The Pharmaceutical Journal Vol 264 No 7087 p405-410
March 11, 2000 Continuing education

Travel medicine

(4) Malaria

By Larry Goodyer, PhD, MRPharmS

Travel medicine article index

Of the many insect-borne diseases, malaria causes the greatest mortality worldwide. There are over 300m cases a year, resulting in 1-2m deaths,¹ the majority being in young children.
Malaria has long been eradicated from most of Europe and North America, although the mosquitoes capable of transmitting malaria are native to these continents. In the US, there have been occasional reports of malaria. This is usually the result of a person, infected with malaria in another country, being bitten by local mosquitoes. If these mosquitoes are allowed to breed, the disease may be transmitted to other people. However, in order to develop a situation where malaria becomes endemic, a critical number of individuals must be carrying the parasites to create a large enough pool to maintain the disease. The other circumstance in which malaria is occasionally observed outside endemic regions is so called "airport malaria". This occurs when infected mosquitoes enter a country via an aircraft, despite the use of knockdown sprays in the cabins. There are reports from time to time of individuals contracting malaria in and around airports.
Malaria is at its most active in the broad band between the tropics (Figure 1). For the traveller from the UK, increasing tourism to such areas has resulted in malaria presenting a significant risk. Every year approximately 2,000 travellers from the UK contract malaria and up to a dozen deaths occur as a result. This figure has changed little over the past 10 years and, as will be discussed later, over a third of such cases^2,3 occur in people from ethnic groups resident in the UK who have returned to their country of origin for a brief visit.
This article will examine various aspects of malaria that are relevant to travellers from non-endemic countries. The treatment of malaria, other than emergency self-medication, will not be covered. In a future article, bite avoidance, using repellents and other measures, will be examined in greater depth.

Figure 1: World distribution of risk of infection from Plasmodium vivax and Plasmodium falciparum

Forms of malaria and risk to the traveller

Traditionally, malaria has been defined in two classes: the potentially fatal malignant malaria (caused by Plasmodium falciparum) and a less dangerous benign malaria (caused by Plasmodium vivax, Plasmodium malariae and Plasmodium ovale). Figure 1 shows the relative distribution of the two most common forms of malaria - P vivax and P falciparum.
However, there may be local variations within the areas shown. P ovale is found mainly in sub-Saharan Africa and P malariae has a patchy distribution in all endemic areas. As will be discussed later, P vivax remains mostly sensitive to chloroquine alone but there is widespread resistance to P falciparum.
An important aspect of falciparum malaria, in particular, is that those living in highly endemic areas will acquire partial immunity to it. Therefore, in healthy adults living in endemic countries, life threatening falciparum malaria is not often seen. Young children under five years of age have not developed such immunity and mortality in this age group is high. Immunity wanes over a few years once the individual has left the endemic area and is no longer exposed to P falciparum. In a situation where immunity is reduced, for instance during severe illness, resistance may also be lost.⁴
Malaria is very dangerous in pregnancy and is an important cause of spontaneous abortion and still-birth in some endemic areas.
Travellers who have no immunity from the disease may receive inadequate treatment from local clinics that are unused to treating non-immune subjects. For instance, it is common practice for the local population in some countries to receive chloroquine tablets, partly for economic reasons, rather than parenteral quinine, which would generally be given to treat falciparum malaria.
A particular group at risk are immigrants residing in non-endemic areas who return to their country of origin to visit relatives and friends. These individuals will not always take adequate prophylactic measures in the mistaken belief that they still possess a degree of immunity.
The actual level of risk to an individual will depend upon the proportion of mosquitoes which carry the disease, the number of infected bites received and the time spent in the area.⁵ The numbers of mosquitoes carrying malaria will vary between regions and often between times of year relative to the wet or monsoon season.
The risk is often lower in more urban and coastal areas, and is absent above 2,000m, where mosquitoes cannot survive. One of the highest risk areas is the rain forests of west Africa, where an unprotected individual staying for one week has a 2 to 3 per cent chance of contracting malaria. The type of accommodation, eg, the presence or absence of air conditioning, will also be an important determinant of exposure to mosquitoes. The most important determinant that can be controlled by the traveller is the preventive measures taken in terms of personal protection against mosquitoes and malarial chemoprophlaxis.

