EDITOR, - Reviews of chemoprophylaxis against malaria for travellers are welcome; numerous problems surround the advisability of current regimens.(i) Two recently published studies have supported the advisability of using mefloquine for short term chemoprophylaxis in sub-Saharan Africa.(ii, iii) As a result, the authors of the recent update advocate use of mefloquine for most parts of this continent even though the combination of chloroquine plus proguanil remains moderately effective in most countries under consideration.(iv)
Safety and freedom from side effects are of paramount importance in chemoprophylaxis and should override complete efficacy; no regime n even approaches 100% prevention against infection with Plasmodium falciparum. Advocates of widespread use of mefloquine have produced figures purporting to support a rarity of side effects (in particular neuropsychiatric ones), which are seemingly far less common when this agent is used in chemoprophylaxis than when it is used in chemotherapy.(v) A great deal of clinical experience indicates, however, that these reports seriously underestimate the prevalence of side effects in travellers: only rarely does a week pass in which I am not informed (at the Hospital for Tropical Diseases) by at least one traveller of his or her personal experience of side effects of mefloquine (many of them severe) or of similar symptoms in a colleague or fellow traveller. Many travellers refuse to take mefloquine in the light of their experience of its neuropsychiatric side effects.
The regimen of chloroquine plus proguanil has a low incidence of side effects and for much of sub-Saharan Africa is probably only marginally inferior in efficacy to mefloquine. Furthermore, widespread use of mefloquine for chemoprophylaxis raises the likelihood of the emergence of P falciparum resistant to quinine (considerable cross resistance exists between mefloquine and quinine); this is a genuine but understated problem.
I recommend chloroquine plus proguanil for all countries of Africa in which infection with P falciparum is a potential hazard. In addition, travellers should be advised to take standby treat ment (usually quinine) for use in the event of a febrile illness that cannot be adequately assessed or treated at a reputable medical centre. Mefloquine should be reserved for chemotherapy of infection with P falciparum that is resistant to quinine.
G C COOK Consultant physician Hospital for Tropical Diseases London NWI 0PE
i Bradley DJ, Warhurst DC. Malaria prophylaxis: guidelines for travellers from Britain. BMJ 1995;310:709-14. (18 March.) ii Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC. Long term malaria prophylaxis with weekly mefloquine. Lancet 1993;341:848-51. iii Steffen R, Fuchs E, Schildkhecht. J. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet 1993;341:1299-303. iv. Wetsteyn JCFM, de Geus A. Comparison of three regimens for malaria prophylaxis in travellers to east, central, and southern Africa. BMJ l993;307:1041-3. v. Weinke T, Trautmann M, Held T, Weber G, Eichenlaub D, Fleischer K, et al. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg l991;45:86-91.
EDITOR, - The guidelines on malaria prophylaxis for travellers from Britain advise that people who are unable to reach medical advice within 24 hours of becoming ill should be provided with standby treatment for malaria.(i) This point is emphasised several times.
I recently returned from working in a hospital with 210 beds in northern Malawi. In this area falciparum malaria is resistant to chloroquine in a high proportion of cases. Malawi-has been using pyrimethamine-sulfadoxine as first line treatment for malaria since 1992. Resistance to pyrimethamine - sulfadoxine is increasing, and quinine is the recommended second line treatment. Supplies of quinine have been scarce in northern Malawi, and the hospital ran out of stock last February.
Medical advice may be within 24 hours' reach, but this is no guarantee that the necessary drugs will be available. Although this point is mentioned in the review, it is not highlighted. It is difficult to predict this situation from Britain, and I suggest that doctors should not be too restrictive in providing standby treatments for malaria to travellers.
GRAHAM MORRISON General practitioner Kersland House Surgery Milngavie, Glasgow G62 8BT
i. Bradley DJ, Warhurst DC, on behalf of a meeting convened by the Malaria Reference Laboratory. Malaria prophylaxis: guidelines for travellers from Britain. BMJ 1995;310:709-14. (18 March.)
EDITOR - The guidelines for prophylaxis against malaria for travellers from Britain mention reports of vivax malaria resistant to chloroquine in Oceania and recommend vigilance for a year after the travellers have returned from malarious regions.(i) I worked as a locum.paediatrician in Papua New Guinea for three months, leaving there in January 1990 and arriving in England (via Australia, Indonesia, Thailand, Singapore, and Egypt) in May 1990.
I developed a severe flu-like illness in August 1991, 18 months after leaving Papua New Guinea and 15 months after returning to England. I was on call at a hospital in London at the time and started to have a rigor while in the mess, although I felt well. That night I felt hot, although I was initially afebrile, and had severe nausea and vomiting. I arranged for a full blood count before going home the next day.
I remained bedbound, with my temperature regularly over 40¡C and total anorexia, and was too weak to walk to the lavatory. Two days later I phoned for the results of the blood count, which showed a total white cell count of 3.8 x <10 to power 9/litre) and a platelet count of 69 x (10 to power 9) per litre. The blood had been discarded before the film was looked at. I assumed that I had leukaemia.
