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Malaria prevention advice for the traveller: part two

Caroline Turner
MBBS BSc MRCP DIPGUM
Clinical Research Associate

Jane Zuckerman
MD FRCP (Ed) FRCPath FFPM
Senior Lecturer and Honorary Consultant

The Academic Centre for Travel Medicine and Vaccines
WHO Collaborating Centre for Reference, Research and Training in Travel Medicine
London

The majority of cases of malaria in the UK arise in travellers visiting friends and family abroad. This article explores the issues around malaria protection to enable a reduction in the incidence of this preventable infection

In 2009 there were 1,495 cases of malaria in the UK of which there were six deaths.1 The majority of cases were in travellers visiting friends and family abroad. All these cases would have been avoidable if travellers had sought pre-travel advice and armed themselves with the ABCD rule of malaria protection. Throughout this article we shall be referring to the Heath Protection Agency (HPA) guidelines written in association with the Advisory Committee of Malaria Prevention (ACMP) and the National Travel Health Network and Centre (NaTHNaC).2,3

Chemoprophylaxis
Chemoprophylaxis needs to be commenced before, during and after travel to a malarious area. The specific drug(s) of choice will depend on numerous factors, including:

  • The geographic area travelled to and thereby malaria drug resistance.
  • Possible drug-to-drug interactions.
  • Any medical problems that would negate the prescribing of some drugs.
  • The cost and potential side-effects of chemoprophylaxis.

Drug resistance is a continuous, dynamic problem and the emergence of mefloquine resistance in western Cambodia illustrates this well. Although some of these chemoprophylactic drugs may be available abroad, travellers are strongly advised not to obtain them in other countries as the quality of the product is unknown and may not be protective and possibly dangerous (eg, counterfeit, contain contaminants or produced in substandard manufacturing process).4

Many countries do not have a strongly regulated pharmaceutical industry and counterfeit antimalarial drugs pose a serious threat. Trade in counterfeit drugs results in traveller death but it is lucrative and results in minimal criminal penalties.5 A survey in south-east Asia involving 104 purchases of artesunate tablets found that 38% of the tablets contained no drug.6 In Cameroon a further survey found insufficient or inactive ingredients in 38% of preparations labelled chloroquine, 78% of those labelled quinine, and 12% of tablets labelled as an antifolate agent.7

Malaria life cycle
When the infected mosquito bites, it injects 10-15 sporozoites into the unsuspecting traveller. These then pass from the affected limb to the liver where they develop into merozoites and finally schizonts. Drugs directed at this liver stage (causal chemoprophylaxis) prevent the parasite from progressing into the red blood cell (RBC) stage and so need to be taken for seven days from leaving the malarious area (atovaquone/proguanil).

In the context of infection with P vivax and P ovale, the hypnozoites enter a dormant stage in the liver and then months later can reactivate and develop into schizonts. The schizonts then multiply in red blood cells causing clinical illness. Once they rupture they release approximately 30,000 merozoites, which have the potential to infect another red blood cell and so on.

Suppressive chemoprophylaxis is directed at this stage, so treatment would need to be taken for four weeks after leaving a malarious area. Some parasites in the red blood cells do not multiply and divide but form the sexual stages - the gametocytes. At this stage, if a mosquito bites the infected traveller these will go on to develop into sporozoites in the gut of the mosquito. They then migrate to the salivary glands and the cycle is completed.

Chloroquine
The drug is concentrated in the malaria parasite and is thought to act by interfering with malaria pigment formation, causing the generation of a toxic complex, which results in death of the parasite. Chloroquine can be used as a chemoprophylactic agent in destinations where there is no documented evidence of chloroquine resistance such as central America and in combination with proguanil for parts of Asia.

Prophylaxis should start a week before travel, during travel, and on return from a malarious area for four weeks. Reported side-effects include nausea, gastrointestinal disturbance, headache, pruritis (mainly in patients of African descent), blurred vision and insomnia. Generally, these side-effects are tolerated and do not require a switch of therapy.

