Parasitology Today, vol. 5, no. I I, 1989 359

active growth of the bladder wall, unfolding of the tissues from the coiled worm and finally the macroscopical fading of the scolex. The circumstances that lead to this anomalous growth pat- tern remain unknown.

Interestingly these three types of cys- ticerci are generally associated with a sequence of different clinical and patho- logical forms of neurocysticerco- sis 1'2'10'13'14. The benign or asympto- matic form of the disease is generally associated with the cellulose cysticercus, except when it causes obstruction in ventricular cerebral cavities and pro- duces cranial hypertension. In contrast, the intermediate and racemose types are found in the most dangerous forms of basal meningeal neurocysticer- cosis 2'3'6'~°. A severe and progressive inflammatory reaction, mainly in the basal meninges is elicited when the para- site contacts the meninges and causes a conjunctive-vascular proliferation that gives rise to mechanical obstruction of the circulation of the cerebrospinal fluid, intracranial hypertension and finally death, despite surgical intervention.

References I Nieto, D. (I 982)in Cysticercosis. Present State of

Knowledge and Perspectives (Flisser, A, et al., eds), pp I-7, Academic Press

2 Rabiela-C., M. T., Rivas-H., A. and Rodrfguez- Ibarra, J.(1979) Patologia 17, 119-135

3 Rabiela-C., M. T. et al. (1982) in Cysticercosis. Present State of Knowledge and Perspectives (Flisser, A. et al., eds), pp 179-200, Academic Press

4 Hern~ndez-Jauregui, P. and M~rquez-Monter, H. (1973) Am.J. Vet, Res. 34, 451-452

5 Marquez-Monter, H. and Hern~ndez-J~uregui, P. (19 77) Am. J. Vet. Res. 38, 16.41-1642

6 Rabiela-C., M. T. et al. ( 1985)Arch. Invest. Meal. 16, 83-92

7 Aluja, A. and Vargas, G. (1988) Vet. Parasitol. 28, 65-77

8 51ais, J. (1970) The Morphology and Pathogenicity of the Bladder Worms Cysticercus cellulose and Cysticercus boris pp 62-67, Academia Pub- lishing House of the Czechoslovak Academy of Sciences

9 Berman, J. D, et al. ( 1981 ) Am.J. Trop. Med. Hyg. 30,616~SI7

I 0 M~rquez-Monter, H. (I 971 ) in Pathology of Protozoal and Helmintic Diseases (Rojas, M. et al., eds), pp 592-6 17, Williams and Wilkins

II Biagi, F., Brice~o, C. and Ma~tinez, B. (1961) Rev. 8iol. Trop. 9, 141-151

12 Proctor, N. S. (1971) in Pathclogy of Protozoal and Helmintic Diseases (Rojas, IVl. et al., eds), pp 627-634, Williams and Wilkins

13 Rishi, A. K. and McManus, D. P. (1988) Para- sitology 97, 161 - 176

14 Yakoleff-Greenhause, V. eta/. (1982) J. Para- sitol. 68, 39-47

15 Correa, D. et al. (1987)J. Parasitol. 73, 443-445

Teresa Rabiela and Ana Fli~er are at the Instituto de Investigaciones Biom~dicas, Apar- tado Postal 70-228, UNAM, 04510 M~xico DF, M~xico. Angelica Rivas is at the Hospital de Especialidades, CMN, IMSS, M~xico DF, M~xico.

Infectious Disease and the Unesco Basic Education

Initiative M.E, Halloran, D,A.P. Bundy and E. Pollitt

As part of a Basic Education for All campaign, Unesco is exploring ways to improve health and nutrition in school-age children in order to help them take advantage of the only schooling they may ever receive. At the first international Unesco working meeting on health, nutrition and school performance, intestinal helminths were identified as more appropriate immediate targets than malaria and other infectious diseases. Prevalence and intensity of infection in school-age children, the schools as vehicles of intervention, and the availability of interventions contributed to this choice. However, there are still many gaps in our knowledge of the effects of infectious diseases in schoolchildren. Through the improvement of understanding in this area, the parasitology community may be able to contribute to the Unesco project.

