bmj.com Rapid Responses for Croft, 321 (7254) 154-160

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CLINICAL REVIEW:
Ashley Croft
Extracts from "Clinical Evidence": Malaria: prevention in travellers
BMJ 2000; 321: 154-160 [Abstract] [Full text]

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Rapid Responses published:

Evidence only serves to confuse: Martin Goldman (15 July 2000)

Re: Evidence only serves to confuse: Joseph Watine (20 July 2000)

Evidence only serves to confuse: Andrew Jamieson (21 July 2000)

Malaria and mouth ulcers: Charlie Easmon (25 July 2000)

Malaria prevention for children and pregnant women: Mike Starr (4 August 2000)

Evidence only serves to confuse 15 July 2000

Martin Goldman,
Medical Consultant
Nomad Travellers Clinic, London N8, 0PX
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Re: Evidence only serves to confuse

In a recent survey done by me as part of the diploma in travel medicine(1), 134/210 (64%) independent travelers knew correctly, according to current British guidelines, that malaria prophylaxis was needed for their travels. 25/210 (12%) knew that antimalarials were unnecessary. Of those that knew that antimalarials were necessary, only 28/134 (21%) identified the antimalarial therapy that would be most appropriate for their journey, based on the current guidelines. The information laid out in the article on clinical evidence is confusing, as it suggests that there is insufficient evidence that the current mainstays of antimalarial prophylaxis for much of Asia and for short trips, chloroquine and proguanil are effective. Given the confusion that clearly already exists in the minds of travellers, on this occasion evidence based medicine may have only served to make the situation less clear.
(1) Unpublished data to be submitted as part of a thesis for M.Med.Sci/Diploma in Travel Medicine, University of Glasgow, July 2000.

Re: Evidence only serves to confuse 20 July 2000

Joseph Watine,
PH, Eur Clin Chem
H�pital de Rodez
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Re: Re: Evidence only serves to confuse

Patients and health care professionals expect medical practice to be based on scientific evidence, regarding not only effectiveness and safeness, but also cost-effectiveness. In that respect, systematic reviews that meet explicit criteria for validity offer the reader information that is less biased than more traditional unstructured overviews.
Systematic reviews (or evidence-based reviews) thus aim at precisely answering questions. Doctors should not be surprised by the fact that in some cases, evidence-based reviews conclude that the current state of human knowledge makes it impossible to precisely answer a particular question [1].
[1] Ashley Croft, consultant in public health medicine. Clinical review. Extracts from "Clinical Evidence". Malaria: prevention in travellers. BMJ 2000;321:154-160 (15 July) and ensuing letter published in eBMJ: Evidence only serves to confuse, by Martin Goldman.

Evidence only serves to confuse 21 July 2000

Andrew Jamieson,
Medical Director, British Airways Travel Clinics, South Africa
Johannesburg, South Africa
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Re: Evidence only serves to confuse

One of the problems associated with malaria prophylaxis in travellers is that there is a staggering lack of good clinical information on the efficacy and side effects of antimalarials in travellers. Simply finding studies that determine that chemoprohylaxis is of proven medical benefit at allis surprisingly difficult; finding studies of more complexity such as comparing the morbidity and mortality of chemoprophylaxis with early standby treatment is impossible. This simply reflects the cinderella status of this disease generally, but in this era of travel is of especially serious concern. Tourism is one of the largest income generators globally - research funding for studies related to malaria and travel is proportionaltely miniscule.

