The Programme to Eliminate Lymphatic Filariasis (LF), launched in 1997, is a public-sector/private- sector partnership organized as a Global Alliance, with the World Health Organization serving as secretariat. Its principal purpose is to carry out the mandate of the 50th World Health Assembly (1997) to eliminate lymphatic filariasis as a public health problem worldwide, but its tools and strategies for achieving this end also have important additional public health benefits. Foremost among these are the effects the Programme can have on the control of intestinal helminth infections in treated populations, largely because of certain similarities, or overlaps, of the drugs and strategies used in the public health approaches to these parasitic infections. The principal health benefits from treating these intestinal helminth infections are reviewed in detail below, but in addition there might even be an entirely new justification for aggressive treatment and control of these infections if the recently described effects they have on potentiating HIV infections in affected populations can also be further substantiated and extended.

The purpose of this brief introduction to the supplement that follows is to highlight the current unique opportunity to coordinate intestinal helminth control programmes with the relatively new global initiative to eliminate lymphatic filariasis. Such synergy at global, regional, national and local levels has the potential to greatly enhance the impact, decrease the cost and facilitate sustainability in both of these health programmes.

The four most important forms of malnutrition worldwide (protein-energy malnutrition, iron deficiency and anaemias (IDA), vitamin A deficiency (VAD), and iodine deficiency disorders (IDD)) are examined below in terms of their global and regional prevalences, the age and gender groups most affected, their clinical and public health consequences, and, especially, the recent progress in country and regional quantitation and control. Zinc deficiency, with its accompanying diminished host resistance and increased susceptibility to infections, is also reviewed. WHO estimates that malnutrition (underweight) was associated with over half of all child deaths in developing countries in 1995. The prevalence of stunting in developing countries is expected to decline from 36% in 1995 to 32·5% in 2000; the numbers of children affected (excluding China) are expected to decrease from 196·59millions to 181·92millions. Stunting affects 48% of children in South Central Asia, 48% in Eastern Africa, 38% in South Eastern Asia, and 13–24% in Latin America. IDA affects about 43% of women and 34% of men in developing countries and usually is most serious in pregnant women and children, though non-pregnant women, the elderly, and men in hookworm-endemic areas also comprise groups at risk. Clinical VAD affects at least 2·80million preschool children in over 60 countries, and subclinical VAD is considered a problem for at least 251millions; school-age children and pregnant women are also affected. Globally about 740million people are affected by goitre, and over two billions are considered at risk of IDD. However, mandatory salt iodisation in the last decade in many regions has decreased dramatically the percentage of the population at risk. Two recent major advances in understanding the global importance of malnutrition are (1) the data of 53 countries that links protein-energy malnutrition (assessed by underweight) directly to increased child mortality rates, and (2) the outcome in 6 of 8 large vitamin A supplementation trials showing decreases of 20–50% in child mortality.

The Global Burden of Disease caused by the 3 major intestinal nematodes is an estimated 22·1million disability-adjusted life-years (DALYs) lost for hookworm, 10·5million for Ascaris lumbricoides, 6·4million for Trichuris trichiura, and 39·0million for the three infections combined (as compared with malaria at 35·7million) (World Bank, 1993; Chan et al. 1994); these figures illustrate why some scarce health care resources must be used for their control. Strongyloides stercoralis is the fourth most important intestinal worm infection; its nutritional implications are discussed, and the fact that its geographic distribution needs further study is emphasized. Mechanisms underlying the malnutrition induced by intestinal helminths are described. Anorexia, which can decrease intake of all nutrients in tropical populations on marginal diets, is likely to be the most important in terms of magnitude and the probable major mechanism by which intestinal nematodes inhibit growth and development. We present a revised and expanded conceptual framework for how parasites cause/aggravate malnutrition and retard development in endemic areas. Specific negative effects that a wide variety of parasites may have on gastrointestinal physiology are presented. The synergism between Trichuris and Campylobacter, intestinal inflammation and growth failure, and new studies showing that hookworm inhibits growth and promotes anaemia in preschool (as well as school-age) children are presented. We conclude by presenting rationales and evidence to justify ensuring the widest possible coverage for preschool-age children and girls and women of childbearing age in intestinal parasite control programmes, in order to prevent morbidity and mortality in general and specifically to help decrease the vicious intergenerational cycle of growth failure (of low-birth-weight/intrauterine growth retardation and stunting) that entraps infants, children and girls and women of reproductive age in developing areas.

The public health significance of hookworm disease is briefly reviewed. The latest evidence confirms that blood loss caused by the worms' feeding activity in the gut is a contributing factor in the development of poor iron status leading to iron-deficiency anaemia. The World Health Organization has identified adolescent girls and women of child-bearing age as high-risk groups regarding the impact of hookworm disease. The merits of treating pregnant women with anthelminthic drugs after the first trimester are discussed.

