infection is almost inevitable. Side effects following treatment with any of the anti-helminthic drugs above when given at recommended dosages are rare, mild and transitory. Their severity is linked to pretreatment intensity of infection, suggesting that they are mediated by inflammatory reactions to antigens released by dying worms. The most frequent are nausea, vomiting, weakness, diarrhea, epigastric/abdominal pain, dizziness, and headache. Very rarely allergic phenomena such as edema, rashes and urticaria have been described. It should be noted that none of the drugs above is licensed for use in pregnancy or in the first trimester of pregnancy, despite the fact that several studies have failed to find a statistically significant increase in the risk of adverse birth outcomes (abortion,
Helminthic Diseases: Intestinal Nematode Infections
Table 3
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Dosages and recommendations for treatment of ascariasis, trichuriasis and hookworm infections
stillbirth, malformation) in pregnant women administered single-dose albendazole or mebendazole, or inadvertently treated with ivermectin, when compared with untreated women. On the contrary, very little is known about the effects of levamisole and pyrantel on birth outcome. As such, when use of any of the drugs above is considered in clinical practice, health advantages of treating pregnant women should be balanced against the risks of adverse birth outcomes. For their use in public health interventions, WHO has formulated specific recommendations (see sections titled ‘Public health control’).
Public Health Control: Rationale Public health interventions against intestinal nematode infections are focused on control of morbidity associated with such infections. Preventive chemotherapy, the administration of anti-helminthic medicines to populations living in endemic areas, at regular intervals, is the quickest and cheapest measure to address the burden of ascariasis, trichuriasis and hookworm infections. Preventive chemotherapy aims at decreasing intensity of infection and keeping the worm burden in infected individuals below levels associated with disease, achieving significant improvements in physical and cognitive health and development. Even though re-infection in endemic areas will occur until environmental and/or behavioural conditions change, repeated treatments ensure that individuals living in such areas have fewer worms for shorter periods, therefore limiting the potential damage caused by infection. Mass deworming programmes conducted among populations living in STH-endemic areas have been shown to result in increased weight gain and improved school performance among children, and in reduced prevalence of irondeficiency anemia and of low birth weight among women of childbearing age.
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The main target population of preventive chemotherapy interventions is children; not only because they usually have the heaviest worm burdens, but also because the impact of the infections on their nutritional status is exacerbated by the fact that they are in a period of high energy requirement in reason of their intense physical and intellectual growth. They are therefore the population most in need of treatment. Regular treatment starting in early childhood will prevent any progress of infection and establishment of disease, therefore preventing development of morbidity: this concept inscribes deworming among the most important preventive health measures and justifies the term ‘preventive chemotherapy’ used for the WHO-recommended strategy against the major helminth infections, including the main STH infections (ascariasis, trichuriasis, hookworm infections). Frequent and repeated treatment of wide sectors of communities in endemic areas might also reduce local levels of transmission over time, especially where chemotherapy is combined with other measures such as improved sanitation and health education. The relevance of economic development and improvement in sanitation standards to permanently solve the public health problem caused by intestinal nematodes is exemplified by the fact that in previously endemic European countries, significant reductions in prevalence were obtained in the twentieth century with virtually no specific chemotherapy-based control activity. Sanitation and safe disposal of feces aim at reducing soil and water contamination, but these are costly measures necessitating long periods of time and wide geographical coverage to produce an impact, and thus they are of limited value in resource-poor countries. Health education aims at encouraging hygienic behaviours such as the use of latrines and hand-washing and can be an effective supportive measure if applied in areas where latrines and water are actually available. Notwithstanding the fact that at present no WHO-recommended public health control strategy against strongyloidiasis or enterobiasis exists, efforts are being taken to refine existing diagnostic and therapeutic tools and propose appropriate control strategies, including preventive chemotherapy. As of today, it is expected that measures implemented against STH will also benefit individuals infected with strongyloidiasis and enterobiasis, and that additional benefits will be brought by programmes addressing lymphatic filariasis and onchocerciasis as they make use of albendazole and ivermectin, and of ivermectin alone, respectively. Nevertheless, the quantification of such outcomes in terms of reduced public health burden remains challenging.
Public Health Control: Implementation The WHO-recommended strategy for control of ascariasis, trichuriasis and hookworm infections in resource-poor endemic countries is based on a practical approach that limits costs and makes delivery of drugs to target groups feasible. In this regard, community diagnosis using the Kato-Katz technique is preferred to individual diagnosis: according to levels of prevalence found in school-age children in a given community, different treatment options for all risk-groups in that community are recommended. Epidemiological assessments can be undertaken in a limited number of communities, and results from such sentinel sites can be generalised and applied to other sites in the same ecological area (i.e., the area where ecological conditions are comparable to those of the surveyed site). Community treatment through large-scale interventions that make use of existing infrastructure and drug delivery channels (e.g. school-based interventions) allow significant reductions in program costs. In such interventions, any of the four antihelminthic drugs mentioned above might be employed; however, drugs that do not need dosing according to weight, such as albendazole or mebendazole (and levamisole in school-age children only) are considered easier to use. Recommended treatment strategies for the public health control of the three main STH infections are exemplified in Table 4. Table 4
Recommended strategies for public health control of ascariasis, trichuriasis and hookworm infections
Category High-risk community
Low-risk community
Prevalence of any STH infection among school-age children 50%
20% and <50%
Action to be taken Treat all school-age children (enrolled and non-enrolled) twice each yeara
Treat all school-age children (enrolled and non-enrolled) once each year
Also treat:
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Pre-school-age children Women of childbearing age, including pregnant women in the second and third trimesters and lactating women • Adults at high risk in certain occupations (e.g. tea-pickers and miners) Also treat:
• • •
a
Pre-school-age children Women of childbearing age, including pregnant women in the second and third trimesters and lactating women Adults at high risk in certain occupations (e.g. tea-pickers and miners)
If resources are available, a third drug distribution intervention might be added. In this case the appropriate frequency of treatment would be every 4 months.
