Malaria

Dr Mike Townend discusses the management of malaria, including special considerations for women and children, and the plethora of non-drug and drug prophylactic interventions available

Malaria is not the most widespread tropical disease worldwide, this distinction belonging to dengue fever, a disease characterised by severe flu-like symptoms accompanied by a rash and severe myalgia, sometimes progressing to a haemorrhagic fever. Malaria is, however, the most important in terms of morbidity and mortality. Each year about 2000 travellers bring malaria into the UK and about 10 to 12 of them die. Worldwide, there are about two million deaths annually¹.


Aetiology

Malaria is caused by the protozoan parasite Plasmodium which is transmitted to humans by bites from infected female mosquitoes of the genus Anopheles. Anopheline mosquitoes breed in hot climates where there is standing water in which their larval stage lives. Malaria does not occur in temperate climates or at higher altitudes in tropical or sub-tropical countries, where ambient temperatures are lower.

Parasites are injected in their thousands into humans by female mosquitoes, in the form of sporozoites from the mosquito's salivary glands, when they alight on the skin to take a blood meal. Within a few hours the sporozoites have disappeared from the blood to enter the liver where they divide repeatedly, forming schizonts which contain thousands of daughter cells called merozoites. On maturation the schizonts rupture to release merozoites into the blood where the merozoites enter red blood cells. Within the red cells merozoites enlarge to become trophozoites, feeding on the red cells as they do so. The trophozoites divide repeatedly to form further schizonts which rupture into the blood stream, destroying their host red cells and releasing more merozoites, and the process continues.

Types of malaria

There are four species of Plasmodium which cause malaria in humans. They are P falciparum, P vivax, P ovale and P malariae. Of these, P falciparum is now the most significant, because it causes potentially fatal disease, has increased its worldwide distribution and has acquired considerable resistance to some antimalarial drugs. P vivax is the next most important numerically; it is not usually fatal but can remain latent for many months before becoming symptomatic and can cause relapses over a period of many months.

Symptoms

The principal initial symptom is fever which may be accompanied by rigors. Classically, the fever has three stages: a cold stage, when shivering or rigors occur and the temperature rises, a hot stage when the temperature remains high for several hours and a sweating stage when profuse sweating occurs and the temperature begins to fall. After about one week, the fever may fall into the classical pattern of waxing and waning every three days, though this is not always seen, especially in P falciparum malaria.

Falciparum malaria is dangerous and potentially fatal if not rapidly diagnosed and treated: extensive multi-organ damage occurs due to obstruction of capillaries by damaged and destroyed red cells. Jaundice and enlargement of the spleen (an early sign) and anaemia due to haemolysis may occur in all types of malaria. In falciparum malaria, diarrhoea due to gastrointestinal damage, confusion, coma and convulsions due to cerebral damage, pulmonary oedema, renal and hepatic failure may all occur.

P vivax, ovale and malariae parasites may form hypnozoites, dormant forms which remain in the liver for a variable period of days to months. They then become activated and the liver and blood stages of the life cycle begin. This phenomenon explains why vivax, ovale and malariae malaria may have a long initial incubation period and why relapses may occur. If a traveller who has returned from a malarial area within 6 to 12 months develops fever, whether or not he has taken antimalarial drugs, malaria must be excluded.

Malaria has often been misdiagnosed as influenza through failure to consider the possibility of malaria or failure to take an adequate travel history, sometimes with fatal results. All travellers to malarial areas should be warned before travelling that any fever during their travels or within six to 12 months of their return must be investigated as possible malaria.

Investigation

The most important method of diagnosis is the identification of malaria parasites in the peripheral blood. It is not essential to wait until the height of the fever to take blood for testing; if malaria is suspected, a blood specimen must be examined urgently. Thick and thin films are usually requested. The thick film shows larger numbers of blood cells per field and is therefore more likely to show the presence of trophozoites in the cells, whereas the thin film makes identification of the type of parasite easier. In travellers from non-malarial countries, the presence of parasites is diagnostic of malaria but in indigenous people with some degree of immunity to malaria, parasites may be present in the blood in the absence of clinical disease. One negative film does not exclude malaria. If there is clinical doubt, repeated films must be examined. Dipstick tests for falciparum malaria may in the future make early diagnosis easier when there is limited access to a laboratory.

