25
has been found in man does not mean that it has all the other attributes required to produce a devastating epidemic. In fact, the virus did not spread extensively-there were probably about 500 infections in the whole camp and no evidence of spread to civilians outside, even those in close contact with infected soldiers. Although there was one death the virus seemed to cause mild disease on the whole, and this week (p.4) we carry the first report of the results of inoculating the virus to volunteers-strictly isolated, of course - in whom the symptoms were also only mild. The virus was clearly capable of infecting man much more successfully than other antigenically similar viruses taken directly from pigs,2 but it seemed to be milder than a number of viruses isolated in the recent period of "drift", which have no 1918
THE LANCET Planning for Pandemics OVER the years influenza-A viruses change antigenically in a gradual way called "antigenic drift", so that the antibody stimulated by the virus of the past year or two has a reduced protective effect against this year’s virus. Nevertheless, from time to time the antigens may change radically-"antigenic shift"-and this means that antibodies against previous strains, either the antihaemagglutinin or the antineuraminidase, have no protective effect. As a result "shifted" viruses give rise to
extensive worldwide epidemics-as, for example, followed the appearance of the Asian virus with H2N2 antigens in 1957 which replaced all H1N1 strains. Such extensive epidemics are often called pandemics, though the term is usually not precisely defined-which is a pity, because it raises the thought in many minds that such a pandemic will have the characteristics of the infamous three waves of influenza which began in 1918 and which were followed by high mortality. Such thoughts were raised lately as a result of investigation of influenza-A viruses isolated at Fort Dix, an Army camp in the U.S.A. at which recruits are trained. Viruses were isolated from recruits with influenza and these were antigenically very close to the influenza-A virus found in pigs in the Middle West of the U.S.A., viruses which are also probably closely related to those which appeared in 1918, since adults who were children 1 in that year have antibody against the swine virus. This is a finding of great interest, and along with a couple of isolations of similar viruses from immunologically deficient children in the U.S.A., is apparently the first occasion on which an animal virus has been actually caught in the act of spreading from the animal to the human population. Clearly there would be no antibody to prevent it spreading in man, except in individuals 50 years of age and more. Nevertheless, experiments in animals and man have proved that the ability to cause disease is carried by viral genes separate from those determining the surface antigens; so the fact that a virus antigenically like that which caused the
pandemic
pretensions
to
being possible pandemic
being developed which will be tested in subjects, lest swine virus becomes virulent and produces major epidemics. These studies would make it possible to produce live or killed vaccine
strains
are
isolated
which could be used for a mass vaccination campaign if this were called for. Even if vaccination is 2.
Beare, A. S., Schild, G. C., Hall, T. S., Kundin, 305.
1
Wkly epidem. Rec. 1976, 51, 108.
strains. In
fact the virus seems not to have spread in the civilian population in the U.S.A. and has not been isolated in the U.K.3 It seemed to be not very good at infecting man and may have died out as a result. There will be close surveillance during the coming winters to see whether it reappears-particularly in the southern hemisphere in the next few months. Meanwhile, what should we do about it? We should regard it as a warning and an opportunity. The warning is that this may well be one of a series of episodes, one of which may lead to the appearance of a new epidemic human virus. The opportunity is that of testing our ability to use modern technology to produce vaccines rapidly against a new virus in the face of an impending pandemic. In the U.S.A. there are plans to vaccinate the whole population with inactivated vaccine, whether or not there is evidence of an epidemic.4 In Britain no such radical measures are proposed-for reasons discussed by Professor STUART-HARRIS on p.31. Swine antigen will be added to the vaccine which "at risk" patients will be receiving; although many are anyway old enough to have antibody, not all do and they would still be particularly at risk if infected. A small stockpile of a million or so doses of swine vaccine will also be kept, just in case we wish to vaccinate other groups in a hurry. Even though such a need may never arise, this precaution has been suggested by the World Health Organisation. Both in Britain and the U.S.A. new live attenuated
3. Pereira, M. S. Unpublished. 4. Lancet, 1976, i, 921.
W. B. Lancet,
1971,
i,
26 not needed this year, the whole exercise will be valuable practice for doing it when a really new influenza A does finally appear.