Malaria and mouth ulcers 25 July 2000

Charlie Easmon
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Re: Malaria and mouth ulcers

Editor, Ashley Croft 's work is of increasing importance but has several significant omissions and needs updating. Although it is described as Extracts from "Clinical Evidence"it seems reasonable that the methodology should at least be described. I was particularly concerned by the claim that all systematic reviews and RCTs were identified when it is not clear how this was done and whether all languages had been searched for. In the comments sections it would have been reasonable to at least refer to consensus documents as a lower level of evidence but based on expert opinion and conclusions.
The key omission here is the CDR guidelines, which are referred to only in context of the type of mosquitoes which transmit malaria.
The review takes account of research on travellers and artificially excludes some important research on non-travellers. A discussion is required as to the relevance of such evidence to travellers but it should not be ignored.
Work published this year provides updated evidence of the link between mosquito biting rates and the risk of malaria.
The section on aerosol insecticides would have benefited from a short discussion of which ones were reviewed and what data their supposed effectiveness is based on. This is of great importance since these products are sold in their millions world-wide. It would also be sensible if the section on topical insect repellents followed after this.
It is inconsistent to say that "we found little evidence for the effectiveness of insect electrocuters and ultrasonic buzzers in preventing malaria," despite no reference and confirmation of the fact that no systematic reviews or RCTs with malaria as an outcome were found. This section should read "no evidence", especially since the companies that make these products have been taken to court twice under the trade descriptions acts (Professor C Curtis, Personal Communication). Harm can be deduced by the fact that if they do not work, more travellers will get potentially fatal malaria.
With regard to permethrim and insecticide treated nets it is worth commenting that current advice is to retreat them every 6 months, rather than 4 which would otherwise be implied by the article. Other work that has been done on insecticide treated clothing relates to refugees in Afghanistan (Dr Mark Rowlands, personal communication).
The chemoprophylactic agents reviewed are incomplete. Although they are not yet licensed in the UK, it would have been helpful to at least comment on the following agents Tafenoquine , Pyronadine , Savarine . Malarone (Atovaquone and Proguanil) is not yet licensed as a chemoprophylactic in the UK but despite this there are now several RCTS of relevance to this article.
The section on pregnant women is misleading in that we now have evidence that they are more attractive to biting mosquitoes and have known that they are at greater risk of malaria. In balancing out the risks to the pregnant woman in a malarious zone, many specialists would be firmly in favour of both anti-mosquito measures (including repellents) and chemoprophylaxis.
1. Croft A. Extracts from "Clinical Excellence"Malaria: prevention in travellers. BMJ 2000; 154-160
2. Bradley DJ, Warhurst DC. Guidelines for the prevention of malaria in travellers from the United Kingdom. Commin Dis Rep CDR Rev 1997;7:R 137-152
3. Hay S, Rogers D, Toomer J, Snow R. Annual Plasmodium falciparum entomological inoculation rates (EIR) across Africa: literature survey, internet access and review.
4. Lell B, Faucher J-F, Missinou M, Borrmann S, Dangelmaier D, Horton J, Kremaner P. Malaria chemoprophylaxis with tafenoquine: a randomised study. Lancet 2000;355: 2041-45
5. Chen C, Zheng X. Development of the new antimalarial drug pyronaridine: a review. Biomed Enviro Sci 1992; 5(2): 149-60
6. Ambroise-Thomas P. Nouveaux medicaments antipaludiques. Rev Prat 1998;48(3):287-90
7. Lell B, Luckner D, Ndjave M, Scott T, Kremsner P. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998; 351: 709-13
8. Lindsay s, Ansell J, Selman C, Cox V, Hamilton K, Walraven G. Effect of pregnancy on exposure to malaria mosquitoes. Lancet 2000 ; 355:1972
Dr Charlie Easmon specialist adviser in travel health Hospital for Tropical Diseases Travel Clinic Mortimer Market Centre Capper street, off Tottenham Court Road London WC1E 6AU

Malaria prevention for children and pregnant women 4 August 2000

Mike Starr,
Paediatric Infectious Diseases Physician
Royal Children's Hospital Travel Clinic, Royal Children's Hospital, Melbourne, AUSTRALIA
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Re: Malaria prevention for children and pregnant women

