The Global Programme to Eliminate Lymphatic Filariasis: health impact during its first 8 years (2000-2007).

During its first 8 years, the Global Programme to Eliminate Lymphatic Filariasis provided more than 1900 million treatments with antifilarial drugs (albendazole, ivermectin and diethylcarbamazine) to at least 570 million people in 48 countries with endemic lymphatic filariasis (LF). As a result of this impressive global effort and an unprecedented public-private partnership, 8 years of mass drug administration (MDA) have prevented the spread of filarial infection to an estimated 6.6 million newborns, stopped the progression to clinical morbidity in 9.5 million individuals already infected with the parasites that cause LF, and drastically reduced the burden of several co-infections. The resulting health benefits of the MDA, in terms of reduced morbidity and disability-adjusted life-years, are thus enormous. The next step should be an analysis of the Global Programme's economic impact from its first 8 years of MDA.

Development and standardization of a rapid, PCR-based method for the detection of Wuchereria bancrofti in mosquitoes, for xenomonitoring the human prevalence of bancroftian filariasis.

PCR has recently been studied as a promising tool for monitoring the progress of efforts to eliminate lymphatic filariasis. PCR can be used to test concurrently at least 30 pools, with as many as 40 mosquitoes in each pool, for the presence of filarial larvae. The SspI PCR assay for the detection of Wuchereria bancrofti DNA in pools of mosquitoes has been used since 1994 in a variety of laboratories worldwide. During that time, the original assay has been modified in these different laboratories and no standardized assay currently exists. In an effort to standardize and improve the assay, a meeting was held on 15-16 November 2001, at Emory University in Atlanta, with representatives from most of the laboratories currently using the assay. The first round of testing was designed to test the four most promising methods for DNA extraction from pools of mosquitoes. Two of the four methods stood out as clearly the best and these will be now optimised and evaluated in two further rounds of testing.

Xenomonitoring of Culex quinquefasciatus mosquitoes as a guide for detecting the presence or absence of lymphatic filariasis: a preliminary protocol for mosquito sampling.

A protocol for the collection of resting, blood-engorged Culex quinquefasciatus Say and their examination for microfilariae has been developed as a way of detecting whether lymphatic filariasis (LF) occurs in a particular locality. The protocol was first implemented in a pilot study in Trinidad, West Indies. For gathering prevalence data, such xenomonitoring is a suitable alternative to the use of human bait, which is ethically questionable. The resting mosquitoes were collected, either indoors or outdoors, using electrical and mouth aspirators. A 'cocoeya broom', made from a bunch of the midribs of coconut-palm leaves, was found to be useful in flushing out the mosquitoes resting in hard-to-reach areas within bedrooms. The rationale behind the strategy and the five-step methodology, of householder notification, mapping, preparation of equipment, mosquito collecting and laboratory processing, are described. Data from the pilot study indicate that this xenomonitoring protocol may be applicable worldwide, albeit with modifications to take account of variations in the vector species involved and their ecology and resting behaviour.

Worm burden and host responsiveness in Wuchereria bancrofti infection: use of antigen detection to refine earlier assessments from the South Pacific.

A population from the Wuchereria bancrofti-endemic island of Mauke was reevaluated retrospectively by use of the Og4C3 circulating antigen (CAg) enzyme-linked immunosorbent assay to assess active infection in relation to host responses by age and gender. Use of microfilaremia (Mf) alone misclassified approximately 50% of infected people, although CAg and Mf levels were positively correlated. Levels of CAg peaked between those aged 31-60 years; men aged > 60 years had a significantly higher CAg prevalence (> 90%) than women. Filaria-specific immunoglobulin (Ig) G4 reached maximum levels in both genders at age 51-60 years. By analysis of variance, both age and gender significantly influenced CAg and IgG4, with men having higher levels of both in the total population. Individuals positive for CAg had significantly lower lymphocyte proliferation responses to parasite antigen than did CAg-negative people, regardless of clinical status. This study reemphasizes the importance of CAg measurements for accurately assessing filarial prevalence and clinical status and demonstrates the relationship between active infection and immune responsiveness.

Lymphatic filariasis: an infection of childhood.

Lymphatic filariasis (LF), already recognized as a widespread, seriously handicapping disease of adults, was generally thought to occur only sporadically in children. New, highly sensitive diagnostic tests (antigen detection, ultrasound examination) now reveal, however, that LF is first acquired in childhood, often with as many as one-third of children infected before age 5. Initial damage to the lymphatic system by the parasites generally remains subclinical for years or gives rise only to non-specific presentations of adenitis/adenopathy; however, especially after puberty the characteristic clinical features of the adult disease syndromes (lymphoedema, hydrocoele) manifest themselves. Recognizing that LF disease starts its development in childhood has immediate practical implications both for management and prevention of the disease in individual patients and for the broader public health efforts to overcome all childhood illnesses. For the new World Health Organization (WHO)-supported, public-/private-sector collaboration (Global Alliance) to eliminate LF through once-yearly drug treatment, this recognition means that children will be not only the principal beneficiaries of LF elimination but also a population particularly important to target in order for the programme to achieve its twin goals of interrupting transmission and preventing disease.