There have been reports that chloroquine can exacerbate psoriasis and myasthenia gravis, and high doses as used in rheumatoid arthritis are associated with retinopathy. The doses used in prophylaxis, however, are much lower, making this side-effect extremely unlikely. However, travellers who have taken 300 mg chloroquine weekly for more than six years and require further prophylaxis should be screened twice yearly for early retinal changes.

Proguanil
Proguanil inhibits the enzyme dihydrofolate reductase, which results in the disruption of malaria deoxythymidylate synthesis. Proguanil can be used in combination with chloroquine as prophylaxis to areas where there is no documented resistance, such as Pakistan, below 2,000 metres. The ACMP does not recommend its use for travellers to sub-Saharan Africa and other countries with documented resistance; for example, Assam in India. Generally, it is well tolerated with occasional mild gastrointestinal intolerance and diarrhoea.

In combination with chloroquine mouth ulcers and stomatitis occur occasionally. If used in pregnancy folic acid should be co-administered to eliminate its antifolate effects. In combination with atovaquone its effects are synergistic with resultant enhanced antimalarial effects (Malarone™).

Doxycycline
Doxycycline is a tetracycline antibiotic, which also works as an antimalarial by binding to ribosomal mRNA and inhibiting protein synthesis. Its most common side-effects are gastroesophageal reflux, vaginal candidiasis and photosensitivity. Side-effects can be minimised by taking medication on a full stomach, not before going to bed, and limiting exposure to the sun and by using sunscreens.
Doxycycline interacts with the combined oral contraceptive pill so these travellers should use additional forms of contraception (barrier method) during the first three weeks of taking their chemoprophylaxis to avoid conception. Progesterone-only forms of contraception (pill, injectables) do not interact with doxycycline, so no additional methods need to be taken.

Doxycycline is contraindicated in children under the age of 12 years in the UK and pregnant women. It should be taken two days before travel, during travel to malaria endemic country and for 28 days on return. For long-term use there is no documented evidence of harm and can be used safely for up to two years although there is an increased risk of Candida albicans infection.

Mefloquine
Mefloquine's mechanism of action is unknown but it is thought to act as a suppressive chemoprophylaxis. It should be taken weekly, three weeks before travel to a malaria endemic country to illicit any drug intolerance.

It has been associated with rare but serious neuropsychiatric events, such as psychosis, depression, anxiety disorder, confusion, hallucinations, paranoia and encephalopathy, in approximately one in 10,000 travellers. The most common side-effects are gastrointestinal disturbance, headache, insomnia and vivid dreams. It has been documented that some of the neuropsychiatric side-effects reported have continued after the mefloquine was stopped. Therefore, it is contraindicated in travellers with a known hypersensitivity to mefloquine or related compounds (quinine) and in travellers with active depression, anxiety disorder, psychiatric illness (schizophrenia).

It should be used with caution in travellers with a history of depression and is not recommended for travellers with cardiac conduction defects.

Mefloquine should be continued weekly during exposure and then for 28 days on return from a malaria endemic country. Studies have shown there is no increased risk of serious side-effects with long-term use if it is tolerated in the short term and can be used safely for up to three years in the absence of side-effects. Pharmacokinetic data suggest that there is no long-term accumulation of the drug.

Atovaquone/proguanil (Malarone™)
Atovaquone/proguanil inhibits electron transport in the mitochondrial cytochrome b-c1 complex, causing collapse in the mitochondrial membrane potential. Proguanil potentiates this effect. Malarone™ is a fixed combination of the two drugs atovaquone and proguanil. It is usually very well tolerated and side-effects are rare. The most common intolerance is gastrointestinal upset and headache but this is unusual. It should not be used in children under 11 kg, pregnant women, patients with severe renal impairment and used in caution with travellers taking warfarin. It should be taken 24 hours before travel, during travel and for seven days on return from a malarious area. For long-term prophylaxis the data on its use are reassuring but limited at present. It can be used confidently for travel up to 28 days and then under specialist guidance for one year and possibly longer.

