malaria in sub-saharan africa

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Sot. Sci. Med. Vol. 31, No. 6. pp. 667-669, 1990 Printed in Great Britain. All rights reserved 0277-9536190 $3.00 + 0.00 Copyright c 1990 Pcrgamon Press plc MALARIA IN SUB-SAHARAN AFRICA C. G. NEVILL Malaria Unit, AMREF, Wilson Airport, P.O. Box 30125, Nairobi, Kenya Abstract-Malaria as a threat to health has remained undaunted in Sub-Saharan Africa (%A). It has been mathematically modelled, vertically attacked and continuously appraised and yet it continues unabated. Malaria is an acute and chronic disease caused by intracellular protozoa of the genus Plusmodium which are transmitted by the bite of female Anopheles mosquitoes. Approximately 2.6 billion people are at risk worldwide resulting in at least 100 million clinical cases and of the order of 1 million of such morbidity and mortality have not been fatalities. The social and economic consequences adequately documented. EPIDEMIOLOGICAL SUMMARY There is considerable variation in risk ranging from the areas with all year round transmission and low epidemic potential to areas of only seasonal trans- mission with high epidemic potential. Natural trans- mission is dependent on a complex interaction between host, vector, parasite and environment. Fundamentally, the anopheline mosquito vector is infected via blood from an infected host (man). The parasite then matures in the vector finally rendering the vector infective. The mosquito then infects man while feeding on his blood, the latter required for the development of her offspring. The parasite cycles asexually in the liver and red blood cells of the host before sexually differentiating to be infective to the vector once again. Host age and sex play no part in the susceptibility to the disease other than in behavioural differences which render one or another group more likely to be bitten by the vector. However, in endemic areas, infants have some slight passive (material antibody) protection enhanced by the persistence of foetal haemoglobin and lack of p-aminobenzoic acid in breast milk. Thereafter protection becomes relative to the frequency of challenge and hence level of ‘acquired’ immunity. The latter involves humoral production of immunoglobulin classes G, M and A and a less well understood mobilization of cellular components including complement. However it is relatively short lived, requiring repeated infection for maintenance, although when present it tends to reduce the clinical manifestations, parasitaemia etc. As the understanding of this subject is changing almost daily further background reading is advised. Immunosuppression is important and is most appar- ent in prim&avid pregnancies, where the acquired ‘endemic’ immunity is lost and placental infection is common. As a result there is a significant increase in malarial maternal, foetal and infant mortality and morbidity. This does not appear to be the case with later pregnancies. The effect of HIV in this setting is as yet unclear. Genetic factors also influence susceptibility to infection, mainly involving red blood cell charac- teristics, which result in degress of protection from parasite invasion, growth and survival. These include changes in structure of the red cell mem- brane (Duffy -ve phenotype, hereditary ovalocytosis), structural changes in the haemoglobin molecule (a and fi thalassaemia, Hb S, C and F) and alter- ations in intracellular enzyme systems (G6PD deficiency). Surprisingly there is contradictory evidence linking nutrition and malaria. However, malnourished children are likely to be at a disadvantage in terms of the development of anaemia and intercurrent infections. There are 120 plasmodia species of which 4 are of consequence to humans; P. falciparum (PF), P. malariae (PM), P. vivax (PV) and P. ovale (PO). The cycle is summarized in Fig. 1 and the basic character- istics listed in Table 1. Essentially PF is a poorly adapted parasite causing a short duration severe illness, using enormous biological amplification of a single infective sporozoite to cause illness and ensure survival (1 sporozoite produces -f million mero- zoites from the first red blood cell cycle). PV and PO cause a milder illness with few fatalities and PM has an almost symbiotic relationship with the host. There is considerable strain to strain diversity between a species but for such diversity there appear to be species specific epitopes at all development stages. The latter are the cornerstones in the present attempts to develop a vaccine. Parasite drug resistance has had a profound impact on the epidemiology of malaria, resulting in epidemics, increased morbidity and poss- ibly increased mortality. Most importantly drug resistance results in greater parasite longevity in the host which in turn prolongs the period of infective gametocytaemia. It appears that drug resistance and its spread, are related to the: (a) intensity of trans- mission, (b) drug pressure, and (c) the level of parasite mutation. These factors may be important when considering methodologies for malaria control. Human malaria is only transmitted by female anopheline mosquitoes. There are at least 400 anopheline species, ~60 are able to transmit malaria and of those z 30 are important worldwide. However in a given area only two to three will be of note. Their ability or competence to transmit malaria is governed by a complex interaction of environmental, behavioural and biological features, including vector density, blood meal preference, feeding and resting 667