I read with interest the clinical review of malaria prevention by Croft(1). There are some important additional points to be made regarding children and pregnant women. Malaria is more frequent and more severe in children than in adults, and in pregnant women than in other adults. Worldwide, approximately 2 million deaths per year can be attributed to malaria, half of these in children under 5 years of age(2). It is therefore crucial to provide clear recommendations regarding prevention of malaria in these groups.
N,N-diethyl-m-toluamide (DEET) Whilst it is true that there are few data concerning the safety of the insect repellent, DEET in children and pregnant women, it is important to note that most of the case reports of potential toxicity are poorly documented, and that the use of DEET appeared to be inappropriate or excessive in the majority. Veltri et al conducted a retrospective study of over 9000 reports of DEET toxicity to United States poison control centres over 5 years, and found that young children were no more likely to develop adverse effects than older children or adults(3). Almost two thirds of those exposed had no adverse effects or experienced minor symptoms that resolved rapidly. The most common report was eye irritation caused by repellent sprayed in the eyes. Ninety nine percent had no long-term sequelae.
DEET is the most effective of the insect repellents(4) and should be recommended for children and adults, including pregnant women, in concentrations of up to 30%. This accords with the recommendations of the CDC and WHO. Appropriate application is essential, and roll-on preparations are preferable as there is less widespread dissemination of repellent.
Mefloquine It is important to expand on the information provided by Croft about the randomised control trials (RCT) of mefloquine prophylaxis in childhood and pregnancy(5,6). Luxemburger et al documented the efficacy and tolerability of mefloquine given for treatment of malaria (rather than prophylaxis) to 417 children between 3 months and 5 years of age(5). The only side effects were gastrointestinal, the major one being early vomiting. Age under 6 years has been shown to be a risk factor for early vomiting(7). However, this is not a significant problem in children given prophylactic doses. There are no reports of serious neuropsychiatric adverse effects in children given mefloquine at prophylactic doses, and few in those receiving treatment doses(8,9).
One of the preliminary findings from Nosten's RCT in pregnancy was a significant excess of stillbirths in those given mefloquine, although this was not borne out in the overall analysis(6). Moreover, this study was only conducted in women in the second and third trimesters of pregnancy. Nosten et al went on to perform a retrospective comparison of pregnancy outcome in women treated with mefloquine to those treated with other antimalarials or none at all(10). They found that mefloquine treatment at any time during pregnancy was associated with an increased risk of stillbirth. Smoak et al also observed a higher rate of spontaneous abortions in a group of 72 female soldiers who inadvertently took mefloquine before becoming aware of being pregnant(11). However, Steketee et al observed no such increase in 932 pregnant women given one treatment dose of mefloquine followed by weekly prophylaxis(12). There are also non- RCT data suggesting that mefloquine may also be safe in the 1st trimester(13). The excretion into breast milk is minimal(14).
Mefloquine is an acceptable choice for malaria prophylaxis in children from 3 months of age (weighing over 5kg). It remains unclear whether it is safe in pregnant women, although the WHO recommend its use for prophylaxis beyond the 1st trimester. It is safe for use during lactation.
Doxycycline Doxycycline forms a stable calcium complex in any bone forming tissue and a decrease in the fibula growth rate has been observed in premature infants(15). It is also deposited in teeth causing discolouration(16). Mineralisation of the teeth is completed by 5 to 6 years of age.