Numerous studies have shown that anthelminthic treatment can be effective in improving growth rates when given to malnourished children with ascariasis. Recent investigations have also indicated that Ascaris infections can affect mental processing in some school children. Poor socio-economic conditions are among the key factors linked with higher prevalences of ascariasis, as are defaecation practices, geophagia, cultural differences relating to personal and food hygiene, occupational necessity, agricultural factors, housing style, social class and gender. Chemotherapy is currently the major tool used for the strategic control of ascariasis as a short-term goal. In the long term, improvements in hygiene and sanitation are thought to aid long-term control considerably. Targeted treatment, especially when aimed at schoolchildren, has been a major focus of recent control efforts in some areas. Universal treatment reaches more people and thus decreases further aggregate morbidity, especially in nutritionally vulnerable preschool-age children. Selective treatment requires technical effort to identify heavily infected individuals; acceptance by the community may vary in less educated populations when some individuals receive treatment and others do not. Child-targeted treatment may be more cost-effective than population treatment in reducing the number of disease cases and, in high transmission areas, expanding coverage of a population can be a more cost-effective strategy than increasing the frequency of treatment.

An estimated 1049 million persons harbour T. trichiura, including 114 million preschool-age children and 233 million school-age children. The prevalence of T. trichiura is high and may reach 95% in children in many parts of the world where protein energy malnutrition and anaemias are also prevalent and access to medical care and educational opportunities is often limited. The Trichuris dysentery syndrome (TDS) associated with heavy T. trichiura, which includes chronic dysentery, rectal prolapse, anaemia, poor growth, and clubbing of the fingers constitutes an important public health problem, as do lighter but still heavy infections, even if not strictly TDS, especially in children. The profound growth stunting in TDS can be reversed by repeated treatment for the infection and, initially, oral iron. However findings from Jamaica strongly suggest that the significant developmental and cognitive deficits seen are unlikely to disappear without increasing the positive psychological stimulation in the child's environment. The severe stunting in TDS now appears likely to be a reaction at least in part to a chronic inflammatory response and concomitant decreases in plasma insulin-like growth factor-1 (IGF-1), increases in tumor necrosis factor-α (TNF-α) in the lamina propria of the colonic mucosa and peripheral blood (which likely decrease appetite and intake of all nutrients) and a decrease in collagen synthesis. Improvements in cognitive performance have been found after treatment for relatively heavy infections (without chronic dysentery) in school-going children; it is unclear precisely how much T. trichiura interferes with children's ability to access educational opportunities, but treatment of infections whenever possible is obviously sensible. The blood loss that can occur in T. trichiura infection is likely to contribute to anaemia, particularly if the child also harbours hookworm, malaria and/or has a low intake of dietary iron. Community control is important, particularly for the individuals within a population who harbour heavy worm burdens; this means children, with special attention to girls who will experience increased iron requirements and blood loss due to menstruation, pregnancies, and lactation. Mebendazole and albendazole, both of which are on the WHO Essential Drugs List, are very effective against T. trichiura; multiple doses are needed to attain complete parasitological cure in all cases. However the goal of control programmes in endemic areas is morbidity reduction, which follows when intensity of infection is significantly reduced.

In this paper we discuss several established and potential animal models for human parasitic infection, with a focus on rodent, pig and primate models and the nematodes Ascaris, Trichuris and Toxocara spp. Firstly, we discuss the relevance of choosing a suitable animal host to fit the particular study hypothesis, and the interaction between mathematical modelling and animal models. Secondly, we review the use of animal models for the study of nutrition-parasite interaction, evaluation of treatment and control strategies, and bacteria-parasite interactions. We show that rodent, pig and primate models are all very useful in parasitological research, and that each model has its limitations. However, based on recent experience with the pig-Ascaris and pig-Trichuris models, a more extensive use of the pig-parasite model is advocated, especially for the study of the interaction between human malnutrition and helminth infection, and congenital helminth infection.

This comprehensive review briefly describes the history and pharmacology of albendazole as an anthelminthic drug and presents detailed summaries of the efficacy and safety of albendazole's use as an anthelminthic in humans. Cure rates and % egg reduction rates are presented from studies published through March 1998 both for the recommended single dose of 400mg for hookworm (separately for Necator americanus and Ancylostoma duodenale when possible), Ascaris lumbricoides, Trichuris trichiura, and Enterobius vermicularis and, in separate tables, for doses other than a single dose of 400mg. Overall cure rates are also presented separately for studies involving only children 2–15 years. Similar tables are also provided for the recommended dose of 400mg per day for 3 days in Strongyloides stercoralis, Taenia spp. and Hymenolepis nana infections and separately for other dose regimens. The remarkable safety record involving more than several hundred million patient exposures over a 20 year period is also documented, both with data on adverse experiences occurring in clinical trials and with those in the published literature and/or spontaneously reported to the company. The incidence of side effects reported in the published literature is very low, with only gastrointestinal side effects occurring with an overall frequency of just >1%. Albendazole's unique broad-spectrum activity is exemplified in the overall cure rates calculated from studies employing the recommended doses for hookworm (78% in 68 studies: 92% for A. duodenale in 23 studies and 75% for N. americanus in 30 studies), A. lumbricoides (95% in 64 studies), T. trichiura (48% in 57 studies), E. vermicularis (98% in 27 studies), S. stercoralis (62% in 19 studies), H. nana (68% in 11 studies), and Taenia spp. (85% in 7 studies). The facts that albendazole is safe and easy to administer, both in treatment of individuals and in treatment of whole communities where it has been given by paramedical and nonmedical personnel, have enabled its use to improve general community health, including the improved nutrition and development of children.