A Basic Education for All initiative is being launched jointly by Unesco, UNICEF and the World Bank. The initiative aims to provide primary school education to all children in developing countries. As part of this, Unesco is exploring ways to improve health and nutrition in order to help children take advantage of the only schooling they may ever receive. The ten-year special pro- ject includes development of methods to assess health and nutritional status of schoolchildren and implementation of national and local programmes of cost- effective intervention.

At the first Unesco international meeting on this subject in Stockholm in April 1989 ~, infections with the two intestinal helminths Trichuris trichiura and Ascaris lumbricoides were identified over other infectious diseases for immediate intervention initiatives by Unesco. This is somewhat surprising, since the intestinal helminths have been relatively neglected in public health. The main arguments leading to this choice in the context of education are: ( I ) intensity of infection and morbid effects of intestinal helminths peak in school-age children; (2) nutritional deficiencies that are often secondary to helminths have been shown to affect school performance; (3) the feasibility of intervention through schools has been demonstrated for intestinal helminths; (4) the intestinal helminths are ubiquitous in warmer climates.

These points are discussed briefly below with the aim of stimulating more discussion within the parasitology com- munity on how Unesco can effectively improve health in school-age children.

Prevalence and Intensity in Schoolchildren

The target group of the Unesco pro- ject is primary school-aged children. When children in this age group are considered, the patterns of morbidity and mortality show some important dif- ferences from those seen in the overall population (Fig. I). Some diseases that are of enormous importance on a global scale, such as acute diarrhoea, malaria and vaccine-preventable diseases, in particular measles, have their greatest effect before children attain school age. These diseases have been the focus of intensive Child Survival Programs and the Expanded Program of Immunization (EPI) over the past decade. Other important infections, such as schistoso- miasis, filariasis and hookworm, have their greatest morbid effects at an age when children have completed, or are about to complete their basic education. Tuberculosis has a bimodal distribution, with peaks in young children and older adolescents, but rarely in school-age children.

Ascariasis and trichuriasis, on the other hand, reach their peak intensities in school-age children where they contrib- ute directly to malnutrition and anaemia. They are also ubiquitous in warmer cli- mates.

This is not intended to imply that other diseases are irrelevant to the health of schoolchildren, especially in particular localities. In holoendemic areas, the tail of the malaria distribution extends into the school-age class, although morbidity is generally low de- spite parasite rates of up to 95% 2 . In

~) 1989, Elsevier Science Publishers Ltd, (UK) 0169-4707/89/$02.00

360 Parasitology Today, vol. 5, no. I I, 1989

areas of epidemic, unstable malaria and in migrant populations, malaria is distrib- uted more evenly among age groups, including schoolchildren. Morbidity due to schistosomiasis, particularly from S. haematobium infection 3'4 does affect older schoolchildren in endemic areas. Ascariasis and trichuriasis gain in relative importance, however, with the focus of the Unesco project on the primary school-age group.

Evidence of Educational Effects

The goal of the Unesco special project is to facilitate the development of apti- tudes and abilities involved in school learning. The outcomes that Unesco and the Ministries of Education would like to improve through health programmes are therefore educational ones. These include school performance, alertness, information processing, absenteeism, under-enrolment, drop-out rates, and repetition of classes.

The evidence for the direct effects of helminth infection on school perform- ance is scanty. Studies during the Rock- efeller Campaign are suggestive of a link between academic achievement and intestinal helminth infection, but were inadequately controlled. While schisto- somiasis has been shown to affect physi- cal development and fitness adversely s'6, the consequences for mental develop- ment are unclear 7. The role helminth infections play in absenteeism and enrol- ment due to fatigue, malaise or diar- rhoea has also not been quantified.

Very few studies have been conduc- ted to quantify the effect of malaria on school outcome measures, partly

because the definition of a case of ma- laria in semi-immunes has been too unspecific 8. Two studies in holoendemic areas 8'9 indicate that between 0.7 and 2. 1% of school days are missed due to malaria, despite a slide positive rate of 80%. Incidence decreases with age: most attacks occur in younger children, and adolescents suffer only about one attack every two years. The effect of chronic malaria infection on cognitive ability in holoendemic areas, and the effect of acute malaria on the education of migratory populations in unstable transmission areas have not been studied.