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Page 1: Malaria in Sub-Saharan Africa

Sot. Sci. Med. Vol. 31, No. 6. pp. 667-669, 1990 Printed in Great Britain. All rights reserved

0277-9536190 $3.00 + 0.00 Copyright c 1990 Pcrgamon Press plc

MALARIA IN SUB-SAHARAN AFRICA

C. G. NEVILL

Malaria Unit, AMREF, Wilson Airport, P.O. Box 30125, Nairobi, Kenya

Abstract-Malaria as a threat to health has remained undaunted in Sub-Saharan Africa (%A). It has been mathematically modelled, vertically attacked and continuously appraised and yet it continues unabated. Malaria is an acute and chronic disease caused by intracellular protozoa of the genus Plusmodium which are transmitted by the bite of female Anopheles mosquitoes. Approximately 2.6 billion people are at risk worldwide resulting in at least 100 million clinical cases and of the order of 1 million

of such morbidity and mortality have not been fatalities. The social and economic consequences adequately documented.

EPIDEMIOLOGICAL SUMMARY

There is considerable variation in risk ranging from the areas with all year round transmission and low epidemic potential to areas of only seasonal trans- mission with high epidemic potential. Natural trans- mission is dependent on a complex interaction between host, vector, parasite and environment. Fundamentally, the anopheline mosquito vector is infected via blood from an infected host (man). The parasite then matures in the vector finally rendering the vector infective. The mosquito then infects man while feeding on his blood, the latter required for the development of her offspring. The parasite cycles asexually in the liver and red blood cells of the host before sexually differentiating to be infective to the vector once again.

Host age and sex play no part in the susceptibility to the disease other than in behavioural differences which render one or another group more likely to be bitten by the vector. However, in endemic areas, infants have some slight passive (material antibody) protection enhanced by the persistence of foetal haemoglobin and lack of p-aminobenzoic acid in breast milk. Thereafter protection becomes relative to the frequency of challenge and hence level of ‘acquired’ immunity. The latter involves humoral production of immunoglobulin classes G, M and A and a less well understood mobilization of cellular components including complement. However it is relatively short lived, requiring repeated infection for maintenance, although when present it tends to reduce the clinical manifestations, parasitaemia etc. As the understanding of this subject is changing almost daily further background reading is advised. Immunosuppression is important and is most appar- ent in prim&avid pregnancies, where the acquired ‘endemic’ immunity is lost and placental infection is common. As a result there is a significant increase in malarial maternal, foetal and infant mortality and morbidity. This does not appear to be the case with later pregnancies. The effect of HIV in this setting is as yet unclear.

Genetic factors also influence susceptibility to infection, mainly involving red blood cell charac- teristics, which result in degress of protection from parasite invasion, growth and survival. These

include changes in structure of the red cell mem- brane (Duffy -ve phenotype, hereditary ovalocytosis), structural changes in the haemoglobin molecule (a and fi thalassaemia, Hb S, C and F) and alter- ations in intracellular enzyme systems (G6PD deficiency).

Surprisingly there is contradictory evidence linking nutrition and malaria. However, malnourished children are likely to be at a disadvantage in terms of the development of anaemia and intercurrent infections.