This detailed review of the published studies underlying ivermectin's recent registration for use in lymphatic filariasis (LF) demonstrates the drug's single-dose efficacy (over the range of 20–400μg/kg) in clearing microfilaraemia associated with both Wuchereria bancrofti and Brugia malayi infections of humans. While doses as low as 20μg/kg could effect transient microfilarial (mf) clearance, higher dosages induced greater and more sustained mf reduction. The single dose of 400μg/kg yielded maximal responses, but a number of practical considerations suggest that either 400μg/kg or 200μg/kg doses would be acceptable for use in LF control programmes. Associated safety assessments indicate that adverse events, which occur commonly following treatment of microfilaraemic individuals, develop not because of drug toxicity but because of host inflammatory responses to dying microfilariae killed by the ivermectin treatment. Ivermectin is, therefore, a highly effective and generally well tolerated microfilaricide that may soon become an essential component of many public health initiatives to interrupt transmission of lymphatic filarial infection in an effort to eliminate LF globally.

This review of the safety of the co-administration regimens to be used in programmes to eliminate lymphatic filariasis (albendazole+ivermectin or albendazole+diethylcarbamazine [DEC]) is based on 17 studies conducted in Sri Lanka, India, Haiti, Ghana, Tanzania, Kenya, Ecuador, the Philippines, Gabon, Papua New Guinea, and Bangladesh. The total data set comprises 90635 subject exposures and includes individuals of all ages and both genders. Results are presented for hospital-based studies, laboratory studies, active surveillance of microfilaria-positive and microfilaria-negative individuals, and passive monitoring in both community-based studies and mass treatment programmes of individuals treated with albendazole (n=1538), ivermectin (9822), DEC (576), albendazole+ivermectin (7470), albendazole+DEC (69020), or placebo (1144). The most rigorous monitoring, which includes haematological and biochemical laboratory parameters pre- and post-treatment, provides no evidence that consistent changes are induced by any treatment; the majority of abnormalities appear to be sporadic, and the addition of albendazole to either ivermectin or DEC does not increase the frequency of abnormalities. Both DEC and ivermectin show, as expected, an adverse event profile compatible with the destruction of microfilariae. The addition of albendazole to either single-drug treatment regimen does not appear to increase the frequency or intensity of events seen with these microfilaricidal drugs when used alone. Direct observations indicated that the level of adverse events, both frequency and intensity, was correlated with the level of microfilaraemia. In non microfilaraemic individuals, who form 80–90% of the ‘at risk’ populations to be treated in most national public health programmes to eliminate lymphatic filariasis (LF), the event profile with the compounds alone or in combination does not differ significantly from that of placebo. Data on the use of ivermectin+albendazole in areas either of double infection (onchocerciasis and LF), or of loiais (with or without concurrent LF) are still inadequate and further studies are needed. Additional data are also recommended for populations infected with Brugia malayi, since most data thus far derive from populations infected with Wuchereria bancrofti.

DEC-fortified salt has been used successfully as a principal public health tool to eliminate lymphatic filariasis (LF) in China and, less extensively, in several other countries. Studies from 1967 to the present conducted in Brazil, Japan, Tanzania, India, China, and Taiwan involving administration of DEC salt for 18 days to 1 year, have shown this intervention to be effective for both bancroftian and brugian filariasis, as measured by reductions in both microfilarial density and positivity, and in some studies through reduction in mosquito positivity rates as well. Furthermore, studies suggest specific advantages from using DEC salt, including lack of side effects, particularly for bancroftian filariasis, and ability to reduce prevalence below 1% when used in conjunction with standard regimens of DEC tablets. However, use of DEC salt as a control tool suffers from a concern that health authorities might find it difficult to manage a programme involving a commodity such as salt. In the past decade, the very successful global efforts to eliminate iodine deficiency through universal salt iodization have demonstrated that partnership with the salt industry can be both successful and effective as a public health tool. Use of DEC salt can be most successfully implemented in areas in which (a) there is adequate governmental support for its use and for elimination of filariasis, (b) filariasis-endemic areas are clearly defined, (c) political leaders, health officials and the salt industry agree that DEC salt is an appropriate intervention, (d) the salt industry is well-organized and has known distribution patterns, (e) a successful national salt iodization effort exists, (f) a monitoring system exists that ensures adequacy of salt iodine content during production and that can also measure household coverage, and (g) measurement of impact on transmission of LF with the new antigen or filarial DNA detection methods can be established. There are advantages and disadvantages of using DEC-fortified salt compared with other interventions for LF elimination programmes, but rather than being considered as a ‘competing’ intervention, DEC salt should be seen as an additional option. Indeed, it is likely that many countries will derive maximal benefit from the synergistic effects of combining different intervention strategies in their national programmes to eliminate lymphatic filariasis.