I was driven to my local general practitioner and asked for a repeat full blood count and (rather self consciously, not having been abroad for over a year) a malarial film. The remainder is obvious. I had vivax malaria despite having taken 300 mg chloroquine weekly (for six as opposed to the recommended four weeks on my return) and not having been abroad for 15 months. By the time the diagnosis was made I had to be carried downstairs on a stretcher and required transfer to hospital by ambulance and intravenous rehydration in intensive care.
The message is clear: malaria can occasionally occur for the first time after the usually quoted 12 months. In cases in which the diagnosis is uncertain and malaria is possible it is indefensible not to look for malarial parasites.
CHARLES GODDEN Paediatric senior registrar Poole NHS Trust Hospital Poole Dorset BH15 2JBi. Malaria prophylaxis: guidelines for travellers from Britain. BMJ 1995;310:709-14. (18 March.)
EDITOR - The revised guidelines on chemoprophylaxis against malaria perpetuate the notion that mefloquine is relatively innocuous when used for this purpose.(i) This view has been challenged by some authorities,(ii) who argue that the side effects of mefloquine have been greatly underreported. As White recognised in an editorial on mefloquine, this tendency to understate the toxicity of the drug has followed from the poor scientific quality of almost all of the early studies on use of mefloquine.(iii)
Since January the Ministry of Defence has been conducting a double blind randomised controlled trial of chemoprophylaxis with mefloquine versus chloroquine-proguanil. The subjects of the trial are British troops exercising in Kenya. Of the total trial population of 624 soldiers, 317 were randomly assigned, by means of random numbers generated by a computer, to receive mefloquine and 307 to receive chloroquine - proguanil. A questionnaire on "unusual" symptoms or illnesses was administered at eight weeks of chemoprophylaxis and was returned by 145 (46%) soldiers in the mefloquine arm of the trial and 142 (46%) m the chloroquine - proguanil arm.
The preliminary results of the trial show that both mefloquine and chloroquine-proguanil have a much higher mild toxicity than has commonly been recognised. Altogether 131 (90%) respondents given mefloquine reported some toxicity as a result of their (unknown) chemoprophylaxis, as did 126 (89%) responders given chloroquine - proguanil. The profile of adverse reactions for the two regimens has been surprisingly similar. For example, the table shows the reported incidence of adverse events of three to seven days' duration occurring at least once while the soldiers were in Kenya.
Hansford has pointed out that, whereas dosages of prophylactic antimalarial drugs for children are calculated against body weight, for adults a single standard dose is invariably prescribed, irrespective of body weight.(iv) Could it not be that much of the mild toxicity of prophylactic antimalarial drugs is due to this anomaly, coupled with the fact that some antimalarial drugs (mefloquine, for example(v)) are known to be metabolised idiosyncratically?
A more flexible regimen of mefloquine and other prophylactic antimalarial drugs is needed for adults, such that the drugs' therapeutic ratio is improved - that is, the protective action of the drug is maintained while individual toxicity is minimised. Until such regimens are developed a proportion of travellers to malarious regions will continue to feel ill as a result of their prescribed treatment and some of these will stop taking their tablets. Many cases of malaria will thereby result which could otherwise have been avoided.
ASHLEY CROFT Senior registrar in public health medicine Army Medical Directorate Ministry of Defence Aldershot GUI 2 5RR
i. Malaria prophylaxis: guidelines for travellers from Britain. BMJ 1995;310:709-14. (18 March.) ii. Luzzi GA, Peto TEA. Adverse effects of antimalarials - an update. Drug Safety 1993;8:295-311. iii. White NJ. Mefloquine. BMJ 1994;308:286-7. iv. Hansford CH. Malaria prophylaxis dosage.Lancet 1995;345: 1049. v. Desjardins RL, Pamplin CL, Bredow J, Barry KG, Canfield CJ, Kinetics of a new antimalarial, mefloquine. Clin Pharmacol Ther 1979;26:372-9.
Incidence of adverse events to malaria chemoprophylaxis of three to seven days'
duration occurring while soldiers were in Kenya
Percentage (No) of respondents reporting event
Observed difference
Mefloquine arm Chloroquine-proguanil arm (95% confidence interval)
Adverse event (n=145) (n=142) between proportions
Abdommalpajn 0.15 (21) 0.19 (27) -0.05 (-0.13 to O.I)
Nausea 0.12 (18) 0.16 (23) -0.04 (-0.12 to 0.0)
Anorexia 0.09 (13) 0.12 (8) -0.04 (-0.11 to 0.0)
Pever 0.01 (1) 0.03 (5) -0.03 (-0 06 to O.O
Mouthulcers 0.08 (11) 0.07 (10) 0.010 (-0 06 to O.06)
Prurinus 0.07 (10) 0.02 (3) 0.050 (0.0 to 0.10)
Sleeplessness 0.06 (8) 0.08 (12) -0.03 (-0-08 to 0.03)
Abnormal dreams 0.08 (12) 0.08 (11) 0.010 (-0-06 to O.07)
Depression 0.02 (3) 0.03 (4) -0.01 (-0 04 to 0.03)
Anxiety attack 0.01 (2) 0.01 (1) 0.010 (0.2 to O.03)
Paranoid feelings 0.03 (5) 0.00 (O) 0.030 (0-0 to 0 06)
Tremor 0.01 (1) 0.02 (3) -0.01 (-0 04 to 0 01)
EDITOR - Most doctors will have taken chloroquine for short periods when travelling to exotic destinations. I had done so in Egypt, Jordan, and Syria: I had taken chloroquine for six weeks at any one time and felt confident about taking it for two years when I came to Papua New Guinea.
