Preparing your patients to travel abroad safely
Part 3: Reducing the risk of malaria and dengue fever
Roger E. Thomas, MD, PHD, CCFP, MRCGP
OBJECTIVETo provide evidence-based recommendations for family physicians advising travelers on how to reduce their risk of malaria and dengue fever.
QUALITY OF EVIDENCEA search of MEDLINE from 1990 to November 1998 found 671 articles;
randomized controlled trials and systematic reviews were sought. The Cochrane Collaboration was searched for studies relevant to family physicians; meta-analyses of impregnating bed nets with permethrin were found. Health Canada’s evidence-based publications were searched; 10 recommendations based on at least one well-conducted randomized trial were found.
MAIN MESSAGE Good evidence-based advice about the efficacy of mefloquine in chloroquine- resistant areas and for pregnant women and children is available, as is advice on the effectiveness of permethrin-impregnated bed nets.
CONCLUSIONS Family physicians can use evidence-based recommendations to advise their patients on how to prevent malaria. The ways in which patients neglect malaria precautions are well-known. For prevention of both malaria and dengue fever, family physicians should counsel their patients to reduce the risk of being bitten by insects.
OBJECTIFPrésenter des recommandations fondées sur des données probantes aux médecins de famille qui dispensent des conseils aux voyageurs sur les façons de réduire leurs risques de contracter le paludisme et la dengue.
QUALITÉ DES DONNÉESUne recension effectuée dans MEDLINE de 1990 à novembre 1998 a fait ressortir 671 articles; on a recherché des essais aléatoires contrôlés et des études systématiques.
On a consulté le Centre de collaboration Cochrane pour trouver des études pertinentes aux médecins de famille; on y a relevé des méta-analyses sur l’imprégnation de moustiquaires de lit avec du permethrin. Les publications de Santé Canada fondées sur des données probantes ont fait l’objet d’une recherche, faisant ressortir 10 recommandations fondées sur au moins un essai aléatoire en bonne et due forme.
PRINCIPAL MESSAGEIl existe des recommandations fondées sur de bonnes données probantes concernant l’efficacité de la méfloquine dans les régions où le paludisme est résistant à la chloroquine ainsi que chez les femmes enceintes et les enfants. Des renseignements sont aussi disponibles sur l’efficacité des moustiquaires de lit imprégnées au permethrin.
CONCLUSIONSLes médecins de famille peuvent se servir de recommandations fondées sur des données probantes pour conseiller leurs patients sur la prévention du paludisme. Il est notoire que les patients négligent de prendre des précautions contre le paludisme. Pour prévenir à la fois le paludisme et la dengue, les médecins de famille devraient conseiller à leurs patients d’éviter les risques de piqûres de moustiques.
This article has been peer reviewed.
Cet article a fait l’objet d’une évaluation externe.
Can Fam Physician 2000;46:1126-1131.
résumé abstract
onsiderable evidence indicates that travel- ers are insufficiently aware of the risk of malaria and that they prepare inadequate- ly to avoid it. One study showed that fewer than 50% of British travelers understood the risk of malaria, par ticularly for children and pregnant women.1Only 5% of West Africans living in England, who had visited West Africa and were admitted to the Hospital for Tropical Diseases in London with malar- ia, had taken antimalarial drugs for 4 weeks after their return.1 Only 40% of Belgian and 70% of Swiss travelers claimed to have completed 4 weeks of malaria prophylaxis after returning from trips.1
Quality of evidence
A search of MEDLINE from 1990 to November 1998 using the MeSH headings “travel” and “malaria”
found 671 articles; randomized controlled trials and systematic reviews were sought. The Cochrane Collaboration database of systematic reviews was also searched: meta-analyses relevant to family physi- cians concerning permethrin-impregnated bed nets were found. Health Canada’s evidence-based publica- tions were searched; 10 recommendations based on at least one well conducted randomized trial relevant to family physicians were found.
Avoiding mosquito bites
Travelers should try to avoid being bitten by mosqui- toes by staying indoors between dusk and dawn, by wearing long sleeves and long trousers tucked into socks, by staying in screened buildings, by using diethyltoluamide (DEET) on the skin (35% DEET protects for up to 4 hours, 95% DEET protects for 10 to 12 hours), by using a mosquito bed net, and by using permethrin on bed nets and clothes.
