1184 CONCENTRATION OF CHOLESTEROL AND RATIO OF TOTAL CHOLESTEROL TO HDL CHOLESTEROL IN SERUM OF BOYS AGED 7 AND 8 YEARS IN SIXTEEN COUNTRIES i
The wide vertebrate and invertebrate host spectrum of RVF virus undoubtedly aided its spread to Egypt. The virus now circulates in a variety of ecological settings in a 7000 km north-south range across Africa. Bearing in mind these facts, and the historical precedent set in 1944 when African horsesickness (a Culicoides transmitted virus) spread from Southern Africa to Egypt and then through the eastern Mediterranean to southern Europe,6 we wondered if RVF might represent a threat to other sections of the Middle East and to Europe. Our limited studies reported here reveal that, even in this time of restricted land travel across the Sinai peninsula, various means of virus dissemination to the Asian continent exist, and that RVF virus most probably has already spread eastward from
continental Africa. A retrospective serological survey was performed on a small number of sera collected from Swedish United Nations Emergency Forces (UNEF) soldiers stationed in the Sinai; from local Sinai Bedouins, and from sheep from the Sinai Buffer Zone. Microtitre hmmagglutination-inhibition (HI) and complement-fixation (CF) tests were used to measure serum antibodies to RVF virus,’ and an HI titre greater than 1:40 or a CF titre greater than 1:were considered positive. Details of the UNEF study will be published elsewhere,8 but preliminary results reveal that 8 of 170 Swedish UNEF soldiers and 1 of 22 Bedouins had positive HI and CF antibody titres to RVF virus. Only 34 sheep sera were collected, but 8 had positive CF titres to RVF virus. The seropositive Sinai Bedouin was a reliable UNEF employee who claimed he had never travelled from his village area 50 km north-east oflsmailia. He had not crossed the Suez Canal or visited any other African or Middle Eastern country, and during the 1977 and 1978 Egyptian RVF epidemics he was restricted to the Buffer Zone. He most probably contracted the disease on the Sinai peninsula. This incident would represent the first occasion that RVF virus has penetrated beyond the mainland African con*R= rural; U=
urban; t Mean±SEM.
terol ratio may have
a
predictive
tinent. value for the risk of CHD.
Full details of the study will be published elsewhere. The study was supported by Netherlands Heart Foundation grant 78.064.
JAN T. KNUIMAN Department of Human Nutrition, Agricultural University, 6703 BC-Wageningen, Netherlands
CLIVE E. WEST
RUUD J. J. HERMUS JOSEPH G. A. J. HAUTVAST
SPREAD OF RIFT VALLEY FEVER VIRUS FROM CONTINENTAL AFRICA
SIR,-Rift Valley fever (RVF) is an arthropod-borne viral disease primarily affecting domestic animals, with occasional involvement of man.’ Before 1977, RVF was limited to SubSaharan Africa, and caused periodic epizootics of abortion and mortality in domestic animals during which human disease was recorded as a non-fatal febrile illness.2 In 1977, and again in 1978, there were widespread RVF epizootics in parts of the Nile Valley and Delta in Egypt.3-5 Unlike previous RVF epizootics, these outbreaks included extensive human involvement, observed clinically as either an acute febrile, encephalitic, ocular, or fatal haemorrhagic-like disease.5 The 1977 epidemic in Egypt was the largest and most severe RVF epidemic yet recorded, with estimates of morbidity ranging to 200 000 with at least 600 deaths.3 Daubney R, Hudson JR, Garnham PC. J Pathol Bact 1931; 34: 545. Easterday BC. Adv Vet Sci 1965; 10: 65. 3. Meegan JM. Trans Roy Soc Trop Med Hyg (in press). 4. Meegan JM, Hoogstraal H, Moussa MI. Vet Rec 1979; 105: 124. 5. Laughlin LW, Meegan JM, Strausbaugh LJ, Morens DM, Watten Trans Roy Soc Trop Med Hyg (in press). 1. 2.
