Malaria

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Organism There are four human malaria parasites, Plasmodium falciparum, P. vivax, P. malariae and P. ovale. P. falciparum causes the most serious disease and is the commonest parasite in tropical regions, but differs from P. vivax and P. ovale in having no persistent stage (the hypnozoite), from which repeat blood stage parasites are produced. P. vivax has the widest geographical range, being found in temperate and sub-tropical zones as well as the tropics. P. vivax infection will lead to relapses if a schizonticidal drug only is used for treatment and some strains, e.g. the Chesson strain in New Guinea (Papua New Guinea and Irian Jaya) and Solomon Islands requires a more prolonged radical treatment. P. malariae produces a milder infection, but is distinguished from the other three by paroxysms of fever every fourth day. P. malariae can persist as an asymptomatic low-grade parasitaemia for many years, to multiply at a future date as a clinical infection. P. ovale is the rarest of the parasites and is suppressed by infections with the other species.

The malaria parasite reproduces asexu-ally in humans and sexually in the mosquito (Fig. 15.4). A merozoite attacks a RBC, divides asexually, rupturing the cell, each new-formed merozoite attacking another RBC. Toxins are liberated when the cell ruptures, producing the clinical paroxysms. After several asexual cycles, male and female gametes are produced, which are ingested when a mosquito takes a blood meal. These go through a complex developmental cycle in the stomach wall of the mosquito, culminating in the production of sporozoites, which migrate to the salivary glands ready to enter another person when the mosquito next takes a blood meal.

The sporozoite enters a liver cell in which development to a schizont takes place. This ruptures, liberating merozoites, which attack RBCs, thereby starting an erythrocytic cycle. In P. vivax and P. ovale, a persistent liver stage, the hypnozoite is formed, meaning that if parasites are cleared from the blood, relapses can occur, often continuing for many years unless radical treatment is given.

Clinical features Infection commences with fever and headache, soon developing into an alternating pattern of peaks of fever followed by sweating and profound chills. Classically, these take on a pattern of either 3 days (tertiary malaria) or 4 days (quaternary malaria). However, falciparum malaria can present in many different forms including cerebral malaria (encephalopathy and coma) as acute shock, haematuria (black-water fever) and jaundice.

Diagnosis is with a thick blood smear (to detect parasites) and a thin smear (to determine species) (Fig. 15.5). A dipstick method for P. falciparum has made the diagnosis of malaria simpler, but is still too expensive for routine use in many countries. It is particularly useful for surveys. A similar dipstick method for the other malaria parasites has been developed, but is not sufficiently sensitive or specific to replace blood slides.

Malaria Cycle Artesunate
Fig. 15.4. The malaria life cycle.

P. falciparum

Early , trophozoite [ LJ (ring form)

P. falciparum

Late trophozoite'

Late trophozoite'

Rarely seen in peripheral blood

Schizont

Schizont

RBC enlarged

RBC enlarged

12-24 (16) nuclei

12-24 (16) nuclei

Fig. 15.5. Differential diagnosis of Plasmodium spp. RBC, red blood cell.

Epidemiology Cycle Malaria
Table 15.2. The main malaria vectors and their behaviour in relation to control.

Geographical area

Anopheles species

Behaviour in relation to control

More arid areas of sub-Saharan

Anopheles arabiensis

Feeds on animals and humans depending

Africa and Western Arabia

on availability. Some exit after feeding

More humid parts of sub-Saharan

A. gambiae s.s.

Bites humans in the middle of the night.