Non-drug prevention

If the individual is not bitten, malaria will not occur. Avoidance of bites is of prime importance because no regimen of drug prophylaxis is 100 per cent effective. Both methods are of importance, however, because bite avoidance cannot be relied upon.

Covering up. Malaria-carrying mosquitoes bite from dusk to dawn. Between these times it is advisable to keep as much of the skin surface covered with clothing as possible. Mosquitoes and flies carrying other diseases may bite during daylight and similar precautions may be needed by day if this is a local risk. Insect repellents. Areas of skin which cannot be covered should have an insect repellent applied to them.

Insect repellents work by producing a scent which mosquitoes find unpleasant, and prevents them from landing on skin to which repellents have been applied. DEET (diethyltoluamide, found in Jungle Formula and other preparations) should be used in a concentration of at least 20-30 per cent and up to 50 per cent in heavily infested areas. It should not be applied close to the eyes and may damage some fabrics and plastics such as spectacle frames. It is generally safe² but there is some concern about possible toxic effects^3,4, especially in infants and during pregnancy^5,6. One hundred per cent DEET may be used to impregnate clothing such as socks, neckerchiefs and wrist bands to protect partially exposed areas. Lemon eucalyptus-based preparations (Mosiguard) are also effective repellents and a new compound KBR 3023 (Bayrepel), which appears to be both safe and effective⁷, is found in Autan preparations.

Mosquito nets. Sealed air conditioned hotel rooms should offer protection against entry by mosquitoes. Mosquito screens on doors and windows may not be effective or may not fit properly. If there is any doubt or if no screen exists, a mosquito net of small enough mesh should be used over the bed. It must be suspended from above by the suspension point(s) provided and if a frame is provided it should be erected within it to ensure a correct drape. Before use, it must be checked for holes and any which are present must be repaired or temporarily plugged, with cotton wool for example. Nets are much more effective if impregnated with the insecticide permethrin. This may be done by the purchaser but it is easier to buy an already impregnated net. After six months' use the net needs to be re-impregnated. Permethrin kills mosquitoes on contact whether or not they are able to penetrate the mesh. There is also evidence that the effect of an impregnated net will reduce the mosquito population in a room and offer some protection to other occupants of the room. If the net is not impregnated, the sleeper must not come into contact with it because mosquitoes may then be able to bite through the mesh. The net must be tucked in all the way around the mattress, though this is not necessary with an impregnated net if it reaches completely down to the floor. In a tent, it is necessary to use a mosquito net because the mesh built in the tent is seldom effective. When sleeping completely out of doors, it is necessary to improvise suspension points for the net.

Other precautions. Mosquito coils when burned in a room, are not reliable at keeping mosquitoes at bay . Electronic buzzers are ineffective but electric vaporisers which vaporise tablets or liquid insecticide may be effective if electricity supplies are reliable. In addition, it is useful to erect the mosquito net, close the doors and windows and spray a knock-down insecticide into the room about half an hour before retiring for the night.

Drug prophylaxis

Prophylactic antimalarials act only on the blood stages of the malaria parasite. For this reason it is necessary to take them not only throughout the stay in a malarial area but also for a period of four weeks following the end of possible exposure to risk. This allows any parasites which are present to follow through their life cycle to the point at which they are vulnerable to the drugs. Starting a week before exposure to risk allows adequate blood levels to be operative at the start of exposure. In the case of mefloquine, it is advisable to start the drug three weeks before exposure for reasons which are outlined below.

Drug prophylaxis for adults. The choice of drug prophylaxis depends largely on the presence or absence of falciparum malaria at the traveller's destination and the degree of chloroquine resistance present. In areas without drug resistance, travellers can take either chloroquine or proguanil; in areas with low levels of drug resistance both chloroquine and proguanil should be taken; and in areas with drug resistant falciparum malaria either mefloquine, Maloprim plus chloroquine or doxycycline are appropriate. l

Drug prophylaxis for children. The choice of drugs for children depends on their age and body weight (see the BNF and MIMS). Mefloquine is not suitable for very young or very small children, i.e. below two years of age or 15 kg weight.