RH.
The sheep sera were collected in an area 80 km north-east of Ismailia and only 2 km west of the eastern border of the Buffer Zone. The seropositive sheep may have been smuggled into the Sinai; thus they would not represent RVF virus circulation on the peninsula but would instead provide evidence of a means for virus dissemination from Egypt to other areas of the Middle East. Until 1977, RVF was limited to southern Africa, and since 500 Swedish soldiers who had not served in the Middle East were negative for antibodies to RVF virus, the 8 seropositive UNEF soldiers most probably contracted RVF while on duty in Egypt and the Sinai. These soldiers may have been infected with RVF virus while visiting the Nile Delta or Valley of Egypt. Nonetheless, the UNEF frequently move men and supplies from Egypt into or through the Sinai, and a viraemic soldier could bring the virus to the peninsula or infected mosquitoes could be transported inadvertently in vehicles. More important is the threat that a virxmic soldier could return to his homeland and introduce RVF into yet another area of the world. Battalions of UNEF soldiers in the Sinai include troops from Sweden, Canada, Finland, Indonesia, and Ghana, and there are military observers from many countries. Swedish and Canadian military authorities have recently undertaken a RVF vaccination programme for their troops.8 Most of the Sinai is arid or semi-arid but there are areas where mosquitoes are prevalent.9 Additionally, our collections of mosquitoes from the Swedish UNEF camp 50 km north-east of Ismailia have revealed the presence of Culex pipiens, a vector of RVF virus during the Egyptian epidemics." Conse6. Alexander RA. Onderstepoort J Vet Sci Anim Ind 1948; 23: 77. 7. Casals J. Meth Virol 1967; 3: 113. 8. Meegan JM, Niklasson B, Bengtsson E. Scand J Inf Dis (in press). 9. Margalit J, Tahori AS. J Med Entomil 1973; 10: 89. 10. Hoogstraal H, Meegan JM, Khalil GM, Adman FK. Trans Roy Soc Med Hyg (in press).
Trop
1185
quently, some virus activity.
areas
of the Sinai could
We believe that RVF does pose countries.
an
possibly
become foci of
imminent threat
to
other
Research project MR41.09.01-0165, Naval Medical Research and Development Command, National Naval Medical Center, Bethesda, Maryland, U.S.A. Human RVF vaccine is supplied by the U.S. Army Medical Research Institute of Infectious Disease, Frederick, Maryland
21701, U.S.A. U.S. Naval Medical Research Unit 3, c/o American Embassy,
JAMES M. MEEGAN*
Cairo, Egypt
Department of Infectious Disease, Roslagstull Hospital, Stockholm, Sweden *Present address: Yale Arbovirus Research
BOB NIKLASSON ELIAS BENGTSSON Unit, Yale University School of
Medicine, 60 College Street, New Haven, Connecticut 06510, U.S.A.
