S81 Infection and disease in lymphatic filariasis: an epidemiological approach B. T. GRENFELL and E. MICHAEL Department of Zoology, Cambridge University, Downing Street, Cambridge CB2 3EJ, UK Key words: epidemiology, lymphatic filariasis, infection, disease. INTRODUCTION A major question in the study of any parasitic disease is the relationship between infection and clinical disease. The public health importance of lymphatic filariasis has generated a large body of research in this area, both in laboratory studies (Ottesen, 1984,1989; Maizels & Lawrence, 1991) and in the field (Hayashi, 1962; Hairston & Jachowski, 1968; Denham & McGreevy, 1977; Vanamail et al. 19896; Bundy, Grenfell & Rajagopalan, 1991; Srividya et al. 19916). Despite this, there is still no conclusive explanation for the apparently complex relationship between infection and clinical disease observed in human communities. At least part of the problem may lie in the current impossibility of measuring adult worm burden in vivo (Pichon et al. 1980; Denham & Fletcher, 1987; Das et al. 1990; Grenfell et al. 1990). Although there has recently been significant progress in the development of immuno- logical markers for infection status in humans (Ottesen, 1989; Day et al. 1991 a), microfilaraemia is still the most reliable measure of current infection in the field. Studies in endemic areas indicate that, far from there being any simple direct relationship between microfilaraemia and disease status, it is possible to find some individuals with microfilariae in their blood but no disease, and indeed with all other combinations of infection and disease status (Hairston & de-Meillon, 1968; Hairston & Jachowski, 1968; Beaver, 1970; Bryan & Southgate, 1976; Denham & McGreevy, 1977; Pani et al. 1991). Furthermore, the proportions of people in different categories are often observed to vary between endemic areas (Denham & McGreevy, 1977; Day et al. 1991a). Immunological explanations of these patterns have tended to concentrate on the possible role of (possibly genetic) differences between groups of individuals in generating various categories of re- sponse (Ottesen, 1980, 1984). An alternative ap- proach is to focus on the age-specific dynamics of infection and disease using simple mathematical models (Hairston & de-Meillon, 1968; Hairston & Jachowski, 1968; Vanamail et al. 1989 b; Bundy et al. 1991; Srividya et al. 19916). Recent work along these lines provides evidence for the operation of density-dependent (possibly immunologically re- lated) limitations on infection rates (Vanamail et al. 19896; Das et al. 1990), as well as a relatively simple relationship between the rate of loss of infection and the onset of chronic disease (Bundy et al. 1991 ; Srividya et al. 19916). This parallels much current laboratory-based work, which provides evidence for the dynamic nature of immunity to lymphatic filarial infections in animal models and humans from endemic areas (Denham & Fletcher, 1987; Day, Gregory & Maizels, 19916) and the potentially important role of immunological tolerance in modulating the dynamics of infection and disease (Nutman, Kumaraswami & Ottesen, 1987; Lammie et al. 1991; Maizels & Lawrence, 1991). The tolerance hypothesis is that appropriate parasite antigens may induce an anergic (tolerant) state in the host, increasing the duration of infection and perhaps reducing subsequent immunopathology (Nutman et al. 1987; Maizels & Lawrence, 1991). Tolerance may be acquired either transplacentally (Weil et al. 1983) (neonatal tolerance) or from subsequent infection (Maizels & Lawrence, 1991). Recently, Lammie et al. (1991) have produced epidemiological evidence for the operation of neonatal tolerance, in terms of a significantly higher prevalence of infection in the children of infected (compared to uninfected) mothers. This paper discusses the relationship between infection and disease in lymphatic filariasis from a population dynamic viewpoint, based on data from both field and laboratory disciplines. It begins by drawing together the results of recent work in this area, and then refines current models to provide a preliminary analysis of the epidemiological impli- cations of neonatal tolerance. DYNAMICS OF INFECTION AND DISEASE The principal dynamic processes underlying the infection/disease relationship in lymphatic filariasis are summarized schematically in Fig. 1. The fol- Parasitology (1992), 104, S81-S90 Printed in Great Britain