Cobalt in Severe Renal Failure GARDNER,1 SCHLEISNER,2KASANEN
et aI.,3 and the GEILL4 successfully treated anaemia of renal failure with cobalt, but all reported side-effectsnotably, anorexia, nausea, vomiting, and diarrhoea. According to GARDNER,1 these gastrointestinal symptoms were dose-related and were uncommon when the daily dose, as enteric-coated cobaltous chloride tablets, did not exceed 100 mg a day. Other possible toxic effects, in man or in laboratory
deafness,12 skin hypersensitivity,11 hypothyroidism and goitre,6-9 polycythsemia,’° vasodilatation and flushing, 12 hypotension, 11 14 changes in pancreatic islet cells, 15 cardiomyopathy,16-18 optic atrophy,t9 polyneuropathy,20 malignant tumours,21 hyperlipoemia, 22 23 2s renal diffuse interstitial pulmonary fibrosis,24 tubular damage ’20 26 and possible precipitation of angina pectoris.27 In a number of investigations, however, side-effects have been rare and slight. 10 13 28 The common factor in these may have been that the patients had normal renal function, whereas in most other series cobalt had been animals, include tinnitus,l
nerve
5
used to treat the ansemia of renal failure. Because of the gastrointestinal side-effects, cobaltous chloride has usually been prescribed as entericcoated tablets, to be taken after meals, and variation in absorption could account for some of the differences in reported toxicity. 29 A number of groups have tried the effect of 1. Gardner, F. H. J. Lab. clin. med. 1953, 41, 56. 2. Schleisner, P. Acta med. scand. 1956, 154, 177. 3. Kasanen, A., Kulonen, M., Forsström, J. Ann. Med. intern, fenn. 1963, 52, 43 4. Geill, T. Geront. clin. 1969, 11, 48. 5. Browning, E. in Toxicity of Industrial Metals; chap. 13. London, 1961. 6 Knss, J P., Carnes, W. H., Gross, R. T. J. Am. med. Ass. 1955, 157, 117. 7. Sederholm, T., Kouralainen, K., Lamberg, B. A. Acta med. scand. 1968,
184, 301. 8. Little, J. A., Sunico, R. J. Pediat. 1958, 52, 284. 9. Washburn, T. C., Kaplan, E. Clin. Pediat. 1964, 3, 89. 10. Davis, J. E., Fields, J. P. Fedn Proc. 1955, 14, 331. 11. Hopps, H. C., Stanley, A. J., Shideler, A. M. Am. J. clin. Path. 1954, 24, 1374. 12 LeGoff, J. M. J. Pharm. exp. Ther. 1930, 38, 1. 13. Perry, H. M., Schroeder, H. A. Am. J. med. Sci. 1954, 228, 396. 14 Schroeder, H. A., Perry, H. M. J. Lab. clin. Med. 1955, 46, 416. 15. Fodden, J. A. Archs Path. 1956, 61, 65. 16. Morin, Y., Daniel, P. Can med. Ass. J. 1967, 97, 926. 17. Kesteloot, H., Roelardt, J., Willems, J., Claes, H. H., Joossens, J. V. Circulation,
1968, 37, 854.
18. Sullivan, J., Parker, M., Carson, S. B. J. Lab. clin. med. 1968, 71, 893. 19. Licht, A., Oliver, M., Rachmilewitz, E. A. Isr. J. med. Sci. 1972, 8, 61. 20. Schirrmacher, V. O. E Br. med J. 1967, i, 544. 21. Heath, J. C. Br. J. Cancer, 1956, 10, 668. 22. Caplan, R. M., Curtis, A. C. J. Am. med. Ass. 1961, 176, 859. 23. Caplan, R. M., Block, W D. J. invest. Derm. 1963, 40, 199. 24. Coates, E. A., Watson, J. H. L Ann. intern. med. 1971, 75, 709. 25. Delahant, A. B. Archs ind. Hlth, 1955, 12, 116. 26. Holly, R. G. J Am. med. Ass. 1955, 158, 1349. 27. Berk, L., Burchenal, J. H., Castle, W. B. New Engl. J. Med. 1949, 240, 754. 28. Holly, R G Obstet. Gynec. 1957, 9, 299. 29. Paley, K P., Sussman, E S Metabolism, 1963, 12, 975.