Cautions: children
The dose of the chemoprophylactic agent should be calculated according to the child's weight. Giving the medication on a full stomach may reduce the incidence of side-effects. Chloroquine and mefloquine are options for infants and children of all ages depending on the presence of drug resistance at the destination. Doxycycline should not be administered to children under the age of 12.

It should be noted that in the USA the CDC recommends that Malarone may be used in infants weighing more than 5 kg, although this constitutes off label use (11 kg in UK) and specialist travel health advice should be sought.8 It is important to remember that overdose of antimalarial drugs, particularly chloroquine, can be fatal. Medication should be stored in childproof containers and out of the reach of infants and children.

Pregnancy
Where travel to a chloroquine sensitive destination is anticipated, pregnant women can safely take chloroquine/proguanil malaria prophylaxis in addition to supplementation with 5 mg folic acid. It should be remembered, however, that pregnant women are at a significantly higher rate of developing severe malaria compared to their non-pregnant counterparts, so any travel to a malaria endemic region should be discouraged. If it is unavoidable, travel to chloroquine-resistant areas mefloquine is the only safe chemoprophylactic agent if taken in the second and third trimester. Unfortunately, there are limited data on the use of atovaquone/proguanil in pregnancy, so its use cannot be recommended, and doxycycline is contraindicated. Bite avoidance measures are especially important in this group. It is important to reassure the pregnant traveller that DEET at concentrations of 50% is safe in pregnancy. If travel is to areas with limited medical resources the possibility of taking stand-by emergency medical treatment should be discussed.

Breastfeeding
As only very small amounts of drug are secreted in breast milk the breastfed infant will need additional malaria chemoprophylaxis. Since chloroquine and mefloquine are safe in infants the small amounts of secreted drugs are safe and not harmful. Doxycycline is contraindicated and atovaquone/proguanil use is not recommended unless there is no suitable alternative for the mother. The infant will require chemoprophylaxis which should be either chloroquine/proguanil or mefloquine (atovaquone/proguanil is suitable if the infant weights over 11 kg).

Special considerations: drug switch during travel
If a traveller switches from either doxycycline or mefloquine to atovaquone/proguanil during or after travel, the standard duration of prophylaxis for atovaquone/proguanil would not be sufficient. If the switch occurred three weeks or more before departure from the malarious area the atovaquone/proguanil should be taken for the remainder of the stay and then for one week on return. However, if the switch occurred fewer than three weeks before departure (or after departure) atovaquone/proguanil should be taken for four weeks after the switch.8 It is preferable to avoid switching chemoprophylaxis and to prescribe an agent that covers the traveller's itinerary. If a switch is necessary specialist travel health advice should be sought.

Diagnosis malaria: the illness
The management of malaria is dependent on the awareness of the diagnosis and on performing the correct diagnostic tests. There are no specific clinical features of malaria; fever may or may not be present. Often, non-specific symptoms ranging from malaise and flu-like symptoms to cough and diarrhoea exist.

Major features of severe or complicated falciparum malaria in adults consist of impaired consciousness/seizures, renal impairment, acidosis, hypoglycaemia, pulmonary oedema/acute respiratory distress syndrome, anaemia, disseminated intravascular coagulation, shock and haemogloinuria. In children the major features are impaired consciousness/seizures, respiratory distress, hypoglycaemia, severe anaemia, prostration and a parasitaemia over 2%.9

Travellers who have symptoms of ill health should be advised to seek medical advice as soon as possible and explain that they have travelled; suspected malaria is a medical emergency. Peripheral blood microscopy smears to detect and speciate the malaria parasite are the gold standard investigation but it is operator dependent. This should be performed on three consecutive days in an experienced laboratory before malaria can be excluded.

Malaria should be considered in any traveller who has returned from a malaria endemic country, especially in the previous three months as the incubation period is from six days to six months from exposure. Rapid diagnostic assays are available which detect the antigens derived from the malaria parasite. They can be useful when there are limited medical facilities available. The ACMP does not recommend their use for self-diagnosis, although they can be useful in the medical kit of experienced doctors and nurses on expeditions to remote malarious areas.