Helminthic Diseases: Intestinal Nematode Infections
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Large-scale interventions are recommended when prevalence of infection in school-age children exceeds 20%. When prevalence is below such a threshold, children and adults suspected to harbour infections should be referred to health centres for individual diagnosis and treatment. In large-scale interventions distributing drugs against the three mentioned STH infections, the minimal target population is represented by school-age children (5–14 years old), who overall harbour the highest intensity of infection and as such are at highest risk of developing morbidity. However, if resources are available, WHO recommends extending the intervention to pre-school-age children (1–4 years old), to women of child-bearing age (15–49 years old, including pregnant women in the second and third trimesters and lactating women), and to adults ( 15 years old) at high risk of professional exposure to infection, such as tea-pickers and miners. Pre-school-age children are increasingly recognized as a group at significant risk of infection, since as soon as they start crawling and thus having close contact with the soil, infection can occur. Heavy intensity infections and severe morbidity in school-age children might be explained by infection starting very early in a child’s life. Risk of morbidity in very young children is also not negligible: though usually pre-schoolers do not harbour large numbers of worms because of the lower number of reinfection episodes they have undergone, it is intuitive that even few worms can constitute a significant risk of morbidity because they are housed in smaller bodies. Women of childbearing age are at high risk of developing iron-deficiency anaemia because their iron status is already compromised by menstruation and can be precipitated by iron loss due to hookworm infections. They should therefore be included among the target population. Lactating women also deserve attention because of their increased nutritional needs. As mentioned, treating pregnant women has been proven to reduce risk of maternal anemia and to improve newborn birth weight and survival. Such proven benefits, balanced against the hypothetical risk of adverse birth outcomes, support the WHO recommendation of targeting pregnant women with albendazole or mebendazole in areas where prevalence of infection in schoolage children exceeds 20%, with the caution of excluding those in the first trimester of pregnancy. In this regard, the technique based on the date of a woman’s last menstrual period has proven reliable for identification of women who are pregnant and for the definition of the stage of pregnancy. In large-scale interventions targeting young children, tablets might be more practical than oral suspensions or syrups. However in this case special attention should be dedicated to the safety of the treatment procedure, so as to avoid any risk of choking. Children below one year of age should be excluded from large-scale interventions without medical supervision, and they should be dealt with by an individual, case-by-case, clinical approach; in this age group, oral suspensions or syrup formulations are considered more appropriate than tablets. Children between the first and the fifth birthday (pre-school-age children) can be included in the target population of largescale interventions administering anti-helminthic tablets; however such tablets should be chewable. In the 1–3 year-old age group, additional precautions should be taken, and such chewable tablets should also be broken and crushed between two spoons, with water added to help administer the tablets. In children aged 5 years and more, non-chewable tablets might also be employed. As a general rule, children should be administered drugs under supervision and never be forced to swallow tablets so as to minimize the risk of choking. In addition to the drug-distribution interventions specifically implemented to target ascariasis, trichuriasis and hookworm infections, similar preventive chemotherapy interventions are implemented for the control and elimination of other helminthic infections (i.e. lymphatic filariasis, onchocerciasis and schistosomiasis). The significant geographical overlapping among different diseases makes it possible to target all prevalent infections in an area at the same time, through co-administration of different medicines; the most advanced type of co-administration is the triple administration of ivermectin, praziquantel and albendazole to control and eliminate lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted helminthiasis. Mass drug administration for lymphatic filariasis is the single public health intervention contributing most to drug coverage for ascariasis, trichuriasis and hookworm infections, as it entails the distribution of albendazole with ivermectin or diethylcarbamazine to the entire population living in the target area. In 2012 over 595 million individuals were treated through this type of intervention, of which, approximately 168 million were preschool-age and school-age children living in areas endemic for ascariasis, trichuriasis and hookworm infections.
Deworming for Health and Development Hundreds of millions of people do not enjoy a healthy productive life because they are debilitated by helminthic diseases and thus are unable to achieve their full potential. This fact represents a heavy burden on the shoulders of poor countries, and undermines their social and economic development. Those suffering the most from helminthic infections live in resource-poor communities: they have little political influence, and they often live in remote areas, in conflict zones or urban slums where there is minimal or even no access to health care and other services. Parasitic infections - including those caused by intestinal nematodes - are the hallmark of poverty and underdevelopment, and are rightly considered among the neglected tropical diseases, a group of infections currently enjoying much less attention than they deserve. This is why public health control of intestinal nematode infections can be considered a pro-poor strategy, not only aimed at restoring health, but also constituting a highly effective investment in terms of education, poverty reduction and development. In 2001 the World Health Assembly passed resolution WHA54.19 on schistosomiasis and soil-transmitted helminth infections, that urged WHO member states to ensure access to regular administration of anti-helminthics to at least 75% of all school-age children at risk of morbidity by 2010.
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Even though coverage among school-age children was only 28% in 2010, the establishment of a target contributed to motivate national programme managers in endemic countries and stimulated support from partners, especially drug donations from pharmaceutical manufacturers. Over the past few years, efforts to deliver treatment to those in need have been intensified. In 2012, more than 60 countries out of the 112 considered as endemic implemented STH control activities: more than 302 million preschool-age and school-age children were treated for STH, and global coverage in this population groups was 27.7% and 37.5%, respectively. The WHO strategic plan on STH envisages a world free of childhood morbidity due to ascariasis, trichuriasis and hookworm infections. The goal is to reduce morbidity to a level below which it does no longer represent a public health problem in the target area. Such a threshold can be assessed by measuring prevalence of infections of moderate and high intensity among school-age children: when prevalence is below 1%, morbidity is negligible. By 2015, all countries where STH is considered a public health problem should start preventive chemotherapy interventions; by 2020, such interventions should reach 100% geographical coverage (all eligible areas within a country should be targeted) and 75% national coverage (at least three quarters of those in need should be administered treatment).