a day, in patients on maintenance hxmodialysis.3o-33 BowiE and HURLEY3’ gave cobaltous chloride orally in aqueous solution, twice a day, in a total daily dose of 25 mg for the first 4 weeks and then 50 mg for a further 4 weeks. Their 14 patients had little change in haematocrit during the first 4 weeks but, after 8 weeks’ treatment, the 11 who completed the trial had a 23% increase. There was no evidence of thyroid or liver dysfunction but 3 patients had transient loss of hearing, confirmed by audiometry. Serum concentrations of cobalt, determined by atomic absorption spectrophotometry, fluctuated considerably. DucKHAM and LEE32 studied 12 anephric patients on maintenance haemodialysis and gave them enteric-coated tablets of cobaltous chloride 25-50 mg daily for 12 weeks. 6 of 8 patients who completed a course of 50 mg a day for 12 weeks had a significant rise in haemoglobin (26-70%) and then a fall to near the original levels when cobalt was withdrawn. The haemoglobin rose again in 4 patients who had a second course and in 1 patient who had a third course. The serum-cobalt concentration tended to stabilise after 2 months’ continuous therapy in the range of 40-100 µg/dl, and serum-cobalt fell rapidly when therapy was stopped. 1 patient failed to complete the course because of nausea and constipation attributed to cobalt, and 1 patient developed slight high-tone deafness during a second course of treatment, after 40 weeks of cobalt therapy. BOWIE and HURLEY31 and DUCKHAM and LEE32 conclude that cobaltous chloride has a definite place in the treatment of the refractory anaemia of chronic renal failure.
cobaltous chloride, 25-50 mg
CURTIs et al. 33 gave enteric-coated cobaltous chloride in a dose of 50 mg per day for three months to 23 patients on maintenance hæmodialysis, 8 of whom were anephric. About half had a rise in mean haemoglobin of more than 1 g/di (range 1.3-2.6). Side-effects initially seemed acceptable: 4 patients had nausea and vomiting and in 2 of them treatment was stopped. However, 1 patient died of resistant congestive cardiac failure three months after completing a course of cobalt. Suspecting a cardiomyopathy due to cobalt toxicity, CURTIs et al. measured the myocardial cobalt concentration (by neutron activation analysis) in this patient and it was 25-80 times greater than that in 2 other dialysis patients who had never received cobalt and in 2 other patients who had not had renal failure. In addition, whole-blood cobalt concentrations (neutron activation analysis) in dialysis patients who had been treated 13-20 months previously with cobalt were significantly higher than in dialysis patients who had not received 30. Edwards, M. S., Curtis, J. R. Lancet, 1971, ii, 582. 31. Bowie, E. A., Hurley, P. J. Aust. N.Z.J. Med. 1975, 5, 306. 32. Duckham, J. M., Lee, H. A. Q.Jl Med. 1976, 45, 277. 33. Curtis, J. R., Goode, G. C., Herrington, J., Urdaneta, L. E. Clin.
1976, 5, 61.
Nephrol
has been found in man does not mean that it has all the other attributes required to produce a devastating epidemic. In fact, the virus did not spread extensively-there were probably about 500 infections in the whole camp and no evidence of spread to civilians outside, even those in close contact with infected soldiers. Although there was one death the virus seemed to cause mild disease on the whole, and this week (p.4) we carry the first report of the results of inoculating the virus to volunteers-strictly isolated, of course - in whom the symptoms were also only mild. The virus was clearly capable of infecting man much more successfully than other antigenically similar viruses taken directly from pigs,2 but it seemed to be milder than a number of viruses isolated in the recent period of "drift", which have no 1918
THE LANCET Planning for Pandemics OVER the years influenza-A viruses change antigenically in a gradual way called "antigenic drift", so that the antibody stimulated by the virus of the past year or two has a reduced protective effect against this year’s virus. Nevertheless, from time to time the antigens may change radically-"antigenic shift"-and this means that antibodies against previous strains, either the antihaemagglutinin or the antineuraminidase, have no protective effect. As a result "shifted" viruses give rise to
extensive worldwide epidemics-as, for example, followed the appearance of the Asian virus with H2N2 antigens in 1957 which replaced all H1N1 strains. Such extensive epidemics are often called pandemics, though the term is usually not precisely defined-which is a pity, because it raises the thought in many minds that such a pandemic will have the characteristics of the infamous three waves of influenza which began in 1918 and which were followed by high mortality. Such thoughts were raised lately as a result of investigation of influenza-A viruses isolated at Fort Dix, an Army camp in the U.S.A. at which recruits are trained. Viruses were isolated from recruits with influenza and these were antigenically very close to the influenza-A virus found in pigs in the Middle West of the U.S.A., viruses which are also probably closely related to those which appeared in 1918, since adults who were children 1 in that year have antibody against the swine virus. This is a finding of great interest, and along with a couple of isolations of similar viruses from immunologically deficient children in the U.S.A., is apparently the first occasion on which an animal virus has been actually caught in the act of spreading from the animal to the human population. Clearly there would be no antibody to prevent it spreading in man, except in individuals 50 years of age and more. Nevertheless, experiments in animals and man have proved that the ability to cause disease is carried by viral genes separate from those determining the surface antigens; so the fact that a virus antigenically like that which caused the
pandemic
pretensions
to
being possible pandemic
being developed which will be tested in subjects, lest swine virus becomes virulent and produces major epidemics. These studies would make it possible to produce live or killed vaccine
strains
are
isolated
which could be used for a mass vaccination campaign if this were called for. Even if vaccination is 2.