Africa

Rests indoors after feeding. Breeds in

temporary puddles, increasing

considerably in wet season and declining

in dry

Sub-Saharan Africa, including

A. funestus

Bites humans in the middle of the night.

highlands

Rests indoors after feeding. Breeds in

more permanent water bodies, remaining

a constant vector throughout the year

Rural areas of Indian sub

A. culicifacies, species A,

Feeds predominantly on animals, but bites

continent and Southwest Asia

C, D and E

humans sufficiently to be the main rural

vector in India and Sri Lanka. Tends to

bite early in the night. Breeds in water

tanks and pools, but not rice fields

Urban areas of Indian sub

A. stephensi

Feeds on humans and animals throughout

continent and Southwest Asia

night, except in cold weather, when biting

is early. Breeds in wells and water tanks

Indian sub-continent

A. fluviatilis species S

Bites humans and rests indoors.

Associated with hill streams

South and Southeast Asia

A. sundaicus

Mainly bites cattle, but also humans

sufficiently to be a vector. Breeds in salt-

water lagoons

Southeast Asia (including

A. minimus

Feeds on humans and rests indoors, but

northeast India and southwest

due to prolonged insecticide spraying

China)

has changed to outdoor resting and

animal biting in some areas

Southeast Asia

A. dirus

Bites humans indoors, but then exits.

Associated with forests

A. aconitus

Lives indoors. Breeds in rice fields

Nepal, Malaysia, Indonesia

A. maculatus

Bites humans indoors. Breeds in rice fields

Indonesia

A. leucosphyrus

Bites humans and rests indoors

Philippines

A. flavirostris

Bites humans and rests indoors

China

A. sinensis

Mainly bites animals, inefficient vector

A. anthropophagus

Bites humans, efficient vector. Both breed

in rice fields

Melanesia

A. farauti

Bites humans indoors and rests indoors

A. punctulatus,

Breeds in temporary rainwater pools

A. koliensis

Central America, western South

A. albimanus

Bites outside and early in the night. More

America and Haiti

abundant during rainy season

Central and northern South

A. pseudopunctipennis

Bites humans indoors

America

North urban South America

A. darlingi

Bites humans and rests indoors. Biting time

variable in different parts of its range.

More abundant during rainy season

Northern South America

A. nuneztovari

Bites humans indoors, but exits during night

A. aquasalis

Bites outside and early in the night. Breeds

in brackish water

South America

A. albitarsis complex

Bites humans outdoors. Associated with

(A. marajoara)

gold mining

Turkey, Central Asia, Afghanistan

A. sacharovi,

Bites humans indoors

A. superpictus

Transmission is by Anopheles mosquitoes (Table 15.2). The efficiency of the vector will depend upon the species of Anopheles, its feeding habits and the environmental conditions. This varies widely, with A. gam-biae being the most efficient of all malaria vectors, to a species such as Anopheles culi-cifacies, which is comparatively inefficient. This is determined by a number of factors, such as the preferred food source (humans or animals), the time of biting (easier in the middle of the night when people are sleeping) and whether it lives inside the house or outside, but the most important is the mosquito's length of life. Only a few A. culicifa-cies will survive longer than 12 days and so become infective (dying before completion of the extrinsic cycle), whereas 50% of a population of A. gambiae will live longer than 12 days. Longer living mosquitoes are better vectors. A female mosquito must have a blood meal before it can complete its gonotrophic cycle and lay a batch of eggs. The gonotrophic cycle is normally about 2-3 days, but varies with temperature, species and locality. Long-living mosquitoes will be able to lay several batches of eggs and this is used to estimate the longevity of a mosquito species.

Another factor is mosquito density. A large number of mosquitoes have greater transmission potential than a few. Some mosquitoes produce large numbers at certain favourable times of the year, while others maintain more constant populations. The environment largely determines mosquito density.

The most important environmental factors are temperature and humidity, with wind, phases of the moon and human activity having lesser effect. Temperature determines the length of development cycle of the parasite and the survival of the mosquito vector. This means that in temperate climates, malaria can only be transmitted in brief periods of warm weather when the right conditions are available. In tropical regions, altitude alters the temperature and highland areas will have less (although possibly epidemic) malaria.