Helminth infections, and to some extent malaria, do, however, contribute directly to nutritional deficiencies that have been clearly demonstrated to affect cognitive ability (reviewed in Ref. 10). Iron deficiency anaemia, often sec- ondary to helminth infections as well as malaria, is associated with poor men- tal test performance and under- achievement It Significant improve- ments in school achievement tests have been observed following iron sup- plementation in double-blind studies ~2. Growth retardation and stunting, also often the result of helminth infec- tion ~3'~4, have been shown to correlate negatively with cognitive test perform- ance and school attainment, and are associated with late school enrol- merit ~s'~6. The interaction of nutrition and infectious disease 17-19, particularly the helminths, thus contributes to decreased school performance.

This interaction also makes it difficult to study the direct effects of infection on school performance. Short-term effects of deworming can be assessed, but

within a few weeks the nutritional status of the host will have improved so much that any improvement in cognitive ability could be due to the decreased infection, improvement in nutrition, or the inter- action of these two factors. Studies of the long-term direct effects of treatment of infection are therefore difficult to interpret. The same is true, to some extent, for malaria and its relationship to iron-deficient anaemia.

Feasibility of Intervent ion

The feasibility of intervention depends on the methods available and on the appropriateness of using the schools to administer them. In the intesti- nal helminths, the availability of modern drugs has made periodic deworming an effective method to reduce worm bur- dens and to improve the nutritional status of the host ~3'2°. Deworming two or three times a year may be even more cost-effective than nutritional sup- plement programmes for improving growth and nutritional status 21 . Delivery of chemotherapy via schools has been shown to be practical and cost- effective 2°,22.

Deworming programmes have other advantages. Reducing helminth loads in schoolchildren can benefit the entire community, by reducing overall trans- mission 2°'23, and there is little evidence that any putative immunity against the helminths would be impaired. The broad spectrum of activity of modern anthel- mintics offers the additional advantage of reducing the burdens not only of,Ascaris and Trichuris but also of hookworm. The same school-based drug delivery system

Malaria

School- age class

/

/ I

.. .. les

o)

rr

S. mansoni

t Ascaris

J

Age (years)

I 1o o 4o

Age (years)

Fig. I. Age dependency of morbidity due to a selected range of infectious diseases. The data for Trichuri~ Ascaris and hookworm represent anthelminthic-expelled worm burdens (modified from Re~ 29, 30), which provide an index of morbidity 1~'31. The data for measles and falciparum malaria are actual numbers of cases occurring in particular age classes (modified from Refs 32, 33). Data for S. mansoni (modified from Ref. 34) represent egg density in stool samples, which is correlated with clinical signs 3s'36. Units on the x-axis are proport/ons of the maximum values.

Parasitology Today, vol. 5, no. I I, 1989 361

has the potential for delivery of other anthelmintics, such as pra7iquantel, so that the spectrum of activity may be further broadened with few additional delivery costs.

Until recently, little emphasis was placed on the health consequences of helminthiasis, although this is chang- ing 14'21'24. In 1987, as better epidemio- logical understanding and more effective drugs had become available, WHO urged the development of national pro- grammes against intestinal parasites 2~, with UNICEF (A. Lemma., pers. com- mun.) now joining in. A Unesco policy to promote periodic deworming in schools is a natural extension of this trend.

Malaria would appear to be another possible major contender for initiatives by Unesco. Intervention against malaria is more complex, however, in the face of rising morbidity and mortality, migration-induced epidemics, insecticide and drug resistance, vaccine develop- ment failure, and environmental mismanagement. Community-based ma- laria containment prograrnmes today can serve merely to prevent epidemics. Although chemoprophylaxis has been shown to reduce absenteeism and attack rates in schoolchildren 9'25, keeping chil- dren free of parasites is not a viable intervention approach as drug resistance spreads. A periodic round of chemo- therapy to clear malaria parasites would not greatly affect transmission, and unlike with helminths, it takes only one infection to reach the same burden of disease again. Also, clinical symptoms and parasitaemias can be greater upon reinfection after even a short course of protection 26, as immunity against disease is important in malaria and still labile in children.