There are 120 plasmodia species of which 4 are of consequence to humans; P. falciparum (PF), P. malariae (PM), P. vivax (PV) and P. ovale (PO). The cycle is summarized in Fig. 1 and the basic character- istics listed in Table 1. Essentially PF is a poorly adapted parasite causing a short duration severe illness, using enormous biological amplification of a single infective sporozoite to cause illness and ensure survival (1 sporozoite produces -f million mero- zoites from the first red blood cell cycle). PV and PO cause a milder illness with few fatalities and PM has an almost symbiotic relationship with the host. There is considerable strain to strain diversity between a species but for such diversity there appear to be species specific epitopes at all development stages. The latter are the cornerstones in the present attempts to develop a vaccine. Parasite drug resistance has had a profound impact on the epidemiology of malaria, resulting in epidemics, increased morbidity and poss- ibly increased mortality. Most importantly drug resistance results in greater parasite longevity in the host which in turn prolongs the period of infective gametocytaemia. It appears that drug resistance and its spread, are related to the: (a) intensity of trans- mission, (b) drug pressure, and (c) the level of parasite mutation. These factors may be important when considering methodologies for malaria control. Human malaria is only transmitted by female anopheline mosquitoes. There are at least 400 anopheline species, ~60 are able to transmit malaria and of those z 30 are important worldwide. However in a given area only two to three will be of note. Their ability or competence to transmit malaria is governed by a complex interaction of environmental, behavioural and biological features, including vector density, blood meal preference, feeding and resting

667

Page 2: Malaria in Sub-Saharan Africa

668 C.G. NEVILL

MOSQUITO I MAN

Fig. 1. In man: 1. Sporozoires in mosquito salivary glands are injected while feeding and migrate to the liver, staying in the circulation for 5 30 min. 2. Hepatic (liver) stage- the sporozoite, taken up by the Kupffer cells, passes into the hepatocyte and develops into a schizont, releasing 1000s of merozoites into the general circulation. 3. Hypno- zoites only occur in P ovate and P. vivax. They mature unpredictably and release new merozoites responsible for recurrent infections, possibly for life, if not specifically treated. 4. Erythrocytic or blood stage, hepatic merozoites invade red blood cells (RBC) and develop from ‘rings’ into blood schizonts (see Table 1). These schizonts rupture the RBC releasing more merozoites. 5. Gumerocyles-at an unknown stage/time in the RBC cycle ‘sexual’ forms develop which are responsible for the transmission of the parasite. In the mosquito: 6. Sexual reproduction-the male and female gametocytes develop into gametes and fuse in the stomach of the mosquito (zygote). This develops into a mobile ookinete which migrates through the stomach to form. 7. Oocysr which matures and releases >> >> >>. 8. Sporozoites which migrate to the salivary glands ready for

delivery with the next blood meal.

habits, flight range, longevity, humidity and tempera- ture. Generally speaking, anophelines are nocturnal feeders and are rarely found above 2000 m where low temperatures (mean daily temperature of < 1YC) also retard the development of the parasite in the vector.

The importance of environmental factors ensures that socioeconomic features of a given population will considerably influence transmission. Hence, agricultural development, irrigation, availability of drugs and pesticides, knowledge of and attitude to the disease, migration, nocturnal labour etc. will all play a part in the local epidemiology of the

Table I. Characteristics of infection (after L. BruaChwattl

PF PM PV PO

Incubation period 9-14 twor 12-17 or 16-18 or (days) longer 6-12 months longer

Hcpatic schizont - merozoites 3o.OcG 15.000 10,000 I 5,oca

RBC cycle (hr) 48 72 48 “50

RBC schizont -+ merozoites 16 a 15 9

Sporogony (days) in Anopheles at 28°C 9-10 14-16 a-10 12-14

disease. Although social and economic development is usually accompanied by a reduction in trans- mission, it must be remembered that malaria may be easily encouraged by ‘modem’ irrigation schemes and new but uncovered septic tanks. The increas- ing problems of travelling or imported malaria is often a considerable risk to the individual due to ignorance of the disease in non-endemic areas. Care and attention is required to lessen the impact of this on features of economic importance, such as tourism.

THE PROBLEM IN AFRICA

Approximately 500 million people are at ‘risk’ of developing malaria in Africa, the majority of whom (400 million) live in Sub-Saharan Africa (SSA) on which this review will concentrate.

There are an estimated 100 million clinical cases annually resulting, directly or indirectly, in ‘Y 1 million, mainly childhood, deaths. The tragedy of this situation is that it appears to be stable.

