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Epidemic alert: malaria infections in travellers from West Africa
119
malaria infections in travellers from West Africa
Epidemic alert:
SIR,-Frequent reference has been made to the rise in incidence of Plasmodium falciparum malaria in non-immune travellers.1,2 This has been attributed to the increased number of travellers to Africa exposed to infection, and to greater risk of breakthrough as a result of the spread of chloroquine-resistant P falciparum malaria. Chloroquine-resistant malaria was first reported in East Africa in 1978, but has only lately been observed in West Africa.’ The dilemma of chemoprophylaxis against P falciparum infectionswhether to prescribe effective but potentially toxic antimalarial drugs (eg, pyrimethamine/sulphadoxine, pyrimethamine/dapsone) or safe but less effective antimalarials (eg, chloroquine and proguanil)-has thus largely been confined to travellers visiting Effects of 60 mg
sinorphan (oral) on plasma ANF and enkephalinase activity in seven patients with severe congestive heart failure. Data as mean
(SEM).’p<0’05;"p<0’01.
The rise in plasma ANF was associated with two typical responses to ANF-namely, a fall in plasma renin activity (by about 20% 1-3 h after 60 mg sinorphan; not shown) and a lowered puhnonary capillary pressure (PCP). Baseline PCP, recorded 24 h after’Swan Ganz’gauge implantation, were 19.4 (2’ 3) and 18.4 ( 1 6) mm Hg in patients scheduled to receive 30 mg and 60 mg sinorphan, respectively. 3 h after drug administration, at the peak of plasma ANF, PCP fell to 17-6 (3-4) (9%; not significant) and 12-4 (2-0) mm Hg (29%; p < 0-04), respectively. Similar changes were recorded on the second day of treatment with 60 mg sinorphan (26 %; p < 0-02), paired Student’s t test. This action of sinorphan was well tolerated and not accompanied by any significant change in cardiac output, heart rate, or mean arterial blood pressure. Our results establish that enkephalinase inhibition represents an effective means of raising ANF levels, even in severe congestive heart failure, and that this may improve haemodynamic indices. Controlled trials with long-term sinorphan, now in progress, will assess the potential of this approach in the management of
cardiovascular diseases.
J. C. KAHN Hôpital de
M. PATEY
Poissy
J. L. DUBOIS-RANDE
Cardiology Service, Créteil
P. MERLET A. CASTAIGNE
Laboratoire Bioprojet
J. M. LECOMTE
Hôpital
Henri Mondor,
C. LIM-ALEXANDRE
Cardiology Service,
D. DUBOC
Hôpital Cochin, Paris
Neurobiology and Pharmacology Unit, Centre Paul Broca de l’INSERM, 75014 Paris, France
C. GROS J. C. SCHWARTZ
East Africa. Lack of travel statistics and of patterns of chemoprophylactic drug use have hampered our understanding of the risks of malaria and the relative efficacy of chemoprophylactic regimens. Since 1986, denominator data from the Office of Population Censuses and Surveys (OPCS) have been made available to estimate the number of travellers visiting malarious countries each year, by category of travel. The most frequently visited countries with endemic Pfalciparnum are Nigeria, Ghana, and The Gambia in West Africa, and Kenya and Tanzania in East Africa. Malaria attack rates may be calculated by linking these data with numerators obtained through national surveillance of imported malaria infections in Britain.4 Both surveillance systems are continuous and data collection and analysis have remained consistent from year to year. The annual rate of infection among travellers returning to Britain from West Africa has risen sharply (figure). In 1986, malaria attack rates were below 0-4% for visitors to countries in West Africa and below 0-2% for East Africa. By 1988, attack rates had increased to 0-8% for Nigeria and to 1-4% for Ghana. In contrast, attack rates for East Africa did not increase. In West Africa, the group of travellers known to be at greatest risk of P falciparum infection