STEROIDS IN ASTHMA
SIR,-Wyatt et al.’ compared alternate-day prednisone and beclomethasone given by inhaler in asthmatic patients and found similar adrenal suppressive effects with both preparations. They concentrated on the putative diminished risk of beclomethasone, largely neglecting the question of increased benefit. Weinberger et all suggested that the improved adrenal function often reported to result from a change to beclomethasone therapy might be confined to patients previously treated with daily oral steroids. These doubts about beclomethasone have not been fully answered in the correspondence columns of the N.E.J.M. or The Lancet.4-6 Nor are they answerable by Wyatt’s study, which did not compare the effects of the beclomethasone in two treatment groups-i.e., on daily or on
alternate-day prednisone. We have studied two such groups. Risk-benefit assessments made during beclomethsone treatment of 17 asthmatics taking daily prednisone and 1 on alternate-day prednisone. We were
have
data7.8 in
manner relevant to WeinAddition of high-dose beclomethasone to an established regimen of daily low-dose prednisone resulted in a large symptomatic benefit and an additive increase in cortisol suppression. 14 months later, after the patients had been weaned on to the lowest effective dosage of both oral and aerosol steroid (and after prednisone had been stopped where feasible) a mean 20% rise in morning cortisol levels was coupled with sustained symptomatic improvement. The patients who had been on alternate day oral prednisone experienced symptom improvement which was not associated with any similar improvement in adrenal function. These data support Weinberger’s view that most of the improvement in adrenal function reported in steroid-dependent asthmatics after conversion to beclomethasone may result from the change from daily to an alternate day (or no) oral steroids under the aegis of the beclomethasone treatment, and that pa-
analysed
our
Changes in
asthma symptoms and in serum-cortisol when beclomethasone aerosol was added to established oral steroid
regimens. Beclomethasone was added in high dosage to the established oral steroid regimen of 17 asthmatic patients on alternate-day and 17 on daily morning prednisone. The oral and aerosol steroids were subsequently weaned, one at a time, to determine the minimum effective dose of each necessary to control each subject’s asthma. The change in asthma symptoms and morning cortisol levels, relative to the prebeclomethasone baseline levels are illustrated by the clear and shaded bars, respectively. The figures which cap the shaded bars are the group mean 8 A.M. serum levels in ’.g/dl.
a
berger’s questions (see figure).
1.
2. 3.
4. 5. 6. 7.
8.
Waschek J, Weinberger M, Sherman B. Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitaryadrenal function in children with chronic asthma. N Engl J Med 1978, 299: 1387-92. Weinberger M, Sherman B. Prednisone and beclomethasone for treatment of asthma. N Engl J Med 1979; 300: 987. Weinberger M, Sherman B. Inhaled steroid aerosols and alternate-day predmsone. Lancet 1979; i: 871-2. Brown HM, Jackson FA. Are steroid inhalers safer than tablets? Lancer 1979; i. 82. Siegel SC, Karz RM, Rachelefsky GS. Prednisone and beclomethasone for treatment of asthma. N Engl J Med 1979; 300: 986. Dattwyler RJ, Bloch KJ. Prednisone and beclomethasone for treatment of asthma. N Engl J Med 1979; 300: 986-8. Toogood JH, Lefcoe NM, Haines DSM, et al. A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma. J Allergy Clin Immunol 1977; 59: 298-308. Toogood JH, Lefcoe NM, Haines DSM. Minimum dose requirements of steroid-dependent asthmatic patients for aerosol beclomethasone and oral prednisone. J Allergy Clin Immunol 1978; 61: 355-64.
Wyatt R,
tients to
already on alternate day oral prednisone are not likely improve their cortisol levels significantly after beclometha-
conversion. On the other hand, the data conflict with the notion improved adrenal function is the only clinical advantage to be derived from beclomethasone treatment. 3.9 In the alternate-day group, a large improvement in asthma symptoms was coupled with persistently suppressed (but not worse) adrenal function. These results reflect the substitution of about 1 mg beclomethasone for 5.9 mg oral prednisone. This argues for a strong local effect of beclomethasone, since it would be quite unrealistic to expect that amount of symptom benefit to have accrued in severely asthmatic patients if the prednisone dose had been raised by one tablet per day instead. To define the place of topically active aerosol steroids in asthma the efficiency of aerosol steroid and alternate-morning single dose oral prednisone given in bioequivalent doses must be compared directly in patients not previously committed to maintenance steroids. Until such studies are done our data can only suggest, not prove, that beclomethasone has advantages over alternate-day, low-dose prednisone. In such studies, both risk and benefit must be compared. If we are properly to assess the usefulness of aerosol steroids for asthma we must get rid of the misconception that steroids have adrenal suppressive effect at currently recommended dosages and that the absence of significant adrenal suppression is a sine qua non for proof of their clinical usefulness. Such criteria would be absurd if applied in a similar fashion to oral steroids. Physicians have learned to apply a graded system of risk-benefit judgments to fit the particular circumstances of sone