Pathophysiolology and life cycle

Life cycle The life cycle of the malaria parasite is described in many medical textbooks, so only a brief summary is given here.
The insect vectors of malaria are the anopholian family of mosquitoes of which there are a great many species. For the development of eggs in the female mosquito, a blood meal is necessary. It is only the female which bites humans. The mosquito lays eggs in still water (anything from a pond to stagnant water in an old tyre) where the free-swimming larvae will eventually pupate. In order to transmit malaria, a mosquito must pick up the the sexual state of the malaria parasite, called gametocytes, while biting a human. These mature within the mosquito to asexual sporozoites which can then be transmitted to a human through a bite. These sporozoites will then infect the hepatocytes of the human liver, where further development and multiplication, called extra-erythocytic schizogony, takes place. From the hepatocytes, many thousands of merozoites are released, which then invade red blood cells (RBCs). Once inside an RBC, the merozoite develops into a trophozoite and, following further cell division and multiplication, is termed a schizont (erythrocytic schizogony). The schizonts will form eight to 24 mature merozoites which are released into the blood stream to invade further RBCs.
Some of the merozoytes will form sexual gametocytes and if a mosquito takes these up in a bite, the cycle is completed. This, the sexual lifecycle, is clinically irrelevant. Symptoms of malaria result from the invasion and rupture of RBCs in asexual reprodction.
P vivax and P ovale can remain dormant in liver hepatocytes, persisting as hynozoites.

Pathophysiology Apart from the fever and malaise associated with release of merozoites into the blood stream, there are few serious complications resulting from the benign malarias, although anaemia will develop over time if the disease is not treated. However, in the case of falciparum malaria in non-immune travellers, there is a high risk of complications resulting from blood vessel damage. In this form of malaria, the surface of the RBCs becomes altered so that they adhere to blood vessel walls. This leads to sequestration of infected RBCs in deep tissues of various organs.⁶ Sequestration in the brain can lead to the complication known as cerebral malaria.
The persistent hepatocyte stages can lead to a recurrence of symptoms for many years. During such attacks, after infection by P vivax and P ovale, there tends to be a more cyclical nature to the symptoms, with fever and chills recurring every 48 hours.

Clinical presentation The greatest danger of malaria is that early symptoms tend to be non-specific. Often described as "influenza-like" (fever, malaise, headaches), there may also be associated gastrointestinal symptoms of diarrhoea and vomiting. Attacks of malaria are classically described in three phases: coldness and rigors; feeling hot and flushed; and then intense sweating as the attack resolves.
In the case of severe falciparum malaria, the fevers are irregular with coma and death sometimes occurring in as little as 24 hours from initial symptoms. For malaria caused by P vivax and P ovale, cyclical fevers and malaise may afflict the individual for many years if not treated, but in healthy adults such infections would rarely be fatal.
After being bitten by an infected mosquito, onset of symptoms of malaria will take a minimum of a week to appear. In the case of falciparum malaria, it is rarely more than three months before symptoms appear but it can take over a year for other forms of malaria. Hence it is advisable to inquire about travel in the previous year in those presenting with influenza-like symptoms.
Malaria is particularly dangerous in pregnancy, resulting in a high risk of abortion and maternal fatalities. Travel to malaria-endemic areas during pregnancy is therefore usually strongly discouraged unless there are compelling reasons.

Chemoprophylaxis

Adverse effects, contraindications and interactions Adverse reactions are an important aspect of antimalarial prophylaxis in that the risks of serious adverse reactions must be clearly balanced against the chance of contracting malaria. However, due to the low doses employed in chemoprophylaxis, the problems encountered when using the agents to treat malaria would rarely be seen. The pharmacist should be in a position to counsel travellers regarding likely side effects and to screen for potential interactions and contraindications. These are summarised in Table 1 and briefly discussed below.