are those immigrants settled in Britain who return to their country of origin to visit relatives.2 This group seldom take chemoprophylaxis-in 1987, over half such cases had not done SO.5 The risk of malaria in these travellers increased two to three-fold between 1986 and 1988 (table). A second group of travellers to West Africa, who have hitherto been well protected by prophylaxis, are business travellers. The rate of infection in such travellers to Nigeria, as with immigrants, rose 2’5-fold. However, in business travellers to Ghana, infection rates rose over 8-fold. In contrast, in East Africa, there has been no increase in risk among business travellers. Malaria prevention research continues to focus on East Africa,"6 the region of acquisition of most fatal infections. Our data indicate that the malaria situation in East Africa is stable, whereas infection from West Africa is rapidly increasing. These findings are supported by the increased frequency of malaria infection in USA Peace Corps volunteers in West Africa.’ The emergence of chloroquine resistance seems to only partly account for the sharp rise in infection rates. The number of patients with
I Sdiwarrrr JC. Enkephalinase inhibitors as drugs. In: Sandler M, Smith HJ, eds. Design of enzyme inhibitors as drugs. New York: Oxford University Press, 1989: 206-20. 2 Lafferty HM, Gunning M, et al. Enkephalinase inhibition increases plasma atrial natriuretic penide levels, glomerular filtration natriuretic peptide levels, glomerular filtration rate and urinary sodium excretion in rats with reduced renal mass. Circ Res 1989; 65: 640-46. 3. Gros C, Souque A, et al Protection of atrial natriuretic factor against degradation, diuretic and natriuretic responses after m vivo inhibition of enkephalinase (EC 34.24.11). Proc Natl Acad Sci (USA) 1989; 86: 7580-85. 4. Olins GM, Krieter PA, et al. Specific inhibitors of endopeptidase 24-11 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo. Molec Cell Endocrinol 1989, 61: 201-08. 5 Northridge DB, Jardine AG, Alabaster CT, et al. Effects of UK 69 578: a novel atriopeptidase inhibitor. Lancet 1989; ii: 591-93. 6 Schwartz JC, Gros C, Bralet J, Lecomte JM. Enkephalinase inhibitors’ ANF-like
activity and potential clinical applications. research. Amsterdam Elsevier (in press). 7 Goetz KL Physiology and E1-E15.
In: Harms
AF, ed. Trends
in
drug
pathophysiology of atrial peprides Am J Physiol 1988; 254: Malaria attack rates in
returning
British residents, 1986-88.
120
MALARIA ATTACK RATES IN BRITISH RESIDENTS RETURNING FROM PRINCIPAL MALARIOUS COUNTRIES OF EAST AND WEST AFRICA, 1986-88
Trav travellers. RR = relative risk-attack rate 1988/attack rate 1986, shown with 95% confidence hmrts. Source travel statistics from OPCS and Department of Employment, malaria statistics from the Malaria Reference =
P falciparum from Ghana claiming to have taken chloroquine and proguanil has risen (from 2 to 21), as has the proportion of all cases (from 5% to 19%). This rise may be attributable to wider use of this chemoprophylactic combination. The number of cases taking no prophylaxis has also increased from 26 to 59, although the proportion of all cases fell from 60% to 45%. We cannot identify from the data the reason for the increasing frequency of infection in groups such as immigrants visiting relatives, who seldom take chemoprophylaxis. Has transmission of P falciparum increased in association with the spread of chloroquine resistance? Irrespective of the cause, these data strongly indicate that the risk of acquiring malaria in West Africa has increased greatly, and that this is likely to continue with the advancement of chloroquine-resistant P falciparum in West Africa. Travellers and their medical advisers should be aware of this. Hospital for Tropical Diseases, London NW1 OPE, UK
P. A. PHILLIPS-HOWARD J. PORTER R. H. BEHRENS
PHLS Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine, London WC1
D.
