Eric A. Ottesen

The Global Programme to Eliminate Lymphatic Filariasis

Summary 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.

Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset.

The immunological mechanisms involved in maintenance of an asymptomatic microfilaremic state (MF) in patients with lymphatic filariasis remain undefined. MF patients have impaired filarial antigen (Ag)-specific lymphocyte proliferation and decreased frequencies (Fo) of Ag-specific T cells, and yet elevated serum IgE and antifilarial IgG4. To investigate the mechanism of Ag-specific anergy in MF patients in contrast to amicrofilaremic individuals with chronic lymphatic obstruction (CP), the Fo of Ag-specific lymphocytes from peripheral blood mononuclear cells secreting either IL-4 or IFN-gamma were assessed by filter spot enzyme-linked immunosorbent assay, and IL-10 and transforming growth factor-beta (TGF-beta) mRNA transcript levels were assessed by a semiquantitative reverse transcriptase polymerase chain reaction technique. The Fo of filaria-specific IL-4-secreting lymphocytes were equivalent in both MF (geometric mean [GM] = 1:11,700) and CP (GM = 1:29,300 P = 0.08), whereas the Fo of IFN-gamma-secreting lymphocytes were lower in MF (GM = 1:39,300) than in CP (GM = 1:4,200, P < 0.01). When the ratio of IL-4/IFN-gamma (T helper type 2 [Th2]/Th1)-secreting cells was examined, MF subjects showed a predominant Th2 response (8:1) compared with a Th1 response in CP individuals (1:4). mRNA transcript levels of IL-10 were also significantly elevated in MF compared with CP individuals (P < 0.01). Further, IL-10 and TGF-beta were shown to have a role in modulating the Ag-specific anergy among MF subjects, in that neutralizing anti-IL-10 or anti-TGF-beta significantly enhanced lymphocyte proliferation response (by 220-1,300%) to filarial Ags in MF individuals. These findings demonstrate that MF subjects respond to parasite antigen by producing a set of suppressive cytokines that may facilitate persistence of the parasite within humans while producing little clinical disease.

The Global Programme to Eliminate Lymphatic Filariasis: Health Impact after 8 Years

Background In its first 8 years, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) achieved an unprecedentedly rapid scale-up: >1.9 billion treatments with anti-filarial drugs (albendazole, ivermectin, and diethylcarbamazine) were provided via yearly mass drug administration (MDA) to a minimum of 570 million individuals living in 48 of the 83 initially identified LF-endemic countries. Methodology To assess the health impact that this massive global effort has had, we analyzed the benefits accrued first from preventing or stopping the progression of LF disease, and then from the broader anti-parasite effects (‘beyond-LF’ benefits) attributable to the use of albendazole and ivermectin. Projections were based on demographic and disease prevalence data from publications of the Population Reference Bureau, The World Bank, and the World Health Organization. Result Between 2000 and 2007, the GPELF prevented LF disease in an estimated 6.6 million newborns who would otherwise have acquired LF, thus averting in their lifetimes nearly 1.4 million cases of hydrocele, 800,000 cases of lymphedema and 4.4 million cases of subclinical disease. Similarly, 9.5 million individuals—previously infected but without overt manifestations of disease—were protected from developing hydrocele (6.0 million) or lymphedema (3.5 million). These LF-related benefits, by themselves, translate into 32 million DALYs (Disability Adjusted Life Years) averted. Ancillary, ‘beyond-LF’ benefits from the >1.9 billion treatments delivered by the GPELF were also enormous, especially because of the >310 million treatments to the children and women of childbearing age who received albendazole with/without ivermectin (effectively treating intestinal helminths, onchocerciasis, lice, scabies, and other conditions). These benefits can be described but remain difficult to quantify, largely because of the poorly defined epidemiology of these latter infections. Conclusion The GPELF has earlier been described as a ‘best buy’ in global health; this present tally of attributable health benefits from its first 8 years strengthens this notion considerably.

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.

Lymphatic filariasis infection and disease: Control strategies

The purpose of this meeting was to review broadly the current extent and impact of lymphatic filanasis worldwlde. then to evaluate the practical Implications of recent research findings related to filariasis control, and finally to ident+ those control strategies likely to be most effective in eliminating at least filanal morbidity and perhaps even the infection itself. This brief report summarizes the deliberations.

Schistosome Infections in Humans: Perspectives and Recent Findings

Approximately 200 million persons are infected with schistosomes. Of those infected, a small proportion develop serious chronic disease, usually after years of intensive exposure and infection. Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric veins and produce liver fibrosis, which results in portal hypertension and bleeding esophageal varices but little hepatocellular dysfunction. Schistosoma haematobium resides primarily in the pelvic veins and produces mass lesions in the bladder and ureters, which lead to hydroureter and hydronephrosis. The intensity of infection is a major factor determining development of disease, but differences in worm strain and host response may also be important. In acute schistosomiasis there is an intense response to the parasite, which is suppressed as the infection becomes chronic. The marked inflammatory response seen in early and acute schistosomiasis becomes less intense and fibrotic lesions predominate. The recent advent of safe, effective, and easily administered chemotherapeutic reagents will aid in the control of schistosomiasis.