Beare, A. S., Schild, G. C., Hall, T. S., Kundin, 305.
1
Wkly epidem. Rec. 1976, 51, 108.
strains. In
fact the virus seems not to have spread in the civilian population in the U.S.A. and has not been isolated in the U.K.3 It seemed to be not very good at infecting man and may have died out as a result. There will be close surveillance during the coming winters to see whether it reappears-particularly in the southern hemisphere in the next few months. Meanwhile, what should we do about it? We should regard it as a warning and an opportunity. The warning is that this may well be one of a series of episodes, one of which may lead to the appearance of a new epidemic human virus. The opportunity is that of testing our ability to use modern technology to produce vaccines rapidly against a new virus in the face of an impending pandemic. In the U.S.A. there are plans to vaccinate the whole population with inactivated vaccine, whether or not there is evidence of an epidemic.4 In Britain no such radical measures are proposed-for reasons discussed by Professor STUART-HARRIS on p.31. Swine antigen will be added to the vaccine which "at risk" patients will be receiving; although many are anyway old enough to have antibody, not all do and they would still be particularly at risk if infected. A small stockpile of a million or so doses of swine vaccine will also be kept, just in case we wish to vaccinate other groups in a hurry. Even though such a need may never arise, this precaution has been suggested by the World Health Organisation. Both in Britain and the U.S.A. new live attenuated
3. Pereira, M. S. Unpublished. 4. Lancet, 1976, i, 921.
W. B. Lancet,
1971,
i,
26 not needed this year, the whole exercise will be valuable practice for doing it when a really new influenza A does finally appear.
Cobalt in Severe Renal Failure GARDNER,1 SCHLEISNER,2KASANEN
et aI.,3 and the GEILL4 successfully treated anaemia of renal failure with cobalt, but all reported side-effectsnotably, anorexia, nausea, vomiting, and diarrhoea. According to GARDNER,1 these gastrointestinal symptoms were dose-related and were uncommon when the daily dose, as enteric-coated cobaltous chloride tablets, did not exceed 100 mg a day. Other possible toxic effects, in man or in laboratory
deafness,12 skin hypersensitivity,11 hypothyroidism and goitre,6-9 polycythsemia,’° vasodilatation and flushing, 12 hypotension, 11 14 changes in pancreatic islet cells, 15 cardiomyopathy,16-18 optic atrophy,t9 polyneuropathy,20 malignant tumours,21 hyperlipoemia, 22 23 2s renal diffuse interstitial pulmonary fibrosis,24 tubular damage ’20 26 and possible precipitation of angina pectoris.27 In a number of investigations, however, side-effects have been rare and slight. 10 13 28 The common factor in these may have been that the patients had normal renal function, whereas in most other series cobalt had been animals, include tinnitus,l
nerve
5
used to treat the ansemia of renal failure. Because of the gastrointestinal side-effects, cobaltous chloride has usually been prescribed as entericcoated tablets, to be taken after meals, and variation in absorption could account for some of the differences in reported toxicity. 29 A number of groups have tried the effect of 1. Gardner, F. H. J. Lab. clin. med. 1953, 41, 56. 2. Schleisner, P. Acta med. scand. 1956, 154, 177. 3. Kasanen, A., Kulonen, M., Forsström, J. Ann. Med. intern, fenn. 1963, 52, 43 4. Geill, T. Geront. clin. 1969, 11, 48. 5. Browning, E. in Toxicity of Industrial Metals; chap. 13. London, 1961. 6 Knss, J P., Carnes, W. H., Gross, R. T. J. Am. med. Ass. 1955, 157, 117. 7. Sederholm, T., Kouralainen, K., Lamberg, B. A. Acta med. scand. 1968,
184, 301. 8. Little, J. A., Sunico, R. J. Pediat. 1958, 52, 284. 9. Washburn, T. C., Kaplan, E. Clin. Pediat. 1964, 3, 89. 10. Davis, J. E., Fields, J. P. Fedn Proc. 1955, 14, 331. 11. Hopps, H. C., Stanley, A. J., Shideler, A. M. Am. J. clin. Path. 1954, 24, 1374. 12 LeGoff, J. M. J. Pharm. exp. Ther. 1930, 38, 1. 13. Perry, H. M., Schroeder, H. A. Am. J. med. Sci. 1954, 228, 396. 14 Schroeder, H. A., Perry, H. M. J. Lab. clin. Med. 1955, 46, 416. 15. Fodden, J. A. Archs Path. 1956, 61, 65. 16. Morin, Y., Daniel, P. Can med. Ass. J. 1967, 97, 926. 17. Kesteloot, H., Roelardt, J., Willems, J., Claes, H. H., Joossens, J. V. Circulation,
1968, 37, 854.