If these precautions are not followed, risk of malar- ia for a stay of 1 night in a tropical area is 1% if bitten once, 9% if bitten 10 times; and for a stay of 4 weeks is 25% if bitten once and 94% if bitten 10 times.2
Use of permethrin-impregnated bed nets The efficacy of permethrin-impregnated bed nets for preventing malaria in children in areas where malaria is endemic has been shown in a Cochrane Collaboration meta-analysis. The study also conclud- ed that, because mortality from malaria is greatest in the first 3 years of life, children should use preim- pregnated bed nets that should be re-impregnated
every 3 months.3Relative risk of malaria for children using bed nets is 0.82.4Risks for children and adults from countries where malaria is not endemic are much higher.
Counseling about specific sources of risk Physicians should emphasize in their counseling the following factors that affect the efficacy of antimalarial regimens.
Length of exposure increases risk.A visit of 4 to 12 months increases risk 80-fold compared with a visit of 1 week.1 Male travelers are four times more likely than female travelers to acquire malaria in West Africa: it is not known whether they are outside more or take more risks.1
Travelers have inadequate information. Less than 50% of British travelers who went to regions in Africa where malaria is endemic understood the risks, the mosquito vector, or the increased risk to pregnant women and children.1 Responses to a mailed questionnaire indicated that one third of British general practitioners did not give advice about avoiding insect bites.1
Need for compliance. Those least likely to take antimalarial agents and most in need of careful instruction are elderly people traveling to join family abroad; schoolchildren returning to family or school in malarious areas; and those born in malarious areas and now living in the West (not realizing that after 1 to 3 years in the West their immunity is lost).
Delay in diagnosis might result in death. In a United States study, 86% of cases of falciparum malar- ia presented within 1 month of return, 10% within 1 to 2 months, 3% within 3 to 5 months, and only 1.4% after 12 months.5In the United Kingdom, 28% developed symptoms abroad, but 95% of the remainder devel- oped symptoms within 3 weeks of return.1About 100 travelers returning to Europe die of malaria each year due to delay in developing symptoms (usually 2 to 4 weeks after returning); delay in seeking diagno- sis; and delay in physicians’ offices when doctors do not ask for a travel history, are unaware of the delay in symptoms of malaria, or wait for test results through routine channels.
Inadequate avoidance of insect bites.A large on- board survey of passengers traveling to Africa on a Swiss airline (with a follow-up mailed questionnaire
C
Dr Thomas is Professor and Chair of Family Medicine at Memorial University of Newfoundland in St John’s.
12 weeks later) concerning their compliance with malaria prevention found that 90% took their prophy- lactic medication regularly, but only 1% used all four physical preventive measures (mosquito net, insect repellents, insecticides, and long clothing in the evening).6 Permethrin is the greatest nonpharmaco- logic advance in mosquito control, and travelers should buy treated nets or treat their own bed nets and clothing.
Advising on malaria prophylaxis
Travelers should begin antimalarial medications 2 weeks before departure in order to detect potential allergies and to build up good levels in the tissues.
For antimalarial drugs taken weekly, travelers should be advised to take them on the same day of the week, ever y week, while in malarious areas, and for 4 weeks after return to Canada.
Patients can be advised that mefloquine prophy- laxis is highly effective. A MEDLINE search of ran- domized controlled trials of mefloquine found 37 trials, of which 10 met the inclusion criteria for systematic review. Withdrawal due to side effects was higher in the treatment arm than in the placebo arm of the studies (odds ratio [OR] 3.49; 95% confidence inter val [CI] 1.42 to 8.56). The OR for withdrawal compared with trials of other prophylaxis was 1.33 (95% CI 0.75 to 2.36).7
The evidence-based Health Canada publication 1997 Canadian Recommendations for the Prevention and Treatment of Malaria among International Travelers8rates as A1 the following prophylactic reg- imens: in chloroquine-sensitive areas, chloroquine;
in chloroquine-resistant areas, mefloquine or doxy- cycline (or, less optimally, chloroquine plus proguanil) for people unable to take mefloquine;
and, in chloroquine- and mefloquine-resistant areas, doxycycline8 (Table 18).
Pregnant women and children
For pregnant women and children, the following rec- ommendations are rated A18: avoid travel to areas with strong resistance to chloroquine; use personal protective measures in malarious areas; use chloro- quine in the few chloroquine-sensitive areas (Haiti, Dominican Republic, Central America, and the Middle East; use mefloquine in chloroquine-resistant areas when exposure is high; use mefloquine beyond 16 weeks of pregnancy; and refer pregnant women at high risk of falciparum malaria for individual risk assessment and counseling by a tropical disease expert (Table 28-13). Travelers should be advised that there is no safe and effective chemosuppressive for pregnant women and children younger than 8 years traveling to the borders of Thailand with Myanmar and Cambodia.