Long-term effect of prenatal exposure to maternal microfilaraemia on immune responsiveness to filarial parasite antigens

To identify long-term effects of prenatal exposure to maternal filarial-parasite infection, we assessed lymphocyte responses in 21 Polynesian children born 17-19 years previously to mothers diagnosed as being microfilaraemic or infection-free. All children lived on an island endemic for bancroftian filariasis but were free from infection at the time of study. While children (n = 10) of infection-free mothers responded vigorously to microfilarial antigen with lymphocyte proliferation, production of interleukin 2 (IL-2), IL-5, IL-10, granulocyte macrophage colony-stimulating factor (GM-CSF), and interferon gamma (IFN-gamma), cellular hyporesponsiveness was seen in children (n = 11) born to microfilaraemic mothers. The hyporesponsiveness appeared restricted to microfilarial antigens and did not extend to non-parasite antigens. These findings suggest that hyporesponsiveness resulted from in-utero acquisition of tolerance to microfilarial antigens in chronically-infected mothers.

Effects of infused histamine: Correlation of plasma histamine levels and symptoms

Plasma and urine histamine levels were measured during sequential infusions of histamine (0.05, 0.1, 0.25, 0.5, and 1.0 microgram/kg/min histamine base for 30 min each) to determine the plasma level required to elicit flushing, headaches, tachycardia, and diastolic hypotension. Each study was performed with subjects on no medications or after pretreatment with hydroxyzine and/or cimetidine in order to confirm the receptor subtype involved in each of the responses. Resting plasma histamine levels were 0.62 +/- 0.12 ng/ml, and levels rose progressively indirect proportion to the concentration of infused histamine. Plasma levels of histamine required to elicit symptoms were as follows: 1.61 +/- 0.30 ng/ml = 30% increase in heart rate, 2.39 +/- 0.52 ng/ml = significant flush and headache, and 2.45 +/- 0.13 ng/ml = 30% increase in pulse pressure. Cimetidine pretreatment failed to influence the histamine level required to elicit symptoms, hydroxyzine pretreatment significantly raised the level required to increase heart rat by 30%, and the combination of antihistamines significantly raised the threshold for histamine to elicit all the response. Urine histamine was increased in direct proportion to the histamine infusions, and because of stability, accessibility, and the capacity for retrospective diagnosis, urine is the suggested fluid to employ to measure histamine release in humans.

Prenatal allergic sensitization to helminth antigens in offspring of parasite-infected mothers.

Total and filaria-specific immunoglobulin E (IgE) levels were studied in cord blood from infants born in Madras, India, where filariasis and intestinal helminth infections are highly endemic. Increased total IgE levels were observed in 82% of 57 cord sera tested (geometric mean 12.6 ng/ml; range 1-1,900 ng/ml). 33 of these sera also contained IgE antibodies specific for filarial antigens as determined by solid-phase radioimmunoassay. Comparison of ratios of filaria-specific IgE to total IgE in paired maternal and cord sera suggested that cord blood IgE was derived from the fetus in most cases and not from transplacental antibody transfer. Our results suggest that prenatal allergic sensitization to helminth parasites occurs in the tropics. Such sensitization may contribute to the heterogeneity in host immune response and disease expression noted in filariasis and other helminth infections.

Immunopathology of lymphatic filariasis in man

Of the seven filarial parasites which commonly infect man (Table l) three are responsible for producing most of the significant pathology. Two of these, the subjects of the present discussion, are lymphatic dwelling parasites, Wuchereria bancrofti and Brugia malayi; and one is a subcutaneous dweller, Onchocerca voIvulus, which causes ocular pathology and blindness [-33]. These filarial parasites have several important features in common. First, they are all transmitted by biting arthropods (mosquitoes, flies, or midges) and all go through complex life cycles which include a slow maturation (often 3-12 months) from the infective larval stages carried by the insects to the adult worms (4-8 cm in length) which reside either associated with the lymph nodes of the lymphatic system or in the subcutaneous tissue. The offspring of these adults, the microfilariae, are 200-250 gm in length and either circulate in the blood (W. bancrofti and B. malayi) or migrate through the skin (0. volvulus) while waiting to be ingested by the insect vectors destined to propagate the parasites life cycle. Second, patent infection is generally not established unless exposure to infective larvae is intense and prolonged. Third, though exposure to infection occurs throughout childhood in endemic regions, most of the pathology of these infections is found in the adult population.