Table 1: some important adverse reactions and contraindications to antimalarials
Drug	Adverse reactions	Contraindications
Chloroquine	Nausea Visual disturbances Depression Insomnia Dizziness Pruritus Headache	Epilepsy Psoriasis
Proguanil	Mouth ulcers Gastrointestinal disturbance	Renal impairment
Mefloquine	Nausea Headache Dizziness Neuropsychiatric reactions	Pregnancy Psychiatric illness Epilepsy
Pyrimethamine/dapsone	Blood dyscrasias Cutaneous reactions	Pregnancy G6PD deficiency
Doxycycline	Vaginal thrush Photosensitivity	Pregnancy Children

Although a fairly long list of adverse events to chloroquine has been presented, only gastrointestinal upset is relatively common.⁹ This problem can be relieved to some extent by taking the drug after food. Chloroquine also has the potential to cause retinal damage, but this is only apparent at much higher doses than are used for malarial prophylaxis. Prophylactic chloroquine has been observed to cause clonic-tonic seizures and is therefore usually avoided in patients with epilepsy. Likewise, prophylaxis can also result in a flare-up of psoriasis, so should be avoided in individuals with this condition. Chloroquine may suppress the immune response to rabies vaccine if the vaccine is given by the (unlicensed) intradermal route,¹⁰ so the subcutaneous route should be used in such circumstances. Similarly, an inadequate response may result if these antimalarials are taken with an oral typhoid vaccine. There is some racial variation in adverse effects as people with darker skin are more prone to chloroquine-induced pruritus.
Proguanil may increase the effects of warfarin and the INR should be monitored on initiation of therapy. The most frequently observed adverse effect to proguanil is mouth ulcers. Hair thinning has been reported which is probably attributable to proguanil, although chloroquine has also been implicated.
Whether or not to take mefloquine has become a contentious issue since its safety was questioned in the media following anecdotal reports of adverse effects by tourists. Overall, studies have shown that the incidence of side effects to mefloquine is no greater than to chloroquine and proguanil but the type of reactions does differ.³ Dizziness is one of the more common reported reactions, which tends to be self-limiting on continuation of treatment. The most contentious issue concerns the neuropsychiatric reaction which includes anxiety, nightmares, abnormal behaviour and psychosis. In a few cases, such symptoms have been claimed to persist long after discontinuation of therapy and appear to be more common in those taking mefloquine than in those taking proguanil and chloroquine.¹¹
Travellers may therefore need careful explanations of the risk/benefit of taking mefloquine. An example of such an assessment is illustrated in Table 2. It describes the risk of contracting malaria in the forests of west Africa, which is an area of very high transmission, together with the risk of an adverse event occurring which is serious enough to warrant discontinuation of therapy. The argument is that for trips of two or more weeks, the danger of contracting malaria can outweigh the risk of side effects of mefloquine, and that the level of protection from chloroquine/proguanil is very much lower. However, for shorter trips the balance can turn in the other direction, making chloroquine/proguanil an acceptable alternative. This is the reasoning behind the recommendation that mefloquine is not used for short trips to coastal resorts in east Africa.

Table 2: Relative risks of contracting malaria in west and coastal east africa
	Per cent of travellers contracting malaria during a 2 week visit	Per cent of travellers contracting malaria during a 4 week visit
West African rainforest
No prophylaxis	4	8
Chloroquine/proguanil	0.06-1.2	1.2-2.4
Mefloquine	0.02-0.4	0.04-0.8
Coastal east Africa
No prophylaxis	0.6	1.2
(Neuropsychiatric adverse reactions resulting in discontinuation of mefloquine - 0.5 )