Pregnant women should use extra diligence in avoiding insect bites. They should use DEET on their skin in concentrations of 25% or less and wash it off when not needed. Permethrin should be used on clothing and bed nets: there are no known harmful effects during pregnancy.14
In general, travel to areas of chloroquine-resistant Plasmodium falciparum (CRPF) should be avoided during the first 3 months of pregnancy. If patients have to travel, mefloquine should be used, because the risks of CRPF are greater than the risks of side effects from mefloquine.14,15Women in Malawi and on the Thai-Myanmar border have used it without adverse effects.15
Although chloroquine and proguanil are safe dur- ing pregnancy (proguanil is not known to cause harm to fetuses),15the combination in chloroquine-resistant areas is only 50% effective (significantly less effective than mefloquine) and is thus not an adequate choice.
Women pregnant with a first child develop high- er levels of parasitemia. For pregnant women, CRPF is a medical emergency, and quinine (or quinidine) followed by pyrimethamine should be used.14
Other antimalarial agents have been shown to be safe during pregnancy (pyrimethamine is used for toxoplasmosis and dapsone for leprosy). Doxycycline inhibits bone growth, and ar temisinin has been shown to be embryotoxic in animal studies.14
ZONE DRUG OF CHOICE ALTERNATIVES
No chloroquine resistance Chloroquine Doxycycline Chloroquine-resistant Mefloquine 1st choice:
doxycycline 2nd choice:
chloroquine + proguanil
Chloroquine- and mefloquine-resistant
Doxycycline None
Data from Health Canada.8
Table 1.Evidence-based statements about malaria chemosuppressives
Balancing mefloquine’s side effects and benefits
A Swiss study found that mefloquine had 100% pro- phylactic efficacy (but caused nausea and dizziness in 30% of those taking it).6 In Peace Corps volunteers in sub-Saharan Africa, mefloquine was 94% (95% CI 86%
to 97%) more effective than chloroquine and 86% (95%
CI 67% to 94%) more effective than chloroquine plus proguanil.14A summary of a range of studies conclud- ed that the prophylactic efficacy of mefloquine was 91% compared with 82% for pyrimethamine plus sulfa- doxine; 72% for chloroquine plus proguanil; and 10%
to 40% for chloroquine.2
Although concerns have been raised about meflo- quine’s side effects, most people do not have side effects. Falciparum malaria can be fatal. Those at risk of CRPF should take mefloquine: it has been used safely for years by Peace Corps volunteers.16
The main concern is the (rare) risk of seizures (1/13 000 for short-term prophylactic use; 1/1200 to 1/1700 for therapeutic use). Patients with an estab- lished history of hypersensitivity to mefloquine or with neuropsychiatric disorders are counseled not to take mefloquine and, therefore, should strongly consider not going to malarious areas.2Mefloquine lowers the serum level of valproic acid: doses of valproic acid might need to be adjusted for patients with seizures.
Another concern has been that mefloquine might produce dizziness and imbalance. A double-blind placebo-controlled study of mefloquine in 23 Swiss trainee airline pilots, however, found no differences in flying performance, psychomotor function, or body sway.15A study of 420 travelers to Africa found that 11% reported adverse effects, mostly neurologic and psychiatric, but there were no changes in the results of computerized performance tests.17
Self-treatment
Exper ts discourage patients from self-treatment, except in isolated areas where help is not available.
Thick and thin smears are required for diagnosis of malaria, and a series of smears can confirm that the medication is clearing malaria from the bloodstream.