Water is essential for the mosquito to breed. In arid desert countries, the mosquito cannot survive, but water in the wells and that used for irrigation have allowed mosquitoes to breed and malaria to appear. Rainfall generally increases the number of breeding places for mosquitoes, so there is more malaria in the wet season. However, if the rainfall is so heavy as to wash out breeding places, this results in a decrease of mosquitoes.

The mosquito, being a fragile flyer, is easily blown by the wind, sometimes to its advantage, but generally to its disadvantage. On windy evenings, mosquito biting may decrease considerably.

Nocturnal mosquitoes are sensitive to light; so on a moonlit night, there is a reduction in numbers. Measurements of mosquito density must be made on several nights, or ideally over a period of months.

When the mosquito species is mainly zoophilic (feeds on animals), keeping domestic animals in proximity to the household will encourage mosquitoes to feed on them, instead of on the human occupants. It is these environmental factors which determine whether malaria is endemic or epidemic. Where conditions of temperature and moisture permit all-year-round breeding of mosquitoes, endemic malaria occurs, but if there is a marked dry season or reduction in temperature, then conditions for transmission may only be suitable during a part of the year, resulting in seasonal malaria. If conditions are marginal and only favourable every few years, then epidemic malaria can result. Epidemic malaria is devastating, as large numbers of people who have no immunity are attacked. Endemic and epidemic malaria call for entirely different strategies of control.

Malaria can also be transmitted by blood transfusion, from needles and syringes, and rarely congenitally.

Incubation period depends upon the species and strain of the parasite:

P. falciparum

9-14 days

P. vivax

12-17days, but in temperate

climates, it can be 6-9 months

P. malariae

18-40 days

P. ovale

16-18 days

Period of communicability is as long as there are infective mosquitoes. For a mosquito to become infective, it must live long enough for the parasite to complete the developmental cycle (the extrinsic cycle), which depends upon the temperature and species. P. vivax completes this more quickly than P. falciparum.

Species of parasite

Development time (days) at mean ambient temperature

30 °C

24°C 20 °C

P. vivax

7

9 16

P. falciparum

9

11 20

P. malariae

15

21 30

At 19°C, P. falciparum takes in excess of 30 days (beyond the life expectancy of an average mosquito), whereas P. vivax can still complete its cycle in less than 20 days. The absolute minimum temperature for P. vivax is 17°C, but the extrinsic cycle is longer than the lifetime of the mosquito.

Occurrence and distribution In a nonimmune population, children and adults of both sexes are affected equally. In areas of continuous infection with P. falciparum, malaria is predominantly an infection of children in whom mortality can be considerable. The survivors acquire immunity, which is only preserved by the maintenance of parasites in the body, due to re-infection. Should the individual leave an area of continuous malaria, immunity may be reduced. Immunity is also reduced during pregnancy, severe malaria can occur in a pregnant woman, even if she has lived in an endemic area. This is worse in the first pregnancy than subsequently.

The body responds to malaria by an enlargement of the spleen. The degree of enlargement and the proportion of the population with palpable spleens have been used as a measure of endemicity:

• Hypoendemic. Spleen rate in children (2-9 years of age) not exceeding 10%.

• Mesoendemic. Spleen rate in children between 11% and 50%.

• Hyperendemic. Spleen rate in children constantly over 50%. Spleen rate in adults also high (over 25%).

• Holoendemic. Spleen rate in children constantly over 75%, but spleen rate in adults low.

In endemic areas, the gametocyte rate is highest in the very young, but in epidemic malaria or areas where transmission has been considerably reduced, gametocytes occur at all ages.

Malaria is found in the tropics and sub-tropics of the world (Fig. 15.6 and Table 15.2), mostly P. falciparum, but P. vivax is the predominant species in the Indian subcontinent. It used to be more extensive with seasonal malaria in temperate regions, but extensive control programmes have confined it to its present limits. However, increase in population and the development of resistance, both by the parasite and the mosquito, means that malaria is still the most important parasitic disease in the world. Each year, there are some 300 million cases out of which over a million die.