Travellers who are diagnosed with malaria in the early course of disease respond well to treatment, but any delay in diagnosis can have serious or fatal consequences. Specific treatment will vary based on the likelihood of drug resistance. In the UK, uncomplicated P falciparum malaria is treated with quinine, atovaquone plus proguanil or co-artemether. In the context of quinine it should be supplemented with a course of doxycycline. All patients diagnosed with P falciparum should be admitted to hospital for at least 24 hours since they can deteriorate suddenly, especially in the early course of treatment.

Severe P falciparum malaria or infections with a parasite count over 2% should be treated with intravenous quinine or intravenous artesunate although the latter is unlicensed in the EU. These patients should be managed on the intensive care unit in liaison with tropical medicine centres. Malaria is a notifiable disease and so notification to the relevant public health authorities is needed in addition blood samples should be sent to the Malaria Reference Laboratory in the UK for confirmation.

Conclusion
The malaria travel health message was recently internationally emphasised by Cheryl Cole who acquired malaria on a trip to Tanzania. This travel and public health message is vital for the health of travellers and their families. Government support in response to this (see Resources) emphasises the seriousness of this preventable illness and goes further towards putting the message across.

David Beckham, Andy Murray and Denise Lewis have pledged their support to the Malaria No More campaign (see Resources), one of many international networks of organisations dedicated to tackling malaria, including the Gates Foundation as part of the Roll Back Malaria (RBM) partnership.
Malaria is a severe, life-threatening preventable illness with over 1,600 travellers in the UK alone diagnosed in 2009. Travellers should be actively encouraged to seek travel health advice to arm themselves with the necessary chemoprophylaxis, bite avoidance measures and education to protect them from acquiring malaria. It is important to remember that despite the efficacy of chemoprophylaxis being up to 98%, adherence to treatment is the most common reason for prophylactic failure.10

It is vital that prophylactic adherence is emphasised as well as bite avoidance strategies in the travel clinic. All travellers should be advised on the importance of seeking medical advice to exclude malaria should they become unwell during or on return from their trip. Until such a time as safe and efficacious malaria vaccine is available chemoprophylaxis and bite avoidance measures are our only line of defence.

References

  1. Health Protection Agency (HPA). Imported malaria cases and deaths, United Kingdom: 1990-2009. Available from: www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/Malaria/Epidemiolo...
  2. Chiodini P, Hill D, Lalloo D, Lea G, Walker E, Whitty C, Bannister B. Guidelines for malaria prevention in travellers from the United Kingdom 2007. London: Heath Protection Agency; 2007. Available from: www.hpa.org.uk/web/HPAwebFile/HPAweb_C/120349694352
  3. National Travel Health Network and Centre (NaTHNaC). Health Information for Overseas Travel (the "Yellow Book") 2010. London: NaTHNaC; 2010.
  4. World Health Organization (WHO). International Travel and Health 2010. Geneva: WHO; 2010.
  5. Newton PN, White NJ, Rozendaal JA, Green MD. Murder by fake drugs. BMJ 2002;324:800-801.
  6. Newton P, Proux S, Green M et al. Fake artesunate in southeast Asia. Lancet 2001;357:1948-50.
  7. Basco LK. Molecular epidemiology of malaria in Cameroon. XIX. Quality of antimalarial drugs used for self-medication. Am J Trop Med Hyg 2004;70:245-50.
  8. Centers for Disease Control and Prevention (CDC). Travelers' Health - The Yellow Book. Available from: wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/malaria.aspx
  9. Lalloo D, Shingadia D, Pasvol G et al. UK malaria treatment guidelines. J Infect 2007;54:111-121
  10.  Zuckerman J, Batty A, Jones M. Effectiveness of malaria chemoprophylaxis against Plasmodium falciparum infection in UK travellers: retrospective observational data. Travel Med Infect Dis 2009;7:329-36.

Resources
Web page for travellers visiting friends and relatives in malaria endemic areas:
W: www.dh.gov.uk/en/MediaCentre/Pressreleases/DH_118513

Malaria No More campaign
W: www.malarianomore.org.uk