Travellers should also be advised that if an adverse reaction is going to occur, then in 75 per cent of cases it will have been noticed by the third dose, emphasizing the value of advice to take mefloquine in advance of travel (see below).
A further testament to the usefulness of mefloquine is that, after recommendations to use the drug in Kenya in 1993, there was a three-fold reduction in the cases of reported malaria.¹² However, after a reduction in the use of mefloquine following safety concerns, there was a marked rise in imported malaria from east Africa, only partly explained by an increase in malaria transmission.¹³
Mefloquine can potentiate the effect of quinine, and convulsions have been observed when intravenous quinine has been administered to those taking mefloquine prophylaxis. Care should also be taken if administering mefloquine to patients with epilepsy or with certain arrhythmias, and it may potentiate digoxin.
Maloprim and Fansidar have both been associated with severe blood dyscrasias and, apart from increased resistance to these agents, this has been the principal reason for their reduction in use as prophylactics. There is also a risk of sensitivity reactions to their various components.
Doxycycline can cause a photosensitivity reaction in about 3 per cent of individuals, and sunscreens do not appear to offer much protection. An additional problem for women is the occurrence of vaginal thrush. This may be compounded by the increased incidence of fungal infection when travelling to hot and humid areas. Cases of Clostridium difficile-associated diarrhoeas have also been associated with doxycyline chemoprophylaxis.¹⁴

Use in pregnancy Only chloroquine and proguanil are currently recommended for use in pregnancy, because the risk of malaria far outweighs the risk of adverse events from medication. It is advisable that pregnant women take folic acid supplements if receiving proguanil (because it is a folate antagonist). There is mounting evidence that mefloquine may be taken in pregnancy as recent case studies have revealed no teratogenicity or other problems.^5,15 However, during early studies in animals, malformations were observed when using high doses for prolonged periods and the current data sheet stringently states that mefloquine should not be used during any stage of pregnancy. Very little of any of the antimalarials are excreted in breast milk, and only doxycycline should be avoided when breast-feeding.

Compliance to antimalarials Compliance is a major consideration, particularly in the scenario where medication needs to be taken regularly over long periods of time. In addition, as such medication is being taken for prophylaxis, even minor side effects are likely to reduce compliance in an individual.¹⁶
There have been a few studies examining compliance to antimalarials. One such study¹⁷ identified that 48 per cent of travellers did not comply with their regimen. Another study¹⁸ found that non-compliance was more likely in the under 55s, in trips of longer duration and non-package tours, and in those who received travel heath advice from more than one source. A similar Dutch study¹⁹ found that compliance rates differed between destinations; from 45 per cent in those travelling to South America to 78 per cent in east Africa. Young age and more adventurous travel were also found to increase non-compliance. Fear of adverse events and belief that medication does not work may be particular reasons why some fail to take prophylaxis.²⁰ Overall, malaria contracted while taking antimalarials is just as likely to be due to poor compliance as drug resistance.²¹
It may well be that adopting the concordance approach will result in a better outcome than insisting on complete compliance to a regimen with which the traveller is unhappy. Therefore if, for instance, an individual is unhappy to take mefloquine even if it gives the best level of protection, an alternative regimen should be negotiated.

Use of antimalarials Prophylactic medication must always be taken in advance of travel, both to allow identification of potential side effects and to allow blood levels to rise sufficiently to inhibit the parasite. All antimalarials except mefloquine should be started one week before travel. The advice for mefloquine is that it should be commenced two and a half weeks before travel in order to allow three full doses to be taken, for the reasons described above. All antimalarials should then be taken while away and for four weeks on return in case any parasites are emerging from the pre-erythrocytic stage.
It is important that daily doses of antimalarials are taken at the same time each day and weekly doses at the same time each week. Some antimalarials should be taken with or after food (eg, chloroquine, proguanil and mefloquine) so it may be useful to time doses to coincide with the evening meal.
Travellers must be made aware that no regimen will offer complete protection. However, if malaria is contracted while taking prophylaxis it is less likely to prove fatal. Because no antimalarial can offer complete protection, bite avoidance measures must always be taken.