Bednets are currently being examined as a possible way to prevent infection mechanically 2s'27, but results of studies in schoolchildren living at home have not shown significant reductions in mor- bidity 8,28.

Immediate treatment of clinical cases of malaria is probably the best method available for use in the schools, if only to limit the short-term effect of clinical ma- laria on education. The policy is often to treat only if fever is accompanied by confirmed parasitaemia because of the potential for selecting for resistance. However, if the child has fever and no parasitaemia, then there will actually be no selection pressure (J. Ribeiro, pers. commun.). School treatment pro- grammes still need to be designed and tested.

The transmission and epidemiology of malaria is also intimately tied to the

ecology of specific localities, and inter- vention needs to be developed at a local level. In this context, it is difficult for Unesco to take an independent antima- laria initiative beyond joining the fire- fighting by treating clinical cases in the schools, where malaria does not, in any event, have its major morbid effects. Since the vaccine-preventable diseases generally occur in younger children, and intervention programmes such as GOBI (growth monitoring, oral rehydration, breast feeding, immunization) and EPI already exist, there seems little necessity for Unesco to develop initiatives in this area. Scabies infections have been men- tioned as a potential distraction in schoolchildren (J. Ribeiro, pers. com- mun.), however, and may warrant more attention.

Discussion

Health in school-age children, and especially its contribution to school per- formance, has received little attention in the past. While for now helminths seem a more appropriate and feasible target than malaria and other infectious dis- eases for Unesco initiatives, there are still many gaps in our knowledge. This may change as more information or interven- tion possibilities become available. As more community-based malaria studies are initiated, measures of educational outcome such as absenteeism and cogni- tive function tests could be included for very little cost. Schoolchildren could be sentinel populations for observing dis- ease trends, at the same time as school outcomes are recorded. Also, many stud- ies have probably already been done that would yield pertinent information if the data were re-examined.

Unesco is not an organization primar- ily concerned with health, but its initiative could be an important impetus for encouraging more cooperation from the schools in health and environmental education. For example, how to build and use latrines could be taught and practised in schools, supplementing community-based sanitary and water management programmes. The Unesco project also augments the WHO in- itiative to develop primary health care based on community support and inter- sectoral collaboration, with the schools as one of the vehicles of intervention. The local mobilization planned by Unesco is also essential to balance the ten- sion between centrally planned pro- grammes, such as the Unesco project, and local needs.

Overall the Unesco special project is a

means to fuel the positive feedback loop between health education in the schools, implementation of health programmes, improved education, and long-term bet- terment of community health. The Edu- cation for All campaign is an important initiative in long-term efforts of people in developing countries to improve their quality of life and increase their self- determination. The special project to improve health, nutrition, and primary school performance gives members of the parasitology community an oppor- tunity to contribute.

Acknowledgement MEH is supported by NSF grant DMS87- 03503.

References I Bundy, D.A.P. (1989) Parasitology Today 5, 168 2 Trape, J.F. et al. (1987) Trans. R. Sac. Trap. Med.

Hyg, 81 (Suppl.2), 34-42 3 Forsyth, D.M. (1969) Bull. WHO 40, 77 I 4 Bradley, D.J. and McCullough, F,S. (I 984) Trans.