Further Reading Albonico M, Allen H, Chitsulo L, Engels D, Gabrielli AF, and Savioli L (2008) Controlling soil-transmitted helminthiasis in pre-school-age children through preventive chemotherapy. PLoS Neglected Tropical Diseases 2: e126. Albonico M, Montresor A, Crompton DWT, and Savioli L (2006) Intervention for the control of soil-transmitted helminthiasis in the community. In: Molyneux DH (ed.) Control of human parasitic diseases. Advances in Parasitology, vol.61. Allen H, Crompton DWT, de Silva N, LoVerde PT, and Olds GR (2002) New policies for using anthelminthics in high risk groups. Trends in Parasitology 18: 381–382. Bisoffi Z, Buonfrate D, Montresor A, Requena-Me´ndez A, Mun˜oz J, Krolawiecki AJ, Gotuzzo E, Mena MA, Chiodini PL, Anselmi M, Moreira J, and Albonico M (2013) Strongyloides stercoralis: A plea for action. PLoS Neglected Tropical Diseases 7: e2214. Casey GJ, Montresor A, Cavalli-Sforza LT, Thu H, Phu LB, Tinh TT, Tien NT, Phuc TQ, and Biggs BA (2013) Elimination of iron deficiency anemia and soil transmitted helminth infection: Evidence from a fifty-four month iron-folic acid and de-worming program. PLoS Neglected Tropical Diseases 11(7): e2146. Crompton DWT and Nesheim MC (2002) Nutritional impact of intestinal helminthiasis during the human life cycle. Annual Review of Nutrition 22: 35–59. Crompton DWT and Savioli L (2007) Handbook of helminthiasis for public health. Boca Raton/London/New York: Taylor & Francis. de Silva NR, Brooker S, Hotez PJ, Montresor A, Engels D, and Savioli L (2003) Soil-transmitted helminth infections. Updating the global picture. Trends in Parasitology 19: 547–551. Gabrielli AF, Montresor A, Chitsulo L, Engels D, and Savioli L (2011) Preventive chemotherapy in human helminthiasis: Theoretical and operational aspects. Transactions of the Royal Society of Tropical Medicine and Hygiene 105: 683–693. Holland CV and Kennedy MW (eds.) (2002) The geohelminths: Ascaris, trichuris and hookworm. In: World Class Parasites Vol 2. Boston/Dordrecht/London: Kluwer Academic Publishers. Hotez PJ, Bundy DAP, Beegle K, Brooker S, Drake L, de Silva N, Montresor A, Engels D, Jukes M, Chitsulo L, Chow J, Laxminarayan R, Michaud CM, Bethony J, Correa-Oliveira R, Shu-Hua X, Fenwick A, and Savioli L (2006) Helminth infections: Soil-transmitted helminth infections and schistosomiasis. In: Disease control priorities in developing countries, 3rd edn., pp. 467–482. Oxford: Oxford University Press. Knopp S, Steinmann P, Keiser J, and Utzinger J (2012) Nematode infections: Soil-transmitted helminths and trichinella. Infectious Disease Clinics of North America 26: 258–341. Krolewiecki AJ, Lammie P, Jacobson J, Gabrielli AF, Levecke B, Socias E, Arias LM, Sosa N, Abraham D, Cimino R, Echazu´ A, Crudo F, Vercruysse J, and Albonico M (2013) A public health response against Strongyloides stercoralis: Time to look at soil-transmitted helminthiasis in full. PLoS Neglected Tropical Diseases 7: e2165. McCarthy J, Loukas A, and Hotez PJ (2011) Chemotherapy of helminth infections. In: Brunton LL, Chabner BA, and Knollmann BC (eds.) Goodman and Gilman’s The pharmacological basis of therapeutics, 12th edn., pp. 1443–1462. Princeton: The McGraw-Hill Companies. Muller R (2002) Worms and human disease, 3rd edn. Wallingford-New York: CABI Publishing. Passerini L, Casey GJ, Biggs BA, Cong DT, Phu LB, Phuc TQ, Carone M, and Montresor A (2012) Increased birth weight associated with regular pre-pregnancy deworming and weekly iron-folic acid supplementation for Vietnamese women. PLoS Neglected Tropical Diseases 6: e1608. Savioli L, Bundy D, and Tomkins A (1992) Intestinal parasitic infections: A soluble public health problem. Transactions of the Royal Society of Tropical Medicine and Hygiene 86: 353–354. Scha¨r F, Trostdorf U, Giardina F, Khieu V, Muth S, Marti H, Vounatsou P, and Odermatt P (2013) Strongyloides stercoralis: Global distribution and risk factors. PLoS Neglected Tropical Diseases 7: e2288. Urbani C and Albonico M (2003) Anthelminthic drug safety and drug administration in the control of soil-transmitted helminthiasis in community campaigns. Acta Tropica 86: 215–222. Utzinger J and Keiser J (2004) Schistosomiasis and soil-transmitted helminthiasis: Common drugs for treatment and control. Expert Opinion on Pharmacotherapy 5: 263–285. World Health Organization (2006) Preventive chemotherapy in human helminthiasis. Coordinated use of anthelminthic drugs in control interventions. Geneva: World Health Organization. World Health Organization (2011) Helminth control in school-age children. A guide for managers of control programmes, Second edition Geneva: World Health Organization. World Health Organization (2012) Soil-transmitted helminthiasis. Eliminating soil-transmitted helminthiases as a public health problem in children. Progress Report 2001–2010 and Strategic Plan 2011–2020 Geneva: World Health Organization. World Health Organization (2014). PCT Databank. Soil-transmitted helminthiases. http://www.who.int/neglected_diseases/preventive_chemotherapy/sth/en/.
Relevant Websites http://www.who.int/neglected_diseases/en/ – Websites of the WHO Department of Control of Neglected Tropical Diseases which contains a section on soil-transmitted helminths.
Introduction Biology Distribution Transmission Epidemiology Pathogenesis, Morbidity and Burden of Disease Diagnosis Therapy Public Health Control: Rationale Public Health Control: Implementation Deworming for Health and Development
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Introduction Intestinal nematode infections are a group of helminth (worm) infections in which the adult worm lives in the intestine of the human final host. The main group of intestinal nematode infections is represented by the soil-transmitted helminth (STH) infections, so called because they are all acquired through direct contact with the soil, where the infective stage of the worm undergoes development. The three most common STH infections are: ascariasis (caused by the roundworm, Ascaris lumbricoides), trichuriasis (caused by the whipworm, Trichuris trichiura), and hookworm infections (ancylostomiasis, caused by Ancylostoma duodenale and necatoriasis, caused by Necator americanus). A fourth STH infection is strongyloidiasis (caused by the threadworm, Strongyloides stercoralis). Another common intestinal nematode infection that cannot be considered a STH infection as it does not require soil for transmission is enterobiasis (caused by the pinworm, Enterobius vermicularis).