Lymphatic filariasis in children: adenopathy and its evolution in two young girls.

Lymphatic filariasis is a widespread infectious disease of children in endemic areas, but little is known about the early lymphatic damage in children and its evolution, either with or without treatment. Two girls (ages 6 and 12 years) from a Wuchereria bancrofti endemic region of Brazil presented with chronic inguinal adenopathy. Neither had microfilaremia. By ultrasound both were shown to have living adult worms in their enlarged inguinal nodes and had occult local lymphatic damage (lymphangiectasis). One girl spontaneously developed acute adenitis in the affected node prior to any intervention; this adenitis resolved within 10 days and was associated with the progressive disappearance over 45-90 days of all local abnormalities detectable by ultrasound. In the other child, after treatment with a single dose of diethylcarbamazine (DEC), the same clinical picture of transient adenitis and resolving abnormalities (detectable by ultrasound) occurred. These findings demonstrated filariasis as the cause of adenopathy in children, and also both spontaneous and treatment-induced worm-death, with subsequent reversal of lymphatic abnormalities.

Evolution of immunologic responsiveness of persons living in an area of endemic bancroftian filariasis: a 17-year follow-up.

On an island in which bancroftian filariasis is endemic, 29 microfilaremic and 16 "endemic normal" (EN) subjects initially studied in 1974-1975 were reevaluated 17 years later. Eleven persons remained microfilaremic, whereas 18 had cleared both microfilaremia and antigenemia. Despite decreased infection on the island, antibody levels remained relatively constant for the subjects with persistent microfilaremia (Mf(+/+)), in contrast to sharp decreases for both EN subjects and subjects with cleared microfilaremia (Mf(+/-)). Although clinically indistinguishable from the EN subjects, the Mf(+/-) group had antibody levels (IgG, IgG4, and IgE) significantly lower than those of the EN subjects. Lymphocyte responses to parasite antigens were marginally greater in Mf(+/-) than in Mf(+/+) subjects, but both groups remained less cell responsive (as measured by proliferation, interleukin-5, interleukin-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) than did the EN subjects. These findings suggest that, for microfilaremic persons, complete clearance of infection is not sufficient to restore "normal" immune responsiveness; filarial infection may induce very long-term deficits in the ability to respond to parasite antigens.

The global programme to eliminate lymphatic filariasis.

Ten years ago, no one foresaw that in the year 2000 there would be a Global Programme to Eliminate Lymphatic Filariasis (GPELF) that is already 2 years old, active in 18 of the 80 endemic countries, and operating under a wholly new paradigm in public health - a paradigm affirming that public/private sector partnerships are essential in sharing both responsibilities and responses to global health problems. What has driven the LF Elimination Programme to this point? Where it is now headed? What will be required to sustain its momentum? What will its impact be? These are the issues addressed below.

Ivermectin: effectiveness in lymphatic filariasis.

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 20-400 microg/kg) in clearing microfilaraemia associated with both Wuchereria bancrofti and Brugia malayi infections of humans. While doses as low as 20 microg/kg could effect transient microfilarial (mf) clearance, higher dosages induced greater and more sustained mf reduction. The single dose of 400 microg/kg yielded maximal responses, but a number of practical considerations suggest that either 400 microg/kg or 200 microg/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.

An analysis of the safety of the single dose, two drug regimens used in programmes to eliminate lymphatic filariasis.

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 90,635 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 (69,020), 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.

Malnutrition and parasitic helminth infections.

The Global Burden of Disease caused by the 3 major intestinal nematodes is an estimated 22.1 million disability-adjusted life-years (DALYs) lost for hookworm, 10.5 million for Ascaris lumbricoides, 6.4 million for Trichuris trichiura, and 39.0 million for the three infections combined (as compared with malaria at 35.7 million) (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.

Global malnutrition.

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 196.59 millions to 181.92 millions. 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 2.80 million preschool children in over 60 countries, and subclinical VAD is considered a problem for at least 251 millions; school-age children and pregnant women are also affected. Globally about 740 million 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 role of albendazole in programmes to eliminate lymphatic filariasis.

Citing earlier advances in the treatment of lymphatic filariasis [particularly the effectiveness of single-dose diethylcarbamazine (DEC) in reducing microfilaraemia and its enhanced effectiveness when co-administered with single-dose ivermectin], Eric Ottesen, Mahroof Ismail and John Horton consider recent studies on the antifilarial activity of albendazole that have led to the current recommendations for its use in single-dose regimens in conjunction with either DEC or ivermectin for large-scale control/elimination programmes. Furthermore, the potential of albendazole as a macrofilaricide for treating individual patients with lymphatic filarial infections is emphasized as one of a number of important research questions that remain to be explored.