P. falciparum is responsible for ~90 + % of the caseload and P. malariae contributes significantly to the incidence of chronic renal disease. Additionally, P. falciparum chloroquine resistance has now been reported from every country in SSA, having spread from east to west. This problem, apart from tending to increase the morbidity and mortality in general, also poses a serious financial constraint when alter- native therapies are considered by central govem- ment (see cost sheet). At present chloroquine remains the f&t line treatment for endemic people whose natural immunity helps to bolster the activity of the failing drug. However non-immune patients require second or even third generation drugs for complete cure.

The major vectors of importance are An. gambiae (a complex of 6 sibling species), An. jiunestus, An. melas and An. arabiensis; exhibiting as a group, enormous diversity and adaptability. This coupled with the enormous range and area of possible breed- ing sites makes their control/eradication nothing more than a dream.

WHAT IS HAPPENING TO THIS PROBLEM

From the above it can be appreciated that the overall situation is worsening. Antimalarial resis- tance is ‘encouraging’ the disease and the general debilitation that the latter results it appears to be. causing more serious malaria amongst endemic peoples, especially children. Additionally, vertical control programmes like those of the island commu- nities of Zanzibar and Sri Lanka, having shown initial success, have recently shown a disturbing reestablishment of preintervention levels of the dis- ease. This has undoubtedly been catalysed by the inability of central government to cope with large scale continuous expenditure, as required by such programmes.

This picture is complicated by the continuing decline in health finance and management, which is exacerbated by world inflation and population growth.

Page 3: Malaria in Sub-Saharan Africa

Malaria in Sub-Saharan Africa 669

WHAT IS TO BE DONE? IS THERE SUCH A METHODOLOGY AVAILABLE?

The major problem to be confronted in SSA is the lack of realistic ‘tools’ that may be used in a manner supportable within the constraints discussed above. Chemoprophylaxis with increasingly expensive and toxic compounds will never be advocated for widespread use; it will remain as an additional element for the protection of high risk groups alone. Improved case finding and treatment, includ- ing simple but vital laboratory confirmation/follow up, should always be a central component of any control initiative; but as it is unlikely that government will be able to support national preven- tion programmes, it is necessary that preventive ‘tools’ are devised for use by the people at household level. These novel ‘tools’ need to be cheap, effective, universally applicable and non-toxic. In fact ‘utopian’. Vertical methods have heen tried in these countries and have met with conspicuous failure; it is possible that an element of those methods might he used in urban settings. However for the majority of malaria sufferers in the rural communities a more appropriate and very different approach is required.

Mosquito nets appear to have many of the charac- teristics required. They can be manufactured, sold and used at the appropriate level and research to date suggests that although they do not alter the morbidity pattern a great deal, that they reduce the mortality amongst children quite dramatically. This ‘barrier’ effect is enhanced by dipping the nets in a pyrethroid insecticide which has both a contact insecticidal action as well as a repellant action.

This reduction of mortality is surely the primary aim of any control programme. However neither the mechanisms for introducing such a technology into communities on a large scale nor the cost feasibility of the idea are well understood. A great deal of research is required, in varying communities, before mass campaigns might be launched in order that the people may help themselves.

In parallel, research will continue on immuno- logical ‘tools’ and novel antimalarials, as well as more appropriate cost-effective methods of surveillance. The latter should concentrate on providing more objective information on which to base future activi- ties and evaluate present interventions.

APPENDIX

Antimalarial Drug Costs

Based on bulk retail costs in Kenya, per 1000 patient treatments

Drug (formulation + number) Cost K/- Increase x

Chloroquine 150 mg (10) 1950 0 Amodiaquine 200 mg (8) import 4320 2.2 Fansidar 500/25(3) generic 3310 1.7 Fansidar 500/25(3) import 9930 5.1 Metakelfin 500/25(3) import 13,005 6.7 Fansimef (3) import unlicensed 33,700 17.3 Quinine @.o., 600 mg, tdsx3) Fansidar (3) gen 49,000 25.1 Quinine (P.o., 600 mg, tdsx7) generic 113,400 58.2 Quinine (iv., 600 mg. tdsx7) generic 136,500 70.0