Travel Clinic,
J. BRADLEY
Phillips-Howard PA, Bradley DJ, Blaze M, Hurn M. Malaria in Britain, 1977-1986 Br Med J 1988; 296: 245-48. 2. Bradley DJ. Changing pattern of malaria in Britain JR Soc Med 1989; 82 (suppl): 1.
8-13. 3 Peters W.
Chemotherapy and drug resistance in malaria. London: Academic Press,
1987.
Phillips-Howard PA, Breeze E, Lakin C, Bradley DJ
Short term travel to malarious malaria risk in UK travellers. Trav Med Intern 1988; 6: 51-60. 5. Phillips-Howard PA, Radalowicz A, Mitchell J, Bradley DJ. The risk of malaria in British residents returning from malarious areas. Br Med J (in press) 6. Lobel HO, Phillips-Howard PA, Brandling-Bennett AD, et al Malaria incidence and prevention in European and North American travellers to Kenya. Bull WHO (in 4.
areas:
press). JS, Bernard KW. The spread of chloroquine-resistant malaria JAMA 1989; 262: 245-48
7. Moran
in
Africa
Mefloquine failure in child contracting falciparum malaria in West Africa SIR,-A 6-year-old boy from Paris travelled overland to Morocco, Senegal, and the Ivory Coast with his parents in June, 1988. Two weeks before leaving France he was started on mefloquine prophylaxis 100 mg per week (4-35 mg;kg) and he had been on continuous prophylaxis for 4 weeks before he reached the malaria
Laboratory.
endemic
area of Senegal. The family reached the Ivory Coast in where August, they stayed in small villages, and the boy was exposed to mosquitoes. On Aug 31 the family returned to France and mefloquine was continued for 4 more weeks, the last dose being on Sept 24. At the end of October the child had a fever with chills and headache, and was admitted to hospital in Paris, where uncomplicated Plasmodium falciparum malaria with high-grade parasitaemia was diagnosed. An adult dose of mefloquine was given (750 mg, 500 mg, and 250 mg doses 8 h apart from a total dose of 65 mg/kg instead of 25 mg/kg). The fever resolved and a smear was negative for parasites within 48 h. 3 weeks later (Nov 17) the patient again had fever with chills, sweating, severe headache, and drowsiness. He was admitted to 1’Hopital Pitié-Salpêtrière. Except for pallor, the physical and neurological findings were essentially normal. He had 07% P falciparum trophozoites on a thick smear; a normal blood count except for a slighly increased white cell count at 11 270/µl; and slightly increased total bilirubin (25 rnmol/1). The malaria immunofluorescent titre 1800 and was antibody immunoelectrophoresis was positive (two arcs). Blood and urine cultures and blood tests ruled out other medical conditions. The child was put on quinine by infusion (150 mg every 6 h for 5 days or 25 mg/kg daily). The fever resolved in 3 days; the parasite count fell in 2 days and was negative by the 4th day. He was then given oral quinine (’Quinimax’) at the same dose for 5 days. The patient had no side-effects from this treatment and his parasite count remained negative at follow-up. In-vitro drug sensitivity tests to chloroquine, quinine, and mefloquine were done but parasite growth was uninterpretable. His plasma level of mefloquine at admission was 328 ng/ml, which could explain the partial inhibition of parasite growth in the drug
sensitivity tests. Despite an adequate plasma drug level (328 ng/ml more than 2 weeks after the last therapeutic dose), prophylactic and, subsequently, therapeutic use of mefloquine failed in this child. To our knowledge, this is the first case of in-vivo type I mefloquine resistance in a child with recurrent P falciparium malaria acquired in West Africa. In adults one case of induced infection in a volunteer with the Vietnam Smith strainl and a case of mefloquine-resistant malaria acquired in Tanzania2 have been reported. Elimination of mefloquine is slow, with a half-life in healthy adults of about 3 weeks,3but it is more rapid in children with acute malaria .4 It was unexpected for mefloquine-resistant malaria to be contracted in Senegal or the Ivory Coast, areas with low levels or no resistance to
malaria infections in travellers from West Africa
Epidemic alert:
SIR,-Frequent reference has been made to the rise in incidence of Plasmodium falciparum malaria in non-immune travellers.1,2 This has been attributed to the increased number of travellers to Africa exposed to infection, and to greater risk of breakthrough as a result of the spread of chloroquine-resistant P falciparum malaria. Chloroquine-resistant malaria was first reported in East Africa in 1978, but has only lately been observed in West Africa.’ The dilemma of chemoprophylaxis against P falciparum infectionswhether to prescribe effective but potentially toxic antimalarial drugs (eg, pyrimethamine/sulphadoxine, pyrimethamine/dapsone) or safe but less effective antimalarials (eg, chloroquine and proguanil)-has thus largely been confined to travellers visiting Effects of 60 mg
sinorphan (oral) on plasma ANF and enkephalinase activity in seven patients with severe congestive heart failure. Data as mean
(SEM).’p<0’05;"p<0’01.