9. Editorial. Are steroid inhalers safer than tablets? Lancet 1979; i: 589-90.
The wide vertebrate and invertebrate host spectrum of RVF virus undoubtedly aided its spread to Egypt. The virus now circulates in a variety of ecological settings in a 7000 km north-south range across Africa. Bearing in mind these facts, and the historical precedent set in 1944 when African horsesickness (a Culicoides transmitted virus) spread from Southern Africa to Egypt and then through the eastern Mediterranean to southern Europe,6 we wondered if RVF might represent a threat to other sections of the Middle East and to Europe. Our limited studies reported here reveal that, even in this time of restricted land travel across the Sinai peninsula, various means of virus dissemination to the Asian continent exist, and that RVF virus most probably has already spread eastward from
continental Africa. A retrospective serological survey was performed on a small number of sera collected from Swedish United Nations Emergency Forces (UNEF) soldiers stationed in the Sinai; from local Sinai Bedouins, and from sheep from the Sinai Buffer Zone. Microtitre hmmagglutination-inhibition (HI) and complement-fixation (CF) tests were used to measure serum antibodies to RVF virus,’ and an HI titre greater than 1:40 or a CF titre greater than 1:were considered positive. Details of the UNEF study will be published elsewhere,8 but preliminary results reveal that 8 of 170 Swedish UNEF soldiers and 1 of 22 Bedouins had positive HI and CF antibody titres to RVF virus. Only 34 sheep sera were collected, but 8 had positive CF titres to RVF virus. The seropositive Sinai Bedouin was a reliable UNEF employee who claimed he had never travelled from his village area 50 km north-east oflsmailia. He had not crossed the Suez Canal or visited any other African or Middle Eastern country, and during the 1977 and 1978 Egyptian RVF epidemics he was restricted to the Buffer Zone. He most probably contracted the disease on the Sinai peninsula. This incident would represent the first occasion that RVF virus has penetrated beyond the mainland African con*R= rural; U=
urban; t Mean±SEM.
terol ratio may have
a
predictive
tinent. value for the risk of CHD.
Full details of the study will be published elsewhere. The study was supported by Netherlands Heart Foundation grant 78.064.
JAN T. KNUIMAN Department of Human Nutrition, Agricultural University, 6703 BC-Wageningen, Netherlands
CLIVE E. WEST
RUUD J. J. HERMUS JOSEPH G. A. J. HAUTVAST
SPREAD OF RIFT VALLEY FEVER VIRUS FROM CONTINENTAL AFRICA
SIR,-Rift Valley fever (RVF) is an arthropod-borne viral disease primarily affecting domestic animals, with occasional involvement of man.’ Before 1977, RVF was limited to SubSaharan Africa, and caused periodic epizootics of abortion and mortality in domestic animals during which human disease was recorded as a non-fatal febrile illness.2 In 1977, and again in 1978, there were widespread RVF epizootics in parts of the Nile Valley and Delta in Egypt.3-5 Unlike previous RVF epizootics, these outbreaks included extensive human involvement, observed clinically as either an acute febrile, encephalitic, ocular, or fatal haemorrhagic-like disease.5 The 1977 epidemic in Egypt was the largest and most severe RVF epidemic yet recorded, with estimates of morbidity ranging to 200 000 with at least 600 deaths.3 Daubney R, Hudson JR, Garnham PC. J Pathol Bact 1931; 34: 545. Easterday BC. Adv Vet Sci 1965; 10: 65. 3. Meegan JM. Trans Roy Soc Trop Med Hyg (in press). 4. Meegan JM, Hoogstraal H, Moussa MI. Vet Rec 1979; 105: 124. 5. Laughlin LW, Meegan JM, Strausbaugh LJ, Morens DM, Watten Trans Roy Soc Trop Med Hyg (in press). 1. 2.
RH.