Biology Nematodes are whitish/yellowish/greyish/pinkish worms, grossly cylindrical in shape and tapering at both ends. They are dioecious, that is, they have separate sexes, with individuals having female reproductive organs, and other individuals having male reproductive organs; as such, they undergo sexual reproduction. The length of the adult worm varies according to the species: 2.0–2.7 mm (S. stercoralis), 2–13 mm (E. vermicularis), 7–11 mm (N. americanus), 8–13 mm (A. duodenale), 30–50 mm (T. trichiura), 150–400 mm (A. lumbricoides). Female worms are morphologically distinguishable from male worms, and in all species they are larger and longer than the males. Female worms produce eggs that are characteristic in shape and morphology (length: between 50 and 90 mm according to the species).
Distribution Intestinal nematode infections are among the most common infections worldwide. STH infections are cosmopolitan and widespread in tropical, subtropical and temperate climates. Estimates suggest that A. lumbricoides infects over 1.2 billion individuals, T. trichiura approximately 800 million and hookworms approximately 750 million. Among hookworm infections, ancylostomiasis is typical of the Mediterranean basin, the Middle East, and the eastern coast of Africa, while necatoriasis is common to western coasts of Africa and the Americas. However, areas of overlap are not infrequent, especially in southern and eastern Asia where both species coexist. Strongyloidiasis is also cosmopolitan but less prevalent with estimates ranging between 30 and 370 million human cases. Enterobiasis is very abundant, especially in temperate climates, with over 1 billion estimated cases worldwide.
☆
Change History: October 2014. L Savioli, A Montresor, and AF Gabrielli updated the text of all sections and the list of references. The sections on public health control were reorganized and expanded. Current Tables 1 and 2 were added.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.03106-8
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2
Helminthic Diseases: Intestinal Nematode Infections
Transmission The common characteristic of STH infections is that they are transmitted to humans through contact with soil contaminated with feces containing infective worm eggs or larvae. The mechanism of infection can be:
• •
ingestion of the parasite embryonated eggs adhering to soil, food, fingers and water (A. lumbricoides and T. trichiura), or transcutaneous penetration of parasite larvae present in the soil (A. duodenale, N. americanus and S. stercoralis). Penetration site is usually between the toes or fingers, however oral infection by salad vegetables contaminated with larvae has also been described, especially in the case of A. duodenale.
Once in the human body, worms undergo subsequent developmental stages that may entail a passage through the lungs until full maturation (adulthood) is reached. Adult worms live in the intestine of the host, usually the small intestine except T. trichiura (and E. vermicularis, see following discussion), which live in the large intestine and in the cecum. Female worms produce large numbers of eggs (T. trichiura: 3000–5000 eggs per worm per day; N. americanus: 6000–20 000; A. duodenale: 25 000–30 000; A. lumbricoides: over 200 000) that are shed with feces, thus contaminating the soil and closing the life cycle. There is no risk of direct person-to-person transmission or auto-infection from fresh feces because eggs passed in feces need 2–3 weeks in the soil where they undergo subsequent developmental stages before they become infective. In the case of S. stercoralis, however, eggs hatch before being shed with feces and release larvae that can develop into infective stages before leaving the body. When larvae are deposited with faecal matter on the perianal skin, they might penetrate it and re-infect the individual. This explains why some individuals are still infected after having left endemic areas many years prior. In the case of E. vermicularis, human-to-human transmission does not require contact with soil. It mainly takes place indoors, involves ingestion of the parasite eggs and is typically mediated by contaminated bedclothes, nightclothes and dust. Autoreinfection through ingestion of eggs deposited by gravid female worms on the perianal and perineal skin is also a very common event in enterobiasis, and is the result of intense itching and consequent scratching. Even if some animal species have been found to be infected with N. americanus, T. trichiura, S. stercoralis and E. vermicularis, and species similar to A. lumbricoides and A. duodenale (Ascaris suum and Ancylostoma caninum) have been found in pigs and dogs, respectively, the overall importance of animals as reservoir hosts is considered negligible. The lifespan of adult worms in the human host is about 1 month for E. vermicularis, 1 year for A. lumbricoides, T. trichiura, and A. duodenale, and 3–5 years or more for N. americanus. Human hosts can remain infected from S. stercoralis for decades due to autoreinfection. Table 1 summarizes the main features related to transmission of intestinal nematodes.
Epidemiology STH infections show a characteristic age-related pattern of prevalence of infection (proportion of individuals infected in a given population) and intensity of infection (usually expressed as eggs per gram of feces as a proxy for number of adult worms harbored in the intestine of the human host). Prevalence of infection with A. lumbricoides and T. trichiura typically peaks in childhood and subsequently reaches a plateau that is maintained into adulthood. Hookworm infections and strongyloidiasis have a more delayed pattern whereby peak and plateau are reached in adolescence and early adulthood. With regards to intensity of infection, in ascariasis and trichuriasis the peak of intensity typically coincides temporally with peak of prevalence (i.e. in childhood), but radically decreases in adolescence and adulthood. In hookworm infections and Table 1
Main features related to transmission of intestinal nematodes
( ) Once a person is infected with S. stercoralis, auto-reinfection by infective larvae deposited with fecal matter on the perianal skin is possible; in this case contact with soil is no further required for transmission.
Helminthic Diseases: Intestinal Nematode Infections
3
strongyloidiasis, intensity of infection gradually rises throughout childhood and adolescence, reaches its maximum in early adulthood, and is maintained throughout adulthood. For those STHs that do not replicate in the human host, the number of worms in a given individual only increases through subsequent re-infections. The pattern of intensity of infection therefore reflects the age-dependent adoption of behaviors likely to increase or decrease risk of infection or reinfection. Rates of reinfection with STHs depend on prevalences in the community; however they are typically among the highest of all helminth infections; individuals living in highly endemic areas therefore reacquire infection within months after treatment with anti-helminthic drugs, which justifies more than one treatment per year in such areas (see sections titled ‘Public health control’). A group infection pattern has been described in enterobiasis, which typically involves children and frequently clusters in families and in institutions such as boarding schools, hospitals, psychiatric institutions, and orphanages.