Eosinophil sequestration and activation are associated with the onset and severity of systemic adverse reactions following the treatment of onchocerciasis with ivermectin.

To investigate the role of eosinophil activation and sequestration in the development and severity of adverse reactions after the treatment of Onchocerca volvulus infection, 40 O. volvulus-infected Ghanaians were randomized to receive placebo or standard- or high-dose ivermectin. Subjects were examined for typical physiologic and clinical events before and up to 48 h after treatment. Plasma samples were tested for interleukin (IL)-5 and eosinophil degranulation products (e.g., eosinophil-derived neurotoxin, EDN). After treatment, peripheral eosinophil counts declined in ivermectin-treated groups (P<.001), whereas circulating levels of IL-5 (P<.01) and EDN (P<.05) increased. Cumulative levels of IL-5 and EDN correlated with reaction scores (P<.01). High-dose ivermectin was associated with more-severe reactions, more-profound eosinopenia, and higher circulating levels of IL-5 and EDN, compared with the standard dose. These results suggest that eosinophil sequestration and activation/degranulation are associated with the initiation and severity of ivermectin-associated adverse reactions.

Filariasis and erisipela in Santo Domingo.

This study examined acute-convalescent changes in diagnostic anti-streptococcal antibodies by the anti-streptolysin O (ASO) and anti-DNAase B (ADAB) tests among patients (n 28) with lymphedema and recurrent erisipela of the lower limb, comparing them with endemic normal control residents (n=25). The study was based in Villa Francisca, an urban focus of Bancroftian filariasis in eastern Santo Domingo, capital of the Dominican Republic. The acute signs and symptoms of erisipela were consistent with a diagnosis of bacterial cellulitis. The ASO test was especially successful at demonstrating a rise in mean titer during convalescence, whereas the ADAB produced about the same frequency of significant increases (0.2 log titer) as did the ASO. When subjects were scored as responders if mounting a minimal titer increase by either test, patients were found more frequently positive than were controls (chi2=5.3, P=0.02). About half (54%) of all patients mounted at least a minimal antibody increase. Filaria-specific IgG4 antibodies were absent from all sera of 20 residents of a nonendemic Dominican mountain town but appeared in about two-thirds of the sampled residents of the endemic barrio. Notably however, levels did not change between the acute phase and convalescence. These findings are consistent with the hypothesis that recurrent streptococcal invasion of the lymphatics may be a significant factor triggering or amplifying lymphedema and elephantiasis in patients with chronic filariasis.

Strategies and tools for the control/elimination of lymphatic filariasis.

Lymphatic filariasis infects 120 million people in 73 countries worldwide and continues to be a worsening problem, especially in Africa and the Indian subcontinent. Elephantiasis, lymphoedema, and genital pathology afflict 44 million men, women and children; another 76 million have parasites in their blood and hidden internal damage to their lymphatic and renal systems. In the past, tools and strategies for the control of the condition were inadequate, but over the last 10 years dramatic research advances have led to new understanding about the severity and impact of the disease, new diagnostic and monitoring tools, and, most importantly, new treatment tools and control strategies. The new strategy aims both at transmission control through community-wide (mass) treatment programmes and at disease control through individual patient management. Annual single-dose co-administration of two drugs (ivermectin + diethylcarbamazine (DEC) or albendazole) reduces blood microfilariae by 99% for a full year; even a single dose of one drug (ivermectin or DEC) administered annually can result in 90% reductions; field studies confirm that such reduction of microfilarial loads and prevalence can interrupt transmission. New approaches to disease control, based on preventing bacterial superinfection, can now halt or even reverse the lymphoedema and elephantiasis sequelae of filarial infection. Recognizing these remarkable technical advances, the successes of recent control programmes, and the biological factors favouring elimination of this infection, the Fiftieth World Health Assembly recently called on WHO and its Member States to establish as a priority the global elimination of lymphatic filariasis as a public health problem.

Evidence for protective immunity to bancroftian filariasis in the Cook Islands.

To challenge the concept of protective immunity in lymphatic filariasis, 19 adult residents of a Wuchereria bancrofti-endemic island who had been diagnosed 17 years earlier as putatively immune endemic normals (PI/EN) were reexamined. Even with continued exposure to infection, all 19 had maintained their apparent infection-free status. Studies to define the mechanisms underlying this putative immunity revealed that cellular immune responses (including proliferation; generation of interleukin [IL]-2, IL-5, IL-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) to adult- and microfilarial-stage antigens, but not antibody responses, were markedly greater than those of 20 age-matched, infected patients. Furthermore, the PI/EN group was comprised of high- and low-responding persons who were clinically indistinguishable. These findings provide evidence that protective immunity to lymphatic filariasis does occur and that it is probably T cell-mediated.