R. Sac. Trap. Med. Hyg. 80, 706-718 5 Stephenson, L.S. et al. (1985) Am. J. Trap. Med.

Hyg. 34, 322-330 6 Stephenson, L.S. (1987) Impact of Helminth

Infections on Human Nutrition Taylor and Francis

7 Kvalsig, J.D. (1988) Parasitology Today 4, 206-208

8 Trape, J.F. et al. (1987) Am. J. Epidemiol. 126, 193-201

9 Colbourne, M.J. (1955) Trans. R. Sac. Trap. Med. Hyg. 49, 356-369

I0 Pollitt, E. The Impact of Poor Nutrition and Disease on Educational Outcomes: Determi- nants Presently Excluded from Educational Plan- ning Unesco (in press)

I I Pollitt, E., Haas, J. and Levitsky, D., eds Am. J. Clin. Nutr. (in press)

12 Soemantri, A.G. et al. (1985) Am. J. Clin. Nutr. 42, 1221-1228

13 Stephenson, L.S. Am. J. Trap. Med. Hyg. (in press)

14 Cooper, E,S. and Bundy, D.A.P, (1988) Parasit- ology Today4, 301-306

15 Moock, P.R and Leslie, J. (1986)J. Dev. Econ. 20, 33-52

16 Anon. (1987) Nutritional Status, Physical Work Capacity and Mental Function in Schoolchildren Nutritional Foundation of India

17 Oppenheimer, S.]. et al. (1986) Trans. R. Sac. Trap. Med. Hyg. 80, 603-612

18 Edirisinghe, J.S. (I 986) Ann. Trap. Paediatr. 6, 233-237

19 Oppenheimer, S.J. (1989) Parasitology Today 5, 77-79

20 Bundy, D.A.P. et al. Trans. R. Sac. Trap. Med. Hyg. (in press)

21 Expert Committee (1987) Prevention and Con- trol of Intestinal Parasitic Infections. (WHO Tech. Rap. Ser. No. 749)

22 King, C.H. (1988) Am. J. Trap. Med. Hyg. 39, 295-303

23 Wilkins, H.A. (1989) Parasitology Today 5, 83-87

24 Crompton, D.W.T., Nesheim, M.C. and Paw- Iowski, Z.S. (I 985) Ascariasis and its Public Health Significance Taylor and Francis

25 Nevill, C.G. et al. (1988) Br. Med. J. 297, 401-403

362 Parasitology Today, vol. 5, no. I I, 1989

26 Pringle, G, and Avery-Jones, S. (1966) Bull WHO 34, 269-272

27 Rozendaal, J.A. (1989) Technical Report WHO/ VBCJ89.965

28 Snow, R.W. et al. (1988) Trans. R. Sac. Trap. Meal. Hyg. 82, 212-215

29 Bundy, D.A.P. et al. (1987) Trans. R. Sac. Trap. Meal. Hyg. 8 I, 987-993

30 Pritchard, D. etal. Parasitology(in press) 31 Pawlowski, Z.S. and Davis, A. (1989) in

Ascaris and i~s Prevention and Control (Crompton, D.W.T., Nesheim, M.C. and

Pawlowski, Z.S,, eds), pp 7147, Taylor and Francis

32 Morley, D.C. (1962) Am. J. Dis. Child. 103, 230-236

33 Marsh, K. et al, (I 988) Trans. I~ Sac. Trap. Med. Hyg. 82, 532-537

34 Jordan, P. (1985) Schistosomiasis: the St. Lucia Project Cambridge University Press

35 Cook, J.A, et al. (1974) Am. J. Trap. Meal. Hyg. 23,625

36 C1ine, B.L. et aL (1977)Am. J. Trap. Meal. Hyg. 26, 109

Elizabeth Halloran is currently a~liated with the Biology Department at Princeton University, and will be at the Department of Epiderniology and Biostatistics, Emory University, 99 Clifton Road NE., Atlanta, GA 30329, USA, Don Bundy is at the Parasite E_pidemiology Research Group, Department of Pure and Applied Biology, Imperial College, London SW7 2BB, UK and Ernesto Pollitt is at the Department of Applied Behavioral Sciences, University of California at Davis, Davis, CA, USA.

The Role of CD4 + T-cells in the Immune Response to Plasmodium chabaudi

J, Langhorne The development of protective immunity to Plasmodium requires the presence of T-lymphocytes. This is obvious from many experimental models showing that parasJt- aemia cannot be controlled in T-cell-de[icient animals I-3. In addition, protection against plasmodia can be achieved in adoptive transfer experiments using specific T-cells from immune animals 4's. In this brief article Jean Langhorne discusses the different responses of one particular subset of T-lymphocytes, the CD4 + T-cells, to the parasite, emphasizing their role in the development of protective immunity to the erythrocytic stages of infection.