A copy of the Health Canada dosages for self-treat- ment of malaria should be given to ever y traveler who might go to areas where medical help is unavail- able.8 There is an excellent discussion of self-treat- ment in Schlagenhauf and Phillips-Howard.18
Avoiding dengue fever
Dengue is the most frequent arbovir us infection among travelers in the tropical regions of Africa,
DOSAGES FOR SUPPRESSION DOSAGES FOR TREATMENT ADULTS
Doxycycline: 100 mg daily 100 mg twice daily for 7 days Proguanil: 200 mg daily NA
Chloroquine: 300 mg (base, weekly)
300 mg in two tablets twice daily on days 1 and 2 and 300 mg in two tablets on day 3 Mefloquine: 250 mg
(base, weekly)
20 mg base/kg (max 1500 mg) in two doses 6 hours apart Quinine sulfate 600 mg three times daily for
7 days. During this period, add a single dose, ie, three tablets, of oral pyrimethamine sulfadoxine CHILDREN
Doxycycline: contraindicated for < 8 years. For ≥8 years:
1.5 mg salt/kg daily (max 100 mg/d)
For ≥8 years: 1.5 mg salt/kg twice daily (max 200 mg/d)
Chloroquine (base, weekly)
• < 4 months: 25 mg
• 4-11 months: 50 mg
• 1-2 years: 75 mg
• 3-4 years: 100 mg
• 5-7 years: 125 mg
• 8-10 years: 200 mg
• 11-13 years: 250 mg
• ≥14 years: 300 mg
25 mg/kg base total over 3 days
Mefloquine (base, weekly)
• Contraindicated if < 5 kg
• 5-19 kg: 1/4 tablet
• 20-30 kg: 1/2 tablet
• 31-45 kg: 3/4 tablet
• > 45 kg: 1 tablet
For > 5 kg: 20 mg base/kg (max 1500 mg) in two doses 6 hours apart
Proguanil (daily)
• < 8 months: 25 mg
• 8 months-3 years: 50 mg
• 4-7 years: 75 mg
• 8-10 years: 100 mg
• 11-13 years: 150 mg
• ≥14 years: 200 mg
NA
Quinine sulfate 10 mg/kg three times daily for 7 days. During this period, add a single dose of oral
pyrimethamine sulfadoxine (see product monograph).
Table 2.Malaria chemosuppressive agents:
Schedules and dosages for uncomplicated falciparum malaria.
NA – Not applicable.
Data from Health Canada,8Molyneux and Fox,9Steffen et al,10 Bradley,11van Hensbroek et al,12and Guelmezoglu and Garner.13 For side effects, see Steffen et al.10
For a discussion of artemether in cerebral malaria, see van Hensbroek et al.12
For a discussion of malaria during pregnancy in endemic areas, see Guelmezoglu and Garner.13
South America, Central America, the Caribbean, Asia, and Oceania. Dengue fever has been seen consider- ably more frequently since 1980 in Central and South America and the Caribbean. There is no vaccine to prevent it. It is transmitted by the day-biting Aedes genus of mosquitoes, which is adapted to living in water receptacles in urban areas. Similar precautions to those taken for malaria will reduce the likelihood of contracting dengue fever.19
Symptoms are myalgias, arthralgias, headache, and a rash (similar to measles, or small red spots, or small bleeding spots under the skin). Dengue fever is usually mild and self-limited. Diagnosis might not be straightforward: of 130 German tourists with clinical symptoms, only 7% had the confirmator y rise in dengue IgG and IgM.20
Dengue fever can present in a severe form, dengue hemorrhagic fever, which is rare in travelers from the developed world but more common among those younger than 15 years or having a second attack. Its symptoms include hemorrhage, shock, high fever, intense muscle aches (“breakbone fever”), and headaches.21
Conclusions
• Family physicians can give good, evidence-based advice to their patients traveling to the tropics.
• Avoiding being bitten by mosquitoes is an impor- tant way to avoid malaria and dengue fever.
• Meta-analyses support the efficacy of permethrin- impregnated bed nets in preventing malaria.
• Meta-analyses strongly endorse the effectiveness of mefloquine in chloroquine-resistant areas.
• Health Canada has published detailed, evidence-based recommendations for chemoprophylaxis for travelers, including pregnant women and children.
Correspondence to: Dr Roger E. Thomas, Memorial University of Newfoundland, St John’s, NF A1B 3V6; tele- phone (709) 737-6742; fax (709) 737-2040; e-mail [email protected]
References
1. Behrens RH, Curtis CF. Malaria in travelers: epidemiology and prevention. Br Med Bull 1994;49(2):363-81.
2. Lobel HO, Kozarsky PE, Von Sonnenburg F. Malaria: chemo- prophylaxis. In: DuPont HL, Steffen R, editors. Textbook of travel medicine. Hamilton, Ont: BC Dekker Inc; 1997. Chap.
13.2, p. 108-14.
3. Snow RW, Lengeler C, de Savigny D, Cattani J. Insecticide- treated nets in control of malaria in Africa. Lancet
1995;345:1056-7.
4. Lengeler C. Insecticide treated bed nets and curtains for malaria control. Systematic review. Cochrane Lib 1998;3:1-43.
5. Jong EC, McMullen R. The travel and tropical medicine man- ual. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995. p. 54.