Pathogenesis, Morbidity and Burden of Disease Acute clinical manifestations might include itching and burning (‘ground itch’) at the larval site of entry in infections transmitted by transcutaneous penetration (hookworm infections and strongyloidiasis); and cough due to bronchitis or pneumonitis in infections characterized by larval migration through the lungs (ascariasis, hookworm infections and strongyloidiasis). Once the adult worms reach the intestine, symptoms are usually mild and nonspecific; as such, many recently established intestinal nematode infections go unnoticed. The most common symptoms include diarrhea associated with other gastrointestinal disorders such as vomiting, nausea and loss of appetite. In strongyloidiasis, urticaria and the itchy, visible rapid movements of the worms’ larvae under the skin (larva currens) are typical findings, as is severe itching in the perianal and perineal region (pruritus ani) in enterobiasis. The chronic phase of infection is the one typically associated with the most severe morbidity. In this phase, the severity of symptoms and signs experienced by an infected individual is associated with the number of adult worms harbored in the intestine (i.e. with intensity of infection). A correlation between intensity of infection and associated morbidity has been established, such that morbidity is present when intensity reaches moderate or high levels, while it is negligible when intensity is light. For ascariasis, trichuriasis and hookworm infections, classes of intensity have been established and are summarized in Table 2. Intestinal nematodes induce reduced intake (by decreased appetite) and absorption (by chronic intestinal inflammation) of nutrients and micronutrients. The consequence is an overall lowered energy intake and deficiencies in protein, fat, iodine, vitamin A, folate, B12, iodine and iron metabolisms. In addition, hookworm infections and trichuriasis are responsible for significant loss of blood resulting in iron-deficiency anemia, attributable to both blood feeding (mainly in hookworms) and haemorrhage (mainly in trichuriasis, in which the whiplike anterior part of each worm becomes embedded in the host’s mucosa causing inflammation and lacerations). Blood loss (and the resulting anaemia) caused by an equivalent number of worms is more severe in infections caused by A. duodenale (0.14–0.25 ml per worm per day), followed by N. americanus (0.03–0.05 ml per worm per day), and by T. trichiura (0.005 ml per worm per day). The main outcome of chronic intestinal nematode infections as a whole is the reduced physical and cognitive development of affected individuals, resulting in poor educational and societal outcomes. Such disturbances are at most appreciable in infected school-age children in which school performance and physical growth are significantly compromised, and absenteeism and stunting are frequent findings. Adults are also affected with decreased fitness and the consequential reduced work capacity and productivity. Furthermore, anaemia in pregnancy is associated with increased maternal and fetal morbidity and mortality due to a higher risk of complications in pregnancy, resulting in premature delivery and reduced birth weight. In addition to such chronic illness, intestinal nematode infections can be associated with acute complications during the chronic phase. Such acute complications account for most deaths attributable to intestinal nematodes. Intestinal obstruction due to a knotted bolus of worms is a possible outcome of infections with A. lumbricoides - the risk being proportional to the number of worms in the intestine and inversely correlated with the size of the lumen, hence the higher risk in younger children; biliary obstruction is another described event. Heavy-intensity trichuriasis can result in severe colitis with diffuse edema and ulcerations. This picture is frequently complicated by severe dysentery (bloody diarrhea) resulting in the so-called Trichuris dysentery syndrome (TDS), which can also be further complicated by prolapse of the rectum, especially in children.
Table 2
Classes of intensity for ascariasis, trichuriasis and hookworm infections, by stool examination, expressed as eggs per gram of feces (epg)
Organism
Light-intensity infections
Moderate-intensity infections
Heavy-intensity infections
A. lumbricoides T. trichiura Hookworms (A. duodenale and N. americanus)
1–4999 1–999 1–1999
5000–49 999 1000–9999 2000–3999
50 000 10 000 4000
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Helminthic Diseases: Intestinal Nematode Infections
Individuals with an impaired immune system may experience – as a result of accelerated auto-reinfection - a complicated and often fatal form of strongyloidiasis associated with invasion of several tissues (especially the gastrointestinal tract, the lungs, and the central nervous system) by large numbers of worms. Severe inflammation of the mucosa and submucosa of the intestine might be further complicated by ulcerative and fibrotic processes with extensive haemorrhage and paralytic ileus. It is difficult to estimate the number of infected people who are actually suffering morbidity or dying from intestinal nematode infections because of the nonspecificity of the symptoms and signs they provoke, and of the frequent coinfection with other parasitic and non-parasitic diseases. Conservative estimates regarding two of the most common STH infections, ascariasis and hookworm infections, suggest that individuals showing morbidity are 200 million and 90–130 million, respectively, while deaths per year are 60–100 000 and 65 000, respectively.
Diagnosis The cellophane faecal thick-smear (Kato-Katz technique) for parasite eggs (or larvae in the case of S. stercoralis) remains the best option for diagnosis of STH infections. Since it is carried out on a fixed amount of feces, the Kato-Katz technique allows for a quantification of the intensity of infection by calculating the number of eggs per gram of feces (e.p.g.). Due to its quantitative technique and its easy logistics, the Kato-Katz is recommended by the World Health Organization (WHO) for population-based assessments of prevalence and intensity of infection in endemic areas and for monitoring and evaluating the impact of control programs among targeted communities. Cellophane faecal thick smear slides can be prepared in the field and stored for subsequent readings, since eggs remain visible in slides for months (with the exception of hookworm eggs which are no longer visible 2 h after preparation). If the slide is prepared 24 h or more after collection of feces, differentiation is needed between larvae of hookworms (possibly hatched from eggs) and those of S. stercoralis. Different egg size and shape allow for differentiation between worm species, however eggs of A. duodenale and N. americanus are indistinguishable. Because of the small quantity of feces examined, the Kato-Katz technique might miss light infections. In clinical practice it is therefore recommended to prepare several slides from different stool samples of the same individual so as to decrease the possibility of a false-negative diagnosis. Alternatively, if STH infection is still suspected despite negative Kato-Katz, a concentration technique using the formalin-ether (or formalin-ethyl acetate) method might be employed. Such technique, however, does not allow an easy measurement and comparison of intensity of infection in a field setting because of the inconsistent quantity of feces analyzed. However, the Kato-Katz technique is not very sensitive for the diagnoses of strongyloidiasis and the best laboratory method for this parasite are the Baermann funnel technique or the Koga agar plate. Since eggs of E. vermicularis are not usually found in faecal samples, a swab technique using adhesive tape is the recommended diagnostic procedure. The sticky side of a transparent adhesive tape is rubbed over the anal region and subsequently stuck to a slide. The swab technique is simple but not very sensitive and should be repeated for several days before a negative diagnosis is made.