Global climatic change has resulted in an increase in epidemic malaria (infecting new or infrequently involved areas) and the development of endemic malaria in highland areas, which were normally protected by their lower temperatures (see also Section 1.4.7).

Control and prevention Mathematical models were introduced in Section 2.4, malaria being one of the best examples in which they can be used to work out the strategy for control. The parasite life cycle was described above and illustrated in Fig. 15.4, while each of these stages can be represented mathematically as schematically shown in Fig 15.7. The stages and values for each of the places where the life cycle can be interrupted are given below:

1. In humans

• reduction of the duration of infection (1/r) by chemotherapy;

• prevention of infections with gametocytes (b) by chemoprophylaxis and vaccination.

Malaria Epidemiology
Fig. 15.6. The occurrence of malaria in the world. (Reproduced by permission of the World Health Organization, Geneva.)

2. In mosquitoes

• prevention of human biting (a x a — a2) by personal protection and mosquito nets;

• decreasing mosquito density (m) with lar-viciding and biological control;

• reduction of the proportion surviving to infectivity (pn) by residual insecticides and treated mosquito nets;

• reduction of the mosquito expectation of life (l/-lnp) by knock-down and residual insecticides.

(p is the probability of a mosquito surviving through 1 day, n the time taken to complete the extrinsic cycle, and ln the natural logarithm.)

The complete formula becomes zo ma2bpn where z0 is the basic reproductive rate (see Section 2.2.3).

Each of the parameters can be given values that have been measured in the field so that the level of control required to interrupt transmission can be calculated (reduce the basic reproductive rate below 1).

Some useful modifications of the formula are the

Vectorial capacity —

ma2pn and the critical density of mosquitoes below which the infection will die out given by

a2bpn

More complex models have been developed to overcome some of the shortcomings of this model, such as the development of immunity, but even in this limited form, it is very valuable.

The effectiveness of any potential strategy can be estimated from the algebraic

Mosquito

Mosquito

Epidemiology Cycle Malaria
Fig. 15.7. Mathematical model of malaria based on the schematic life cycle of the parasite.

expression given to each part of the formula without making any calculations:

• 1/r - the duration of infection reduced by chemotherapy, demonstrates the small effect of just treating malaria cases, and that control efforts, such as MDA used in malaria eradication programmes, need to be total, covering every single person, virtually impossible to achieve.

• b - this is actually a notation normally applied to mosquitoes, being the proportion that ingest gametocytes so that the parasite sexual cycle can take place, but can be applied to the human part of the cycle as any method which prevents the production of gametocytes. This can either be by preventing infection in the first place with vaccination or chemopro-phylaxis, the use of gametocidal drugs, or preventing the mosquito feeding on a malaria case by keeping them under a mosquito net. However, b is only a unitary factor, so all of these methods will need to be nearly perfect to work.

• a - the number of bites that need to be made by the mosquito. One bite is needed to introduce infection and another to take up gametocytes, so the interruption of mosquito biting could be quite an effective strategy. Therefore, personal protection with clothing, repellents and mosquito nets is a valuable method of control.

• m - the density of mosquitoes is only a unitary factor demonstrating the poor results of larviciding and biological methods in malaria control.

• p - mosquito survival consists of two factors, its expectation of life (short-lived vectors are poor transmitters) and the number of mosquitoes living long enough to complete the extrinsic cycle. In this p is raised to the nth power showing that reducing the length of life of the mosquito (mainly by the use of insecticides) is the best control strategy.

personal protection Methods of personal protection have been covered in Section 3.4.1. They include clothing, mosquito nets and repellents. Items of clothing, such as socks and shawls, can be treated with repellents, which retain activity for some time, or repellents can be applied directly to the skin. Some naturally occurring plants have repellent properties, such as African marigolds (Tagetes minuta).