The rise in plasma ANF was associated with two typical responses to ANF-namely, a fall in plasma renin activity (by about 20% 1-3 h after 60 mg sinorphan; not shown) and a lowered puhnonary capillary pressure (PCP). Baseline PCP, recorded 24 h after’Swan Ganz’gauge implantation, were 19.4 (2’ 3) and 18.4 ( 1 6) mm Hg in patients scheduled to receive 30 mg and 60 mg sinorphan, respectively. 3 h after drug administration, at the peak of plasma ANF, PCP fell to 17-6 (3-4) (9%; not significant) and 12-4 (2-0) mm Hg (29%; p < 0-04), respectively. Similar changes were recorded on the second day of treatment with 60 mg sinorphan (26 %; p < 0-02), paired Student’s t test. This action of sinorphan was well tolerated and not accompanied by any significant change in cardiac output, heart rate, or mean arterial blood pressure. Our results establish that enkephalinase inhibition represents an effective means of raising ANF levels, even in severe congestive heart failure, and that this may improve haemodynamic indices. Controlled trials with long-term sinorphan, now in progress, will assess the potential of this approach in the management of
cardiovascular diseases.
J. C. KAHN Hôpital de
M. PATEY
Poissy
J. L. DUBOIS-RANDE
Cardiology Service, Créteil
P. MERLET A. CASTAIGNE
Laboratoire Bioprojet
J. M. LECOMTE
Hôpital
Henri Mondor,
C. LIM-ALEXANDRE
Cardiology Service,
D. DUBOC
Hôpital Cochin, Paris
Neurobiology and Pharmacology Unit, Centre Paul Broca de l’INSERM, 75014 Paris, France
C. GROS J. C. SCHWARTZ
East Africa. Lack of travel statistics and of patterns of chemoprophylactic drug use have hampered our understanding of the risks of malaria and the relative efficacy of chemoprophylactic regimens. Since 1986, denominator data from the Office of Population Censuses and Surveys (OPCS) have been made available to estimate the number of travellers visiting malarious countries each year, by category of travel. The most frequently visited countries with endemic Pfalciparnum are Nigeria, Ghana, and The Gambia in West Africa, and Kenya and Tanzania in East Africa. Malaria attack rates may be calculated by linking these data with numerators obtained through national surveillance of imported malaria infections in Britain.4 Both surveillance systems are continuous and data collection and analysis have remained consistent from year to year. The annual rate of infection among travellers returning to Britain from West Africa has risen sharply (figure). In 1986, malaria attack rates were below 0-4% for visitors to countries in West Africa and below 0-2% for East Africa. By 1988, attack rates had increased to 0-8% for Nigeria and to 1-4% for Ghana. In contrast, attack rates for East Africa did not increase. In West Africa, the group of travellers known to be at greatest risk of P falciparum infection are those immigrants settled in Britain who return to their country of origin to visit relatives.2 This group seldom take chemoprophylaxis-in 1987, over half such cases had not done SO.5 The risk of malaria in these travellers increased two to three-fold between 1986 and 1988 (table). A second group of travellers to West Africa, who have hitherto been well protected by prophylaxis, are business travellers. The rate of infection in such travellers to Nigeria, as with immigrants, rose 2’5-fold. However, in business travellers to Ghana, infection rates rose over 8-fold. In contrast, in East Africa, there has been no increase in risk among business travellers. Malaria prevention research continues to focus on East Africa,"6 the region of acquisition of most fatal infections. Our data indicate that the malaria situation in East Africa is stable, whereas infection from West Africa is rapidly increasing. These findings are supported by the increased frequency of malaria infection in USA Peace Corps volunteers in West Africa.’ The emergence of chloroquine resistance seems to only partly account for the sharp rise in infection rates. The number of patients with
I Sdiwarrrr JC. Enkephalinase inhibitors as drugs. In: Sandler M, Smith HJ, eds. Design of enzyme inhibitors as drugs. New York: Oxford University Press, 1989: 206-20. 2 Lafferty HM, Gunning M, et al. Enkephalinase inhibition increases plasma atrial natriuretic penide levels, glomerular filtration natriuretic peptide levels, glomerular filtration rate and urinary sodium excretion in rats with reduced renal mass. Circ Res 1989; 65: 640-46. 3. Gros C, Souque A, et al Protection of atrial natriuretic factor against degradation, diuretic and natriuretic responses after m vivo inhibition of enkephalinase (EC 34.24.11). Proc Natl Acad Sci (USA) 1989; 86: 7580-85. 4. Olins GM, Krieter PA, et al. Specific inhibitors of endopeptidase 24-11 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo. Molec Cell Endocrinol 1989, 61: 201-08. 5 Northridge DB, Jardine AG, Alabaster CT, et al. Effects of UK 69 578: a novel atriopeptidase inhibitor. Lancet 1989; ii: 591-93. 6 Schwartz JC, Gros C, Bralet J, Lecomte JM. Enkephalinase inhibitors’ ANF-like
activity and potential clinical applications. research. Amsterdam Elsevier (in press). 7 Goetz KL Physiology and E1-E15.
In: Harms
AF, ed. Trends
in
drug
pathophysiology of atrial peprides Am J Physiol 1988; 254: Malaria attack rates in
returning
British residents, 1986-88.
120
MALARIA ATTACK RATES IN BRITISH RESIDENTS RETURNING FROM PRINCIPAL MALARIOUS COUNTRIES OF EAST AND WEST AFRICA, 1986-88
Trav travellers. RR = relative risk-attack rate 1988/attack rate 1986, shown with 95% confidence hmrts. Source travel statistics from OPCS and Department of Employment, malaria statistics from the Malaria Reference =
P falciparum from Ghana claiming to have taken chloroquine and proguanil has risen (from 2 to 21), as has the proportion of all cases (from 5% to 19%). This rise may be attributable to wider use of this chemoprophylactic combination. The number of cases taking no prophylaxis has also increased from 26 to 59, although the proportion of all cases fell from 60% to 45%. We cannot identify from the data the reason for the increasing frequency of infection in groups such as immigrants visiting relatives, who seldom take chemoprophylaxis. Has transmission of P falciparum increased in association with the spread of chloroquine resistance? Irrespective of the cause, these data strongly indicate that the risk of acquiring malaria in West Africa has increased greatly, and that this is likely to continue with the advancement of chloroquine-resistant P falciparum in West Africa. Travellers and their medical advisers should be aware of this. Hospital for Tropical Diseases, London NW1 OPE, UK
P. A. PHILLIPS-HOWARD J. PORTER R. H. BEHRENS
PHLS Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine, London WC1
D.