Major Subsets of T-lymphocytes

Most mature T-lymphocytes can be divided into two major subpopulations based on the expression of one or other of two cell surface glycoproteins, CD8 and CD4. CD4 + T-cells are involved in a variety of functions such as (I) help for the generation of antibody-secreting plasma cells from B-cell precursors, (2) induction of CD8 + killer T-cells from their resting precursors and (3) me- diation of delayed-type hypersensitivity reactions (reviewed in Ref. 6). These CD4 + T-cells recognize and are acti- vated by antigenic peptides presented on class II MHC cell surface molecules, normally expressed on macrophages and B-cells. CD8 + T-cells contain a cyto- lytic machinery which, on antigenic stimu- lation, kills the appropriate target cells. CD8 + T-cells recognize and respond to antigenic peptides presented on class I MHC molecules (present on all nu- cleated cells).

In malaria, CD4 + T-cells are necess- ary for the development of a protective immune response at both stages of the infection in the mammalian host: the exoerythrocytic cycle in the liver and the erythrocytic cycle. At the exoerythro- cytic stage, CD4 + T-cells act as helper cells for antibody production and, more importantly, as helper cells for the gen- eration of CD8 + effector cells, which kill

the parasite within the hepatocyte via a 7-interferon (IFN-7)-mediated path- way 7-IO. The CD8 + T-cell pathway seems not to be so important in the erythrocytic stages, where CD4 + T-cells appear to play a pivotal role, both as helper cells for antibody production, and as effector cells. This assumption is based on several experiments. First, mice that have been depleted of CD4 + T-cells are unable to clear their infections in the erythrocytic stages If't2, and second, mice receiving immune CD4 + T-cells in adoptive transfer experiments can con- trol a challenge infection 4'12. Some of these results could be explained by assuming that CD4 + T-cells act as helper cells for B-cells that produce specific antibody. However, other reports sug- gested that mice that are depleted of B-cells are able to control an infection of P. chabaudi adami, and that serum anti- body alone is often insufficient to trans- fer immunity 13-i s. Hence, it is clearly not just in their role as helper cells for anti- body that CD4 + T-cells are important. Several investigators have therefore proposed a role for T-cell-induced macrophage-derived factors in the destruction of intraerythrocytic para- sites 14-19.

Heterogeneity of the CD4 + T-ceU Subset

CD4 ÷ T-cells of the mouse are func-

tionally heterogeneous. The expression of CD4 molecules correlates well with the recognition of antigens in the context of class II MHC molecules. However, the term helper T-cell, commonly used to describe these cells, can be misleading as it implies that all CD4 + T-cells are helper cells for antibody production. This is probably not the case. Based on the properties of long-term T-cell lines and clones, mouse CD4 + T-cells have been broadly divided into two major func- tional types-those that provide help for the specific antibody production, and those that mediate delayed-type hyper- sensitivity 6'2°'2~ . The assumption that the corresponding functions are mediated in viva by distinct and separate subsets of CD4 + T-cells has not been unequivo- cally established, but these subsets pro- vide an attractive hypothesis for the division of labour among CD4 ÷ T-cells in immune responses (Table I). All CD4 ÷ T-cells produce interleukin-3 (IL-3) and granulocyte-macrophage colony- stimulating factor (GM-CSF). The subset THI produces, in addition, IL-2 and IFN-7 and activates macrophages. TH2- cells produce, in addition, IL-4 and IL-5, which are necessary for the activation of B-cells and their differentiation into antibody-producing cells.

The Heterogeneity of the CD4 + T-cell Response

We are interested in dissecting the nature of the T-cell response elicited during an erythrocytic infection of m. chabaudi chabaudi in C57BL16 mice in an attempt to determine important protec- tive mechanisms to these stages of the parasite. To this end we have performed a quantitative analysis of lymphokine production and helper activity for anti-

(~) 1989, Elsevier Science Publishers Ltd. (UK) 0169-4707/891502.00