Therapy Four antihelminthic drugs are currently recommended by WHO for treatment of ascariasis, trichuriasis and hookworm infections: albendazole, mebendazole (both benzimidazoles), levamisole and pyrantel. Dosages and recommendations applicable to both clinical practice and public health interventions are summarized in Table 3. Albendazole and mebendazole have excellent safety profiles and are effective against both larval and adult stages of all STH species when administered in single dose, both in terms of cure rate (proportion of treated individuals that are cured) and egg reduction rate (posttreatment decrease in egg per gram of feces, expressed as a percentage of the pretreatment count). The same can be said of levamisole and pyrantel with the proviso that they have only a limited effect on trichuriasis. Ivermectin 200 mg kg 1 or 200 mg kg 1 per day on two consecutive days is the treatment of choice for strongyloidiasis. Alternatively albendazole 400 mg once or twice daily for 3 days can be used. Enterobiasis can be treated with albendazole 400 mg, mebendazole 500 mg or pyrantel 10 mg kg 1. Such drugs given at single dose achieve excellent cure rates; however, in order to tackle auto-reinfection episodes occurring between administration of drugs and clearance of eggs in anal and perianal region, at least one further dose should be administered 2–4 weeks after the first dose. When an individual is diagnosed with enterobiasis, it is advisable to treat the entire family or group (e.g. school or other institution), otherwise re-infection is almost inevitable. Side effects following treatment with any of the anti-helminthic drugs above when given at recommended dosages are rare, mild and transitory. Their severity is linked to pretreatment intensity of infection, suggesting that they are mediated by inflammatory reactions to antigens released by dying worms. The most frequent are nausea, vomiting, weakness, diarrhea, epigastric/abdominal pain, dizziness, and headache. Very rarely allergic phenomena such as edema, rashes and urticaria have been described. It should be noted that none of the drugs above is licensed for use in pregnancy or in the first trimester of pregnancy, despite the fact that several studies have failed to find a statistically significant increase in the risk of adverse birth outcomes (abortion,
Helminthic Diseases: Intestinal Nematode Infections
Table 3
5
Dosages and recommendations for treatment of ascariasis, trichuriasis and hookworm infections
stillbirth, malformation) in pregnant women administered single-dose albendazole or mebendazole, or inadvertently treated with ivermectin, when compared with untreated women. On the contrary, very little is known about the effects of levamisole and pyrantel on birth outcome. As such, when use of any of the drugs above is considered in clinical practice, health advantages of treating pregnant women should be balanced against the risks of adverse birth outcomes. For their use in public health interventions, WHO has formulated specific recommendations (see sections titled ‘Public health control’).
Public Health Control: Rationale Public health interventions against intestinal nematode infections are focused on control of morbidity associated with such infections. Preventive chemotherapy, the administration of anti-helminthic medicines to populations living in endemic areas, at regular intervals, is the quickest and cheapest measure to address the burden of ascariasis, trichuriasis and hookworm infections. Preventive chemotherapy aims at decreasing intensity of infection and keeping the worm burden in infected individuals below levels associated with disease, achieving significant improvements in physical and cognitive health and development. Even though re-infection in endemic areas will occur until environmental and/or behavioural conditions change, repeated treatments ensure that individuals living in such areas have fewer worms for shorter periods, therefore limiting the potential damage caused by infection. Mass deworming programmes conducted among populations living in STH-endemic areas have been shown to result in increased weight gain and improved school performance among children, and in reduced prevalence of irondeficiency anemia and of low birth weight among women of childbearing age.
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Helminthic Diseases: Intestinal Nematode Infections
The main target population of preventive chemotherapy interventions is children; not only because they usually have the heaviest worm burdens, but also because the impact of the infections on their nutritional status is exacerbated by the fact that they are in a period of high energy requirement in reason of their intense physical and intellectual growth. They are therefore the population most in need of treatment. Regular treatment starting in early childhood will prevent any progress of infection and establishment of disease, therefore preventing development of morbidity: this concept inscribes deworming among the most important preventive health measures and justifies the term ‘preventive chemotherapy’ used for the WHO-recommended strategy against the major helminth infections, including the main STH infections (ascariasis, trichuriasis, hookworm infections). Frequent and repeated treatment of wide sectors of communities in endemic areas might also reduce local levels of transmission over time, especially where chemotherapy is combined with other measures such as improved sanitation and health education. The relevance of economic development and improvement in sanitation standards to permanently solve the public health problem caused by intestinal nematodes is exemplified by the fact that in previously endemic European countries, significant reductions in prevalence were obtained in the twentieth century with virtually no specific chemotherapy-based control activity. Sanitation and safe disposal of feces aim at reducing soil and water contamination, but these are costly measures necessitating long periods of time and wide geographical coverage to produce an impact, and thus they are of limited value in resource-poor countries. Health education aims at encouraging hygienic behaviours such as the use of latrines and hand-washing and can be an effective supportive measure if applied in areas where latrines and water are actually available. Notwithstanding the fact that at present no WHO-recommended public health control strategy against strongyloidiasis or enterobiasis exists, efforts are being taken to refine existing diagnostic and therapeutic tools and propose appropriate control strategies, including preventive chemotherapy. As of today, it is expected that measures implemented against STH will also benefit individuals infected with strongyloidiasis and enterobiasis, and that additional benefits will be brought by programmes addressing lymphatic filariasis and onchocerciasis as they make use of albendazole and ivermectin, and of ivermectin alone, respectively. Nevertheless, the quantification of such outcomes in terms of reduced public health burden remains challenging.
Public Health Control: Implementation The WHO-recommended strategy for control of ascariasis, trichuriasis and hookworm infections in resource-poor endemic countries is based on a practical approach that limits costs and makes delivery of drugs to target groups feasible. In this regard, community diagnosis using the Kato-Katz technique is preferred to individual diagnosis: according to levels of prevalence found in school-age children in a given community, different treatment options for all risk-groups in that community are recommended. Epidemiological assessments can be undertaken in a limited number of communities, and results from such sentinel sites can be generalised and applied to other sites in the same ecological area (i.e., the area where ecological conditions are comparable to those of the surveyed site). Community treatment through large-scale interventions that make use of existing infrastructure and drug delivery channels (e.g. school-based interventions) allow significant reductions in program costs. In such interventions, any of the four antihelminthic drugs mentioned above might be employed; however, drugs that do not need dosing according to weight, such as albendazole or mebendazole (and levamisole in school-age children only) are considered easier to use. Recommended treatment strategies for the public health control of the three main STH infections are exemplified in Table 4. Table 4
Recommended strategies for public health control of ascariasis, trichuriasis and hookworm infections
Category High-risk community
Low-risk community
Prevalence of any STH infection among school-age children 50%
20% and <50%
Action to be taken Treat all school-age children (enrolled and non-enrolled) twice each yeara
Treat all school-age children (enrolled and non-enrolled) once each year
Also treat:
• •
Pre-school-age children Women of childbearing age, including pregnant women in the second and third trimesters and lactating women • Adults at high risk in certain occupations (e.g. tea-pickers and miners) Also treat:
• • •
a
Pre-school-age children Women of childbearing age, including pregnant women in the second and third trimesters and lactating women Adults at high risk in certain occupations (e.g. tea-pickers and miners)
If resources are available, a third drug distribution intervention might be added. In this case the appropriate frequency of treatment would be every 4 months.