The sheep sera were collected in an area 80 km north-east of Ismailia and only 2 km west of the eastern border of the Buffer Zone. The seropositive sheep may have been smuggled into the Sinai; thus they would not represent RVF virus circulation on the peninsula but would instead provide evidence of a means for virus dissemination from Egypt to other areas of the Middle East. Until 1977, RVF was limited to southern Africa, and since 500 Swedish soldiers who had not served in the Middle East were negative for antibodies to RVF virus, the 8 seropositive UNEF soldiers most probably contracted RVF while on duty in Egypt and the Sinai. These soldiers may have been infected with RVF virus while visiting the Nile Delta or Valley of Egypt. Nonetheless, the UNEF frequently move men and supplies from Egypt into or through the Sinai, and a viraemic soldier could bring the virus to the peninsula or infected mosquitoes could be transported inadvertently in vehicles. More important is the threat that a virxmic soldier could return to his homeland and introduce RVF into yet another area of the world. Battalions of UNEF soldiers in the Sinai include troops from Sweden, Canada, Finland, Indonesia, and Ghana, and there are military observers from many countries. Swedish and Canadian military authorities have recently undertaken a RVF vaccination programme for their troops.8 Most of the Sinai is arid or semi-arid but there are areas where mosquitoes are prevalent.9 Additionally, our collections of mosquitoes from the Swedish UNEF camp 50 km north-east of Ismailia have revealed the presence of Culex pipiens, a vector of RVF virus during the Egyptian epidemics." Conse6. Alexander RA. Onderstepoort J Vet Sci Anim Ind 1948; 23: 77. 7. Casals J. Meth Virol 1967; 3: 113. 8. Meegan JM, Niklasson B, Bengtsson E. Scand J Inf Dis (in press). 9. Margalit J, Tahori AS. J Med Entomil 1973; 10: 89. 10. Hoogstraal H, Meegan JM, Khalil GM, Adman FK. Trans Roy Soc Med Hyg (in press).
Trop
1185
quently, some virus activity.
areas
of the Sinai could
We believe that RVF does pose countries.
an
possibly
become foci of
imminent threat
to
other
Research project MR41.09.01-0165, Naval Medical Research and Development Command, National Naval Medical Center, Bethesda, Maryland, U.S.A. Human RVF vaccine is supplied by the U.S. Army Medical Research Institute of Infectious Disease, Frederick, Maryland
21701, U.S.A. U.S. Naval Medical Research Unit 3, c/o American Embassy,
JAMES M. MEEGAN*
Cairo, Egypt
Department of Infectious Disease, Roslagstull Hospital, Stockholm, Sweden *Present address: Yale Arbovirus Research
BOB NIKLASSON ELIAS BENGTSSON Unit, Yale University School of
Medicine, 60 College Street, New Haven, Connecticut 06510, U.S.A.
STEROIDS IN ASTHMA
SIR,-Wyatt et al.’ compared alternate-day prednisone and beclomethasone given by inhaler in asthmatic patients and found similar adrenal suppressive effects with both preparations. They concentrated on the putative diminished risk of beclomethasone, largely neglecting the question of increased benefit. Weinberger et all suggested that the improved adrenal function often reported to result from a change to beclomethasone therapy might be confined to patients previously treated with daily oral steroids. These doubts about beclomethasone have not been fully answered in the correspondence columns of the N.E.J.M. or The Lancet.4-6 Nor are they answerable by Wyatt’s study, which did not compare the effects of the beclomethasone in two treatment groups-i.e., on daily or on
alternate-day prednisone. We have studied two such groups. Risk-benefit assessments made during beclomethsone treatment of 17 asthmatics taking daily prednisone and 1 on alternate-day prednisone. We were
have
data7.8 in
manner relevant to WeinAddition of high-dose beclomethasone to an established regimen of daily low-dose prednisone resulted in a large symptomatic benefit and an additive increase in cortisol suppression. 14 months later, after the patients had been weaned on to the lowest effective dosage of both oral and aerosol steroid (and after prednisone had been stopped where feasible) a mean 20% rise in morning cortisol levels was coupled with sustained symptomatic improvement. The patients who had been on alternate day oral prednisone experienced symptom improvement which was not associated with any similar improvement in adrenal function. These data support Weinberger’s view that most of the improvement in adrenal function reported in steroid-dependent asthmatics after conversion to beclomethasone may result from the change from daily to an alternate day (or no) oral steroids under the aegis of the beclomethasone treatment, and that pa-
analysed
our
Changes in
asthma symptoms and in serum-cortisol when beclomethasone aerosol was added to established oral steroid
regimens. Beclomethasone was added in high dosage to the established oral steroid regimen of 17 asthmatic patients on alternate-day and 17 on daily morning prednisone. The oral and aerosol steroids were subsequently weaned, one at a time, to determine the minimum effective dose of each necessary to control each subject’s asthma. The change in asthma symptoms and morning cortisol levels, relative to the prebeclomethasone baseline levels are illustrated by the clear and shaded bars, respectively. The figures which cap the shaded bars are the group mean 8 A.M. serum levels in ’.g/dl.