Initially I felt well, but after one month I became lethargic and would fall asleep in meetings. I had early morning waking and became very agitated. These symptoms I attributed to the humidity, then depression, and finally anxiety about being in a foreign country. I continued the treatment even though my hair began to fall out and my eyesight seemed to be getting worse. Medical colleagues advised me that the hair loss was due to stress or the heat. Finally I developed a rash, which was definitely petechial, every Monday after taking chloroquine, and my platelet count was on the lower limit of normal.
I was advised by a doctor to stop taking chloroquine. What was I to take instead, on the edge of the bush in a high malarial zone? Mefloquine was readily available from one of the volunteers with the American Peace Corps, so I took one tablet that night. Throughout the night I had tachycardia, my dreams were vivid, and I was convinced that I was going to die. The next day the flowers were larger and brighter and the stones on the way to work were hairy. I was on a trip that I hadn't planned. Fortunately, that morning four issues of the BMJ arrived; in one of them was an article on prophylaxis against malaria.(i) This gave me the information I needed. My luck was in again. Doxycycline is readily available in Palmalmal, so I started a daily dose. I now feel well and energetic and am sleeping, and my appetite has returned - I feel normal.
Many travellers overseas will have experienced the lethargy, depression, and anxiety that I did and have put it down to the new country and the new job. Have they gone on to feel better, tolerating the drug, or have they put up with these psychotic feelings, never thinking that chloroquine could be the causal agent?
PATRICIA LENCH Voluntary service overseas Palmalmal Papua New Guineai. Bradley DJ, Warhurst DC, on behalf of a meeting convened by the Malaria Reference Laboratory. Malaria prophylaxis: guidelines for travellers from Britain. BMJ 1995;310:709-14. (18 March.)
EDITOR - The guidelines on malaria prophylaxis represent a consensus reached by 44 British specialists. The letters show how difficult it is to reach unequivocal conclusions in this field. The guidelines of 1993 gave equal place to two regimens for Africa(i) and left practitioners to decide between them, which they found unhelpful. The guidelines of 1995 gave a priority recommendation whenever possible. The committee thought that cumulative evidence on the use of mefloquine,(ii) together with some deaths in British travellers taking proguanil plus chloroquine, had tipped the balance slightly in favour of mefloquine for highly endemic areas of sub-Saharan Africa. It is always difficult to balance the risks of rare catastrophic events such as death with those of the more frequent unpleasant side effects of prophylaxis. Clinicians see the latter; national statistics of a reference laboratory cover the former as well.
The guidelines already state that British experience points to a greater frequency of side effects from mefloquine than that in the widely quoted Swiss study, which showed greater prophylactic efficacy for mefloquine over chloroquine plus proguanil.(3) Even Wetsteyn and de Geus, quoted by G C Cook, concur with the use of mefloquine in west Africa. We believe that consensus improves compliance.
We sympathise with the position of Graham Morrison. The current guidelines are cautious about standby treatment because it was overprescribed after the 1993 guidelines were issued. Charles Godden's experience, which was due to persistence of hypnozoites of Plasmodium vivax that was insensitive to chloroquine, is uncommon but not unique. The guidelines primarily aim to make doctors aware of the risk of malaria in returned travellers, and discussion has centred on whether to emphasise the first three months (maximum risk of falciparum malaria) or the first year (98.5% of all cases of imported malaria).
We disagree with Ashley Croft's statement that the guidelines describe mefloquine as innocuous. The high incidence of side effects will not surprise users of antimalarial drugs, but Croft's study lacks a measure of severity. An operational definition, such as cessation of chemoprophylaxis or admission to hospital, would give a sense of proportion. Incidentally, paranoid feelings in this relatively small series were significantly more common in those taking mefloquine. The hypothesis that side effects depend on the ratio of dose to weight could be tested on Croft's data. Given the greater efficacy of mefloquine, Croft's data are consistent with the current guidelines. We agree that no one can be complacent about either malaria or antimalarial drugs.
DAVID BRADLEY Codirector
DAVID WARHURST Codirector
PHLS Malaria Reference Laboratory London School of Hygiene and Tropical Medicine London WCIE 7HT
i Bradley DJ. Prophylaxis against malaria for travellers from the United Kingdom. BMJ 1993,306: 1247-52. ii Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC. Long term malaria prophylaxis with weekly mefloquine. Lancet 1993;341:848-51. iii Steffen R, Fuchs E, Schildkhecht. J. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet 1993;341:1299-303.