Helminthic Diseases: Intestinal Nematode Infections
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Large-scale interventions are recommended when prevalence of infection in school-age children exceeds 20%. When prevalence is below such a threshold, children and adults suspected to harbour infections should be referred to health centres for individual diagnosis and treatment. In large-scale interventions distributing drugs against the three mentioned STH infections, the minimal target population is represented by school-age children (5–14 years old), who overall harbour the highest intensity of infection and as such are at highest risk of developing morbidity. However, if resources are available, WHO recommends extending the intervention to pre-school-age children (1–4 years old), to women of child-bearing age (15–49 years old, including pregnant women in the second and third trimesters and lactating women), and to adults ( 15 years old) at high risk of professional exposure to infection, such as tea-pickers and miners. Pre-school-age children are increasingly recognized as a group at significant risk of infection, since as soon as they start crawling and thus having close contact with the soil, infection can occur. Heavy intensity infections and severe morbidity in school-age children might be explained by infection starting very early in a child’s life. Risk of morbidity in very young children is also not negligible: though usually pre-schoolers do not harbour large numbers of worms because of the lower number of reinfection episodes they have undergone, it is intuitive that even few worms can constitute a significant risk of morbidity because they are housed in smaller bodies. Women of childbearing age are at high risk of developing iron-deficiency anaemia because their iron status is already compromised by menstruation and can be precipitated by iron loss due to hookworm infections. They should therefore be included among the target population. Lactating women also deserve attention because of their increased nutritional needs. As mentioned, treating pregnant women has been proven to reduce risk of maternal anemia and to improve newborn birth weight and survival. Such proven benefits, balanced against the hypothetical risk of adverse birth outcomes, support the WHO recommendation of targeting pregnant women with albendazole or mebendazole in areas where prevalence of infection in schoolage children exceeds 20%, with the caution of excluding those in the first trimester of pregnancy. In this regard, the technique based on the date of a woman’s last menstrual period has proven reliable for identification of women who are pregnant and for the definition of the stage of pregnancy. In large-scale interventions targeting young children, tablets might be more practical than oral suspensions or syrups. However in this case special attention should be dedicated to the safety of the treatment procedure, so as to avoid any risk of choking. Children below one year of age should be excluded from large-scale interventions without medical supervision, and they should be dealt with by an individual, case-by-case, clinical approach; in this age group, oral suspensions or syrup formulations are considered more appropriate than tablets. Children between the first and the fifth birthday (pre-school-age children) can be included in the target population of largescale interventions administering anti-helminthic tablets; however such tablets should be chewable. In the 1–3 year-old age group, additional precautions should be taken, and such chewable tablets should also be broken and crushed between two spoons, with water added to help administer the tablets. In children aged 5 years and more, non-chewable tablets might also be employed. As a general rule, children should be administered drugs under supervision and never be forced to swallow tablets so as to minimize the risk of choking. In addition to the drug-distribution interventions specifically implemented to target ascariasis, trichuriasis and hookworm infections, similar preventive chemotherapy interventions are implemented for the control and elimination of other helminthic infections (i.e. lymphatic filariasis, onchocerciasis and schistosomiasis). The significant geographical overlapping among different diseases makes it possible to target all prevalent infections in an area at the same time, through co-administration of different medicines; the most advanced type of co-administration is the triple administration of ivermectin, praziquantel and albendazole to control and eliminate lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted helminthiasis. Mass drug administration for lymphatic filariasis is the single public health intervention contributing most to drug coverage for ascariasis, trichuriasis and hookworm infections, as it entails the distribution of albendazole with ivermectin or diethylcarbamazine to the entire population living in the target area. In 2012 over 595 million individuals were treated through this type of intervention, of which, approximately 168 million were preschool-age and school-age children living in areas endemic for ascariasis, trichuriasis and hookworm infections.
Deworming for Health and Development Hundreds of millions of people do not enjoy a healthy productive life because they are debilitated by helminthic diseases and thus are unable to achieve their full potential. This fact represents a heavy burden on the shoulders of poor countries, and undermines their social and economic development. Those suffering the most from helminthic infections live in resource-poor communities: they have little political influence, and they often live in remote areas, in conflict zones or urban slums where there is minimal or even no access to health care and other services. Parasitic infections - including those caused by intestinal nematodes - are the hallmark of poverty and underdevelopment, and are rightly considered among the neglected tropical diseases, a group of infections currently enjoying much less attention than they deserve. This is why public health control of intestinal nematode infections can be considered a pro-poor strategy, not only aimed at restoring health, but also constituting a highly effective investment in terms of education, poverty reduction and development. In 2001 the World Health Assembly passed resolution WHA54.19 on schistosomiasis and soil-transmitted helminth infections, that urged WHO member states to ensure access to regular administration of anti-helminthics to at least 75% of all school-age children at risk of morbidity by 2010.
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Helminthic Diseases: Intestinal Nematode Infections
Even though coverage among school-age children was only 28% in 2010, the establishment of a target contributed to motivate national programme managers in endemic countries and stimulated support from partners, especially drug donations from pharmaceutical manufacturers. Over the past few years, efforts to deliver treatment to those in need have been intensified. In 2012, more than 60 countries out of the 112 considered as endemic implemented STH control activities: more than 302 million preschool-age and school-age children were treated for STH, and global coverage in this population groups was 27.7% and 37.5%, respectively. The WHO strategic plan on STH envisages a world free of childhood morbidity due to ascariasis, trichuriasis and hookworm infections. The goal is to reduce morbidity to a level below which it does no longer represent a public health problem in the target area. Such a threshold can be assessed by measuring prevalence of infections of moderate and high intensity among school-age children: when prevalence is below 1%, morbidity is negligible. By 2015, all countries where STH is considered a public health problem should start preventive chemotherapy interventions; by 2020, such interventions should reach 100% geographical coverage (all eligible areas within a country should be targeted) and 75% national coverage (at least three quarters of those in need should be administered treatment).