Travel Clinic,
J. BRADLEY
Phillips-Howard PA, Bradley DJ, Blaze M, Hurn M. Malaria in Britain, 1977-1986 Br Med J 1988; 296: 245-48. 2. Bradley DJ. Changing pattern of malaria in Britain JR Soc Med 1989; 82 (suppl): 1.
8-13. 3 Peters W.
Chemotherapy and drug resistance in malaria. London: Academic Press,
1987.
Phillips-Howard PA, Breeze E, Lakin C, Bradley DJ
Short term travel to malarious malaria risk in UK travellers. Trav Med Intern 1988; 6: 51-60. 5. Phillips-Howard PA, Radalowicz A, Mitchell J, Bradley DJ. The risk of malaria in British residents returning from malarious areas. Br Med J (in press) 6. Lobel HO, Phillips-Howard PA, Brandling-Bennett AD, et al Malaria incidence and prevention in European and North American travellers to Kenya. Bull WHO (in 4.
areas:
press). JS, Bernard KW. The spread of chloroquine-resistant malaria JAMA 1989; 262: 245-48
7. Moran
in
Africa
Mefloquine failure in child contracting falciparum malaria in West Africa SIR,-A 6-year-old boy from Paris travelled overland to Morocco, Senegal, and the Ivory Coast with his parents in June, 1988. Two weeks before leaving France he was started on mefloquine prophylaxis 100 mg per week (4-35 mg;kg) and he had been on continuous prophylaxis for 4 weeks before he reached the malaria
Laboratory.
endemic
area of Senegal. The family reached the Ivory Coast in where August, they stayed in small villages, and the boy was exposed to mosquitoes. On Aug 31 the family returned to France and mefloquine was continued for 4 more weeks, the last dose being on Sept 24. At the end of October the child had a fever with chills and headache, and was admitted to hospital in Paris, where uncomplicated Plasmodium falciparum malaria with high-grade parasitaemia was diagnosed. An adult dose of mefloquine was given (750 mg, 500 mg, and 250 mg doses 8 h apart from a total dose of 65 mg/kg instead of 25 mg/kg). The fever resolved and a smear was negative for parasites within 48 h. 3 weeks later (Nov 17) the patient again had fever with chills, sweating, severe headache, and drowsiness. He was admitted to 1’Hopital Pitié-Salpêtrière. Except for pallor, the physical and neurological findings were essentially normal. He had 07% P falciparum trophozoites on a thick smear; a normal blood count except for a slighly increased white cell count at 11 270/µl; and slightly increased total bilirubin (25 rnmol/1). The malaria immunofluorescent titre 1800 and was antibody immunoelectrophoresis was positive (two arcs). Blood and urine cultures and blood tests ruled out other medical conditions. The child was put on quinine by infusion (150 mg every 6 h for 5 days or 25 mg/kg daily). The fever resolved in 3 days; the parasite count fell in 2 days and was negative by the 4th day. He was then given oral quinine (’Quinimax’) at the same dose for 5 days. The patient had no side-effects from this treatment and his parasite count remained negative at follow-up. In-vitro drug sensitivity tests to chloroquine, quinine, and mefloquine were done but parasite growth was uninterpretable. His plasma level of mefloquine at admission was 328 ng/ml, which could explain the partial inhibition of parasite growth in the drug
sensitivity tests. Despite an adequate plasma drug level (328 ng/ml more than 2 weeks after the last therapeutic dose), prophylactic and, subsequently, therapeutic use of mefloquine failed in this child. To our knowledge, this is the first case of in-vivo type I mefloquine resistance in a child with recurrent P falciparium malaria acquired in West Africa. In adults one case of induced infection in a volunteer with the Vietnam Smith strainl and a case of mefloquine-resistant malaria acquired in Tanzania2 have been reported. Elimination of mefloquine is slow, with a half-life in healthy adults of about 3 weeks,3but it is more rapid in children with acute malaria .4 It was unexpected for mefloquine-resistant malaria to be contracted in Senegal or the Ivory Coast, areas with low levels or no resistance to