Drug selection

Malaria risk and drug resistance may vary not only from country to country but from place to place within a country. In order to select appropriate antimalarial drugs, it is necessary to consult a reliable database. Charts taken from medical periodicals such as Pulse and GP are useful but may not be as fully comprehensive or as frequently updated as some other sources. Computer databases such as Travax and Traveller are more comprehensive and are updated frequently. The Malaria Helpline at the London School of Hygiene & Tropical Medicine (public information line: 0891 600350, open 24 hours; health care professionals: 0171 636 3924, open 09.00 - 16.30) is a very useful source of information. The UK Malaria Guidelines⁸, including a country-by-country guide to prophylaxis, were published in the CDR Review in September 1997 and useful country by country information is also found in Health Information for Overseas Travellers and the WHO's International Travel and Health.

Safety and side-effects

Chloroquine and proguanil. Both drugs may be taken during pregnancy; chloroquine should not be taken by those with a history of epilepsy. Both drugs may be associated with hair loss and there is also a possibility of gastrointestinal upsets and neuropsychiatric side-effects⁸ such as occur with the use of mefloquine (see below).

Mefloquine. Mefloquine (Lariam) is a drug which has been surrounded by controversy, largely provoked by the news media, in recent years. It is recommended for use only in areas which have a high prevalence of chloroquine-resistant falciparum malaria, for which it is currently the drug of choice. This is the type of malaria which is rapidly fatal if not effectively treated, and the risks of the disease are much greater than any risks from taking the medication to prevent it. Mefloquine may be taken in the second and third trimesters of pregnancy. It is not suitable for those with a history of epilepsy, depression or psychotic illness. Neuropsychiatric side-effects such as depression, nightmares, hallucinations, psychosis and convulsions have been reported. There is also a possibility of unsteadiness or dizziness. They are not common events, the more severe effects having a frequency of only about 0.01 per cent, though recent experience suggests that this figure may be higher, with mild or moderate side-effects such as dizziness occurring about twice as often as with a combination of chloroquine and proguanil⁹. Most of these effects occur very early, often within the first three doses. It is advisable to start treatment three weeks before departure so as to 'weed out' those who develop side-effects, stop the drug and substitute an alternative choice of drugs. Taking mefloquine still carries a much lower risk than does falciparum malaria which may be fatal. The overall incidence of side-effects, from serious to trivial, is equal for mefloquine and chloroquine/proguanil, at about 40 per cent⁹.

Doxycycline. Doxycycline may cause photosensitive skin eruptions on exposure to sunlight. Because of tetracycline deposition in bones and teeth, it is not suitable for use in pregnancy or children. It may be started a day or two before departure but needs to be continued for four weeks after exposure.

Pregnancy & childhood

Pregnant women are more susceptible to malaria and may suffer miscarriage or premature labour. It is essential to make sure that they are adequately protected by all available means. If the most effective antimalarial prophylaxis for the area to which they intend to travel is contraindicated in pregnancy there may be a difficult decision as to whether to use a less effective regimen or not to travel at all.

Children are also particularly susceptible to malaria and in areas where there is P falciparum malaria, they can readily develop severe illness such as cerebral malaria. They too must be adequately protected, and again there may be difficult decisions about the necessity to travel if the most effective prophylaxis is contraindicated.

Returning travellers

Malaria occurring in travellers who have returned to the UK is frequently misdiagnosed as influenza, sometimes with fatal results and medicolegal consequences. As some species of the malaria parasite may remain dormant in the liver for many months, it is wise to take a travel history from feverish patients, including not only their most recent trip abroad but going back over their travels during at least the past year. If a malarial area has been visited, blood must be sent urgently to the laboratory for thick and thin smears to identify malaria parasites, repeating tests if there is a negative result initially and suspicion persists.

Conclusion

Malaria is a potentially fatal disease which can be largely prevented, given the plethora of practical measures which can be taken to avoid getting bitten and prophylactic drugs. Patients should be given adequate advise and reminded that the consequences of contracting malaria could be far worse than any side-effects potentially endured by antimalarial tablets.

Mike Townend is a general practitioner in Cumbria and a member of the British Travel Health Association