Mosquito nets are most effective if used properly. Providing subsidized mosquito nets can help in malaria control, especially for mothers and children, who are liable to go to bed early (before mosquito biting starts). This can be improved by treating the nets with synthetic pyrethroid insecticides (such as permethrin, deltame-thrin, alpha-cypermethrin or lambda-cyhalothrin). This repels mosquitoes and kills those which come into contact with the net. When used on a community scale, the concentration of insecticide-treated mosquito nets (ITMN) can produce a mass effect reducing the mosquito population and the sporozoite rate. The method of treating mosquito nets will be found in Section 3.4.1. A recently introduced technology is the manufacture of mosquito nets with the insecticide already in the net, known as long-lasting insecticidal nets (LLIN). These retain activity for at least 4 years, so the regular retreating of nets can be avoided; hence this holds considerable potential as the main method of malaria control.

Mosquito bed nets are more effective and cheaper to maintain than screening the whole house, which is only recommended for people with a high standard of living. A small hole in the netting can render it ineffective. A knock-down spray can be used to kill mosquitoes that have entered a screened house.

The use of smoke from mosquito coils or vaporizing mats can be surprisingly effective and has the advantage that it is a cheaper option for personal protection. Coils are easily manufactured locally and naturally occurring substances, such as pyrethrum, are incorporated. People often sit around fires in the evening and by the addition of certain plants, a repellent smoke can be produced.

Mosquitoes can be deviated to bite other animals if they are the preferred blood meal;

however, if the animals are taken away, such as to market, then the mosquitoes may be forced to take their blood meal from humans. The habits of the malaria vectors will need to be known before encouraging this practice.

residual insecticides The use of residual insecticides has been covered in Section 3.4. These are applied to the inside surface of houses so that the resting mosquito (after it has taken its blood meal) absorbs a lethal dose of insecticide and dies before the parasites it has taken up in the blood can complete development. This was the main method of the malaria eradication programmes used in many countries of the world. Unfortunately, insecticidal resistance, organizational breakdown and reluctance by people to have their houses sprayed, resulted in an abandonment of the goal of eradication. This has been replaced by a policy of malaria control in which house spraying may be a component.

larviciding and biological control The number of larvae determines the density of mosquitoes, so any method which reduces the larval numbers inadvertently reduces the potential number of adults. The larvae can be attacked by several different methods:

• using insecticides and larvicidal substances;

• modification of the environment;

• biological control.

Larvicidal substances can be oils that spread over the surface and asphyxiate the larvae or have insecticidal properties. The size and flow of the body of water will determine which is the preferred method to use. Modification of the environment by drainage or filling-in is the most permanent and effective, but is an expensive undertaking. It is worth spending money on engineering methods in areas of dense population, such as towns, while in rural areas, much can be achieved by using self-help schemes. The considerable advantage of this method is that once done, it lasts for a long period of time, if not permanently, and in these days of resistant mosquitoes, it is seen as an economical proposition in some circumstances (see also Section 3.4.1).

Biological control with fish or bacilli (Bacillus thuringiensis or B. sphaericus) will reduce mosquito larvae to a certain extent, but a balance, as with much of nature, often results. Biological control can also be used directly against adult mosquitoes with the sterile male technique. This has not been successful with mosquitoes because of the very large numbers involved and their short period of life. Another method that is being considered is species competition whereby a non-malarial mosquito from another part of the world is introduced to compete with the resident vector. This has not met with any great success.