Choice of regimen

There are currently five potential regimes described in the UK guidelines:³

• Chloroquine
• Chloroquine and proguanil
• Mefloquine
• Doxycycline
• Maloprim and chloroquine

The duration of the trip is also important, with mefloquine being recommended up to a maximum of one year and doxycycline for just three months. There is no recommended upper limit for chloroquine and proguanil. For expatriates and aid workers planning to spend many years overseas, it is common practice to give an initial supply of the recommended regime. This may be changed after arrival depending on local advice, for instance, only taking medication at times of higher transmission or when travelling to other localities.
Although business travellers may be staying in well screened rooms and air conditioned hotels in cities, urban areas in many parts of Africa can still present a risk. The main danger to business travellers is that they may be inadequately protected while making short, unexpected trips to rural areas.
A further confusion for travellers is that recommendations for prophylaxis differ between countries.²³ For instance, proguanil is not available in the US and mefloquine is more widely prescribed. Travellers from different countries may therefore experience uncertainty when comparing regimes.
For detailed guidelines on prophylaxis for individual countries, the pharmacist should refer at least to the British National Formulary or Communicable Diseases Review (CDR) guide, but more recently updated databases would be ideal, as outlined in the first article (PJ 1999;263:84).
A few points concerning different destinations are worth making:

• North Africa carries quite a low risk. For many destinations, chloroquine alone is sufficient, and is often only required in a few areas at certain times of year. Chloroquine-resistant falciparum malaria is present in a few areas of the Middle East, eg, Yemen and Oman.
• Sub-Saharan Africa carries appreciable risk, particularly the forested areas of west Africa. For many destinations, mefloquine is recommended as first-line and there has been little reported resistance. If this is unsuitable, or the traveller is unhappy about taking mefloquine, then doxycycline can be considered, bearing in mind that it can only be taken for three months and is unlicensed as a malaria prophylactic. In addition, there is some doubt as to its efficacy against P vivax. The combination of chloroquine and proguanil is still an option, provided travellers are aware of the lower level of protection.
• For coastal areas of east Africa, chloroquine and proguanil can be used for trips of two weeks duration or less, where the level of protection has been estimated at around 70 per cent. However, even a short safari into rural areas would indicate mefloquine as a first line choice to achieve 90 per cent protection.²⁴ Those not wishing to take take mefloquine can be offered doxycycline as an alternative.
• In south east Asia, the situation can become confusing and, in some areas, resistance to many prophylactics is reported. For instance, travellers to Thailand may not require any prophylaxis if visiting the usual tourist areas. However, in the areas which border Cambodia and Laos, only doxycycline may be effective. The difficulty arises where travellers are uncertain of their itinerary and indeed these border areas tend to be demilatarised zones to which it can be difficult to gain access. It may often be best to advise no prophylaxis if the visit to such areas is very short, but to counsel on awareness of the signs of malaria and of the need to take stringent bite avoidance measures.
• In most areas of south Asia (eg, India) or South America, chloroquine and proguanil still offer sufficient protection. The Amazon basin is an area of higher chloroquine resistance where mefloquine would be recommended. In some areas of the Pacific, the combination of Maloprim and chloroquine is effective.

Malaria "standby" treatment

If away from medical help for more than 24 hours, some travellers may be advised to take "standby" treatment if malaria is suspected, while still trying to find medical attention. There are a number of possible self-treatment regimes including the use of mefloquine, Fansidar, quinine or atovaquone/proguanil (Malarone). The use of mefloquine would be precluded if that had been used as prophylaxis and there are a number of areas where Fansidar resistance is a problem. Malarone has not yet been included in official guidelines for self treatment, so quinine may be the only alternative. The BNF describes a seven-day course of oral quinine, but owing to side effects, many would find this difficult to complete. Therefore, a shortened three-day course has been recommended by the CDR. If quinine is used, this should always be followed by three Fansidar tablet, given as one dose, or a course of doxycycline. Although mefloquine can increase blood levels of quinine, this does not preclude the use of oral quinine in emergency self-treatment.
Artemesin may be another useful drug for self-treatment if it becomes licensed in the UK.
Also available for travellers are blood testing reagent strips that can be used to detect P falciparum infection from a finger prick.

Dr Goodyer is director of pharmacy practice research at King's College London, and superintendent of Nomad Travel Pharmacy