Tetracyclines cross the placenta(17) and are excreted in breast milk(18). However, the American Academy of Pediatrics recommends that tetracyclines are compatible with breast feeding(19) because there is negligible absorption by infants(18). Croft suggests that doxycycline should not be prescribed for children under 12 years of age, according to the British guidelines for prevention of malaria in travellers(20). However, these guidelines do not provide any evidence for their age recommendation, and they differ from those of the CDC and WHO.
Doxycycline should not be used in children under 8 years of age, or in pregnant women. Where there is an appropriate alternative, it should also be avoided in lactating women.
1. Croft A. Extracts from "Clinical Excellence" Malaria: prevention in travellers. BMJ 2000; 321: 154-160.
2. WHO Expert Committee on Malaria. World Health Organ Tech Rep Ser 2000; 892: 1-74.
3. Veltri JC, Osimitz TG, Bradford DC, Page BC. Retrospective analysis of calls to poison control centers resulting from exposure to the insect repellent N,N-diethyl-m-toluamide (DEET) from 1985-1989. J Toxicol Clin Toxicol 1994; 32: 1-16.
4. Brown M, Hebert AA. Insect repellents: an overview. J Am Acad Dermatol 1997; 36: 243-9.
5. Luxemburger C, Price RN, Nosten F, ter Kuile FO, Chongsuphajaisiddhi T, White NJ. Mefloquine in infants and young children. Ann Trop Paediatr 1996; 16: 281-6.
6. Nosten F, ter Kuile F, Maelankiri L, Chongsuphajaisiddhi T, Nopdonrattakoon L, Tangkitchot S, Boudreau E, Bunnag D, White NJ. Mefloquine prophylaxis prevents malaria during pregnancy: a double-blind, placebo-controlled study. J Infect Dis 1994; 169: 595-603.
7. ter Kuile FO, Nosten F, Luxemburger C, Kyle D, Teja-Isavatharm P, Phaipun L, Price R, Chongsuphajaisiddhi T, White NJ. Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients. Bull World Health Organ 1995; 73: 631-42.
8. Clattenburg RN, Donnelly CL. Case study: neuropsychiatric symptoms associated with the antimalarial agent mefloquine. J Am Acad Child Adolesc Psychiatry 1997 ; 36: 1606-8.
9. Havaldar PV, Mogale KD. Mefloquine-induced psychosis. Pediatr Infect Dis J 2000 ; 19: 166-7.
10. Nosten F, Vincenti M, Simpson J, Yei P, Thwai KL, de Vries A, Chongsuphajaisiddhi T, White NJ. The effects of mefloquine treatment in pregnancy. Clin Infect Dis 1999; 28:808-15.
11. Smoak BL, Writer JV, Keep LW, Cowan J, Chantelois JL. The effects of inadvertent exposure of mefloquine chemoprophylaxis on pregnancy outcomes and infants of US Army servicewomen. J Infect Dis 1997; 176: 831-3.
12. Steketee RW, Wirima JJ, Slutsker L, Khoromana CO, Heymann DL, Breman JG. Malaria treatment and prevention in pregnancy: indications for use and adverse events associated with use of chloroquine or mefloquine. Am J Trop Med Hyg 1996; 55(Suppl):50-6.
13. Phillips-Howard PA, Steffen R, Kerr L, Vanhauwere B, Schildknecht J, Fuchs E, Edwards R. Safety of mefloquine and other antimalarial agents in the first trimester of pregnancy. J Travel Med 1998; 5: 121-6.
14. Edstein MD, Veenendaal JR, Hyslop R. Excretion of mefloquine in human breast milk. Chemotherapy 1988; 34: 165-9.
15. Cohlan SQ, Bevelander G, Tiamsic T. Growth inhibition of prematures receiving tetracycline. Am J Dis Child 1966; 105: 453-461.
16. Porter PJ, Sweeney EA, Golan H, Kass EH. Controlled study of the effect of prenatal tetracycline on primary dentition. Antimicrob Agents Chemother 1965; 5: 668-71.
17. Kline AH, Blattner RJ, Lunin M. Transplacental effect of tetracyclines on teeth. JAMA 1964; 188: 178-180.
18. Posner AC, Prigot A, Konicoff NG. Further observations on the use of tetracycline hydrochloride in prophylaxis and treatment of obstetric infections. Antibiot Annu 1954-55: 594-8.
19. American Academy of Pediatrics Committee on Drugs Policy Statement: The Transfer of Drugs and Other Chemicals Into Human Milk. Pediatrics 1994; 93: 137-50.
20. Bradley DJ. Warhurst DC. Guidelines for the prevention of malaria in travellers from the United Kingdom. Communicable Disease Report. CDR Review. 1997; 7: R137-52.