a
berger’s questions (see figure).
1.
2. 3.
4. 5. 6. 7.
8.
Waschek J, Weinberger M, Sherman B. Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitaryadrenal function in children with chronic asthma. N Engl J Med 1978, 299: 1387-92. Weinberger M, Sherman B. Prednisone and beclomethasone for treatment of asthma. N Engl J Med 1979; 300: 987. Weinberger M, Sherman B. Inhaled steroid aerosols and alternate-day predmsone. Lancet 1979; i: 871-2. Brown HM, Jackson FA. Are steroid inhalers safer than tablets? Lancer 1979; i. 82. Siegel SC, Karz RM, Rachelefsky GS. Prednisone and beclomethasone for treatment of asthma. N Engl J Med 1979; 300: 986. Dattwyler RJ, Bloch KJ. Prednisone and beclomethasone for treatment of asthma. N Engl J Med 1979; 300: 986-8. Toogood JH, Lefcoe NM, Haines DSM, et al. A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma. J Allergy Clin Immunol 1977; 59: 298-308. Toogood JH, Lefcoe NM, Haines DSM. Minimum dose requirements of steroid-dependent asthmatic patients for aerosol beclomethasone and oral prednisone. J Allergy Clin Immunol 1978; 61: 355-64.
Wyatt R,
tients to
already on alternate day oral prednisone are not likely improve their cortisol levels significantly after beclometha-
conversion. On the other hand, the data conflict with the notion improved adrenal function is the only clinical advantage to be derived from beclomethasone treatment. 3.9 In the alternate-day group, a large improvement in asthma symptoms was coupled with persistently suppressed (but not worse) adrenal function. These results reflect the substitution of about 1 mg beclomethasone for 5.9 mg oral prednisone. This argues for a strong local effect of beclomethasone, since it would be quite unrealistic to expect that amount of symptom benefit to have accrued in severely asthmatic patients if the prednisone dose had been raised by one tablet per day instead. To define the place of topically active aerosol steroids in asthma the efficiency of aerosol steroid and alternate-morning single dose oral prednisone given in bioequivalent doses must be compared directly in patients not previously committed to maintenance steroids. Until such studies are done our data can only suggest, not prove, that beclomethasone has advantages over alternate-day, low-dose prednisone. In such studies, both risk and benefit must be compared. If we are properly to assess the usefulness of aerosol steroids for asthma we must get rid of the misconception that steroids have adrenal suppressive effect at currently recommended dosages and that the absence of significant adrenal suppression is a sine qua non for proof of their clinical usefulness. Such criteria would be absurd if applied in a similar fashion to oral steroids. Physicians have learned to apply a graded system of risk-benefit judgments to fit the particular circumstances of sone
9. Editorial. Are steroid inhalers safer than tablets? Lancet 1979; i: 589-90.