In epidemic malaria, using a fogging machine or ULV spray from aircraft can rapidly reduce adult mosquito density. This will cut short the epidemic by killing off flying adults, but needs to be repeated regularly as new adults will continually be produced from larvae that are not affected by the knock-down sprays.

chemoprophylaxis Attempts to use chemo-prophylaxis on a large scale on pregnant women and young children have not met with much success, but could be given to persons at particular risk, such as nonimmune immigrants or migrant workers. Chloroquine 300 mg (two tablets) weekly can be used where chloroquine resistance is not a major problem, but local advice should be sought. It is preferable to give pregnant women and young children priority in the distribution of ITMN or LLIN, or to use chemoprophylaxis in combination with them.

reducing the number of gametocyte Quinine, chloroquine and amodiaquine are active against the gametocytes of P. vivax and P. malariae, but not against the more important P. falciparum. Proguanil and pyr-imethamine act on the development of gam-etocytes within the mosquito on all four parasites. Primaquine has a highly active and rapid action on gametocytes of all species, whether in the blood or mosquito and is used in combination with treatment in the individual. It has also been proposed as a method of reducing the level of gameto-cytes within the population, but would require an almost perfect mass treatment as well as the danger of toxicity (especially with G-6-P-D deficient individuals), and therefore, is not considered a suitable method of malaria control.

Any person found to have malaria should, where possible, be protected by a mosquito net so as not to infect new mosquitoes. This is a particularly important measure during eradication and control campaigns, especially when endemicity is brought to a low level.

vaccines Attempts to produce a vaccine against malaria have been in progress since 1910. A vaccine made from killed sporozo-ites by irradiating mosquitoes is reasonably effective, but cannot be produced on a large scale. Easier to produce are vaccines made by isolating the DNA fragments of the cir-cumsporozoite antigen and cloning them through bacteria or yeasts. This has allowed large quantities of pure antigen to be produced and trials of candidate vaccines. Unfortunately, the response has been limited, so current research is to use a prime-boost technique similar to that for HIV. However, even if a vaccine is developed, all the problems of vaccination programmes, such as coverage, administrative difficulties and response of the public (see Section 3.2) will remain.

prospects for malaria control Malaria attracts the wonder cure - first, it was the eradication programme, now all hope is pinned on the vaccine, but it is more likely to be controlled by simple, non-dramatic methods where care to detail is applied. It is the encouragement of simple protective methods that everybody can follow like ITMN (or LLIN) or community action to modify the environment to make it unsuitable for mosquitoes to breed (see Table 15.2 for the main vectors). A multiplicity of simple methods carried out by many respon sible people is likely to be more successful in the long term than more complex methods.

Treatment of the uncomplicated case of P. vivax, P. malariae and P. ovale malaria is with chloroquine:

• 600 mg of chloroquine base as an initial dose;

• 6h later, 300 mg chloroquine base, followed by

• 300 mg chloroquine base for 3 or more days.

Chloroquine-resistant P. vivax has been reported from Western Pacific Islands, including the island of New Guinea, as well as Guyana in South America.

P. falciparum is resistant to chloroquine and many other anti-malarial drugs, so individual countries will have their own treatment schedules depending on the resistance pattern and the drugs available. Quinine, mefloquine, artemether, artesunate, artemo-til, chlorproguanil/dapsone (LAPDAP) and artemesin-based combination therapies (ACTs), such as artemether/lumefantine are available. Artesunate in single-dose rectal suppositories is a new approach to treating malaria in children, who are not able to take medicines orally.

In P. vivax, chloroquine will only clear parasites from the blood, and to effect radical cure, primaquine is administered in a dose of 15 mg base daily for 14 days (except in the island of New Guinea and other Western Pacific Islands, where more prolonged treatment is required).

Case finding and treatment is an effective strategy where there is a low level of malaria, so it needs to be used in combination with other methods of malaria control.

Surveillance In all areas where malaria is found, a blood slide should be taken from anyone with a fever. Where attempts are being made to eradicate or reduce the level of malaria, then an active system of surveillance may be instituted as described in Section 4.5.2.

Where a control method is in operation, regular checks should be made, such as the proportion of houses with ITMN and the number of people sleeping under them. More will be found on malaria programmes in Sections 4.3-4.5.

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