Further Reading Albonico M, Allen H, Chitsulo L, Engels D, Gabrielli AF, and Savioli L (2008) Controlling soil-transmitted helminthiasis in pre-school-age children through preventive chemotherapy. PLoS Neglected Tropical Diseases 2: e126. Albonico M, Montresor A, Crompton DWT, and Savioli L (2006) Intervention for the control of soil-transmitted helminthiasis in the community. In: Molyneux DH (ed.) Control of human parasitic diseases. Advances in Parasitology, vol.61. Allen H, Crompton DWT, de Silva N, LoVerde PT, and Olds GR (2002) New policies for using anthelminthics in high risk groups. Trends in Parasitology 18: 381–382. Bisoffi Z, Buonfrate D, Montresor A, Requena-Me´ndez A, Mun˜oz J, Krolawiecki AJ, Gotuzzo E, Mena MA, Chiodini PL, Anselmi M, Moreira J, and Albonico M (2013) Strongyloides stercoralis: A plea for action. PLoS Neglected Tropical Diseases 7: e2214. Casey GJ, Montresor A, Cavalli-Sforza LT, Thu H, Phu LB, Tinh TT, Tien NT, Phuc TQ, and Biggs BA (2013) Elimination of iron deficiency anemia and soil transmitted helminth infection: Evidence from a fifty-four month iron-folic acid and de-worming program. PLoS Neglected Tropical Diseases 11(7): e2146. Crompton DWT and Nesheim MC (2002) Nutritional impact of intestinal helminthiasis during the human life cycle. Annual Review of Nutrition 22: 35–59. Crompton DWT and Savioli L (2007) Handbook of helminthiasis for public health. Boca Raton/London/New York: Taylor & Francis. de Silva NR, Brooker S, Hotez PJ, Montresor A, Engels D, and Savioli L (2003) Soil-transmitted helminth infections. Updating the global picture. Trends in Parasitology 19: 547–551. Gabrielli AF, Montresor A, Chitsulo L, Engels D, and Savioli L (2011) Preventive chemotherapy in human helminthiasis: Theoretical and operational aspects. Transactions of the Royal Society of Tropical Medicine and Hygiene 105: 683–693. Holland CV and Kennedy MW (eds.) (2002) The geohelminths: Ascaris, trichuris and hookworm. In: World Class Parasites Vol 2. Boston/Dordrecht/London: Kluwer Academic Publishers. Hotez PJ, Bundy DAP, Beegle K, Brooker S, Drake L, de Silva N, Montresor A, Engels D, Jukes M, Chitsulo L, Chow J, Laxminarayan R, Michaud CM, Bethony J, Correa-Oliveira R, Shu-Hua X, Fenwick A, and Savioli L (2006) Helminth infections: Soil-transmitted helminth infections and schistosomiasis. In: Disease control priorities in developing countries, 3rd edn., pp. 467–482. Oxford: Oxford University Press. Knopp S, Steinmann P, Keiser J, and Utzinger J (2012) Nematode infections: Soil-transmitted helminths and trichinella. Infectious Disease Clinics of North America 26: 258–341. Krolewiecki AJ, Lammie P, Jacobson J, Gabrielli AF, Levecke B, Socias E, Arias LM, Sosa N, Abraham D, Cimino R, Echazu´ A, Crudo F, Vercruysse J, and Albonico M (2013) A public health response against Strongyloides stercoralis: Time to look at soil-transmitted helminthiasis in full. PLoS Neglected Tropical Diseases 7: e2165. McCarthy J, Loukas A, and Hotez PJ (2011) Chemotherapy of helminth infections. In: Brunton LL, Chabner BA, and Knollmann BC (eds.) Goodman and Gilman’s The pharmacological basis of therapeutics, 12th edn., pp. 1443–1462. Princeton: The McGraw-Hill Companies. Muller R (2002) Worms and human disease, 3rd edn. Wallingford-New York: CABI Publishing. Passerini L, Casey GJ, Biggs BA, Cong DT, Phu LB, Phuc TQ, Carone M, and Montresor A (2012) Increased birth weight associated with regular pre-pregnancy deworming and weekly iron-folic acid supplementation for Vietnamese women. PLoS Neglected Tropical Diseases 6: e1608. Savioli L, Bundy D, and Tomkins A (1992) Intestinal parasitic infections: A soluble public health problem. Transactions of the Royal Society of Tropical Medicine and Hygiene 86: 353–354. Scha¨r F, Trostdorf U, Giardina F, Khieu V, Muth S, Marti H, Vounatsou P, and Odermatt P (2013) Strongyloides stercoralis: Global distribution and risk factors. PLoS Neglected Tropical Diseases 7: e2288. Urbani C and Albonico M (2003) Anthelminthic drug safety and drug administration in the control of soil-transmitted helminthiasis in community campaigns. Acta Tropica 86: 215–222. Utzinger J and Keiser J (2004) Schistosomiasis and soil-transmitted helminthiasis: Common drugs for treatment and control. Expert Opinion on Pharmacotherapy 5: 263–285. World Health Organization (2006) Preventive chemotherapy in human helminthiasis. Coordinated use of anthelminthic drugs in control interventions. Geneva: World Health Organization. World Health Organization (2011) Helminth control in school-age children. A guide for managers of control programmes, Second edition Geneva: World Health Organization. World Health Organization (2012) Soil-transmitted helminthiasis. Eliminating soil-transmitted helminthiases as a public health problem in children. Progress Report 2001–2010 and Strategic Plan 2011–2020 Geneva: World Health Organization. World Health Organization (2014). PCT Databank. Soil-transmitted helminthiases. http://www.who.int/neglected_diseases/preventive_chemotherapy/sth/en/.
Relevant Websites http://www.who.int/neglected_diseases/en/ – Websites of the WHO Department of Control of Neglected Tropical Diseases which contains a section on soil-transmitted helminths.