6. Steffen R, Heusser R, Maechler R, Naef U, Somaini B. Malaria chemoprophylaxis in 28 712 European travelers to Africa: a fol- low-up study. In: Steffen R, Lobel HO, Haworth J, Bradley DJ, editors. Travel medicine. Proceedings of the First Conference on International Travel Medicine. Zurich, Switz; 1998 April 5-8.
London, Engl: Springer-Verlag; 1989. p. 141-4.
7. Croft A, Garner P. Mefloquine to prevent malaria: a systematic review of trials. BMJ 1997;315(7120):1412-6.
8. Health Canada. 1997 Canadian recommendations for the pre- vention and treatment of malaria among international travel- ers. Can Commun Dis Rep 1997;23:S5.
Key points
• Avoiding mosquito bites is the most important protective measure against malaria
• Permethrin-impregnated bed nets have positive protective effects.
• In chloroquine-resistant areas, mefloquine offers the best protection; some side ef fects are not uncommon, but serious side effects (seizures) are rare.
• Doxycycline is effective in mefloquine-resistant areas. It can be used when mefloquine is not tol- erated.
• About 20 to 30 million people from non-tropical countries visit malarious countries annually.1 About 30 000 Europeans and North Americans contract malaria each year.
Points de repère
• La plus importante mesure de précaution contre le paludisme est d’éviter les piqûres de mous- tiques.
• Les moustiquaires de lit imprégnées au perme- thrin offrent une bonne protection.
• Dans les régions où le paludisme résiste à la chloroquine, la méfloquine offre la meilleure pro- tection; elle cause cer tains ef fets secondaires, mais les effets indésirables sérieux (l’épilepsie) sont rares.
• La doxycycline est efficace dans les régions où le paludisme est résistant à la méfloquine. Elle peut remplacer la méfloquine si cette dernière est mal tolérée.
• Chaque année, de 20 à 30 millions de personnes de pays non tropicaux visitent des régions où sévit le paludisme1. Environ 30 000 Européens et Nord-Américains contractent le paludisme chaque année2.
9. Molyneux M, Fox R. Diagnosis and teatment of malaria in Britain. BMJ 1993;306:1175-80.
10. Steffen R, Fuchs E, Schildknecht J, Naef U, Funk M, Schlagenhauf P, et al.
Mefloquine compared with other malaria chemoprophylactic regimens in tourists vis- iting East Africa. Lancet 1993;341:1299-304.
11. Bradley D, on behalf of a meeting con- vened by the Malaria Reference Laboratory and the Ross Institute. Prophlylaxis against malaria for travellers from the United Kingdom. BMJ 1993;306:1247-52.
12. Van Hensbroek MB, Onyiorah E, Jaffar S, Schneider G, Palmer A, Frenkel J, et al. A trial of artemether or quinine in children with cerebral malaria. N Eng J Med 1996;338(2):69-75.
13. Guelmezoglu AM, Garner P. Malaria in pregnancy in endemic areas. Systematic review. Cochrane Lib 1998;3:1-11.
14. Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC. Long-term malaria prophylaxis with weekly meflo- quine. Lancet 1993;341:848-51.
15. Schlagenhauf P, Lobel H, Steffen R, Johnson R, Popp K, Tschopp A, et al.
Tolerance of mefloquine by Swiss airline trainee pilots. Am J Trop Med Hyg 1997;56(2):235-40.
16. Jong EC, McMullen R. The travel and trop- ical medicine manual. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995. p. 58.
17. Schlagenhauf P, Steffen R, Lobel H, Johnson R, Letz R, Tschopp A, et al.
Mefloquine tolerability during chemopro- phylaxis: focus on adverse event assess- ments, stereochemistry and compliance.
Trop Med Int Health1996;1(4):485-94.
18. Schlagenhauf P, Phillips-Howard PA.
Malaria: emergency self-treatment by travel- ers. In: DuPont HL, Steffen R, editors.
Textbook of travel medicine. Hamilton, Ont:
BC Dekker Inc; 1997. Chap 13.4, p. 130-7.
19. Committee to Advise on Tropical Medicine and Travel. Travel medicine recommenda- tion: dengue fever and international travel.
Can Commun Dis Rep1996;22-4:25-7.
20. Jelinek T, Dobler G, Hoelscher M, Loescher T, Nothdurft H-D. Prevalence of infection with dengue virus among interna- tional travelers. Arch Intern Med
1997;137:2367-70.
21. Jong EC, McMullen R. The travel and trop- ical medicine manual. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995. p. 218-9.