18. Sullivan, J., Parker, M., Carson, S. B. J. Lab. clin. med. 1968, 71, 893. 19. Licht, A., Oliver, M., Rachmilewitz, E. A. Isr. J. med. Sci. 1972, 8, 61. 20. Schirrmacher, V. O. E Br. med J. 1967, i, 544. 21. Heath, J. C. Br. J. Cancer, 1956, 10, 668. 22. Caplan, R. M., Curtis, A. C. J. Am. med. Ass. 1961, 176, 859. 23. Caplan, R. M., Block, W D. J. invest. Derm. 1963, 40, 199. 24. Coates, E. A., Watson, J. H. L Ann. intern. med. 1971, 75, 709. 25. Delahant, A. B. Archs ind. Hlth, 1955, 12, 116. 26. Holly, R. G. J Am. med. Ass. 1955, 158, 1349. 27. Berk, L., Burchenal, J. H., Castle, W. B. New Engl. J. Med. 1949, 240, 754. 28. Holly, R G Obstet. Gynec. 1957, 9, 299. 29. Paley, K P., Sussman, E S Metabolism, 1963, 12, 975.
a day, in patients on maintenance hxmodialysis.3o-33 BowiE and HURLEY3’ gave cobaltous chloride orally in aqueous solution, twice a day, in a total daily dose of 25 mg for the first 4 weeks and then 50 mg for a further 4 weeks. Their 14 patients had little change in haematocrit during the first 4 weeks but, after 8 weeks’ treatment, the 11 who completed the trial had a 23% increase. There was no evidence of thyroid or liver dysfunction but 3 patients had transient loss of hearing, confirmed by audiometry. Serum concentrations of cobalt, determined by atomic absorption spectrophotometry, fluctuated considerably. DucKHAM and LEE32 studied 12 anephric patients on maintenance haemodialysis and gave them enteric-coated tablets of cobaltous chloride 25-50 mg daily for 12 weeks. 6 of 8 patients who completed a course of 50 mg a day for 12 weeks had a significant rise in haemoglobin (26-70%) and then a fall to near the original levels when cobalt was withdrawn. The haemoglobin rose again in 4 patients who had a second course and in 1 patient who had a third course. The serum-cobalt concentration tended to stabilise after 2 months’ continuous therapy in the range of 40-100 µg/dl, and serum-cobalt fell rapidly when therapy was stopped. 1 patient failed to complete the course because of nausea and constipation attributed to cobalt, and 1 patient developed slight high-tone deafness during a second course of treatment, after 40 weeks of cobalt therapy. BOWIE and HURLEY31 and DUCKHAM and LEE32 conclude that cobaltous chloride has a definite place in the treatment of the refractory anaemia of chronic renal failure.
cobaltous chloride, 25-50 mg
CURTIs et al. 33 gave enteric-coated cobaltous chloride in a dose of 50 mg per day for three months to 23 patients on maintenance hæmodialysis, 8 of whom were anephric. About half had a rise in mean haemoglobin of more than 1 g/di (range 1.3-2.6). Side-effects initially seemed acceptable: 4 patients had nausea and vomiting and in 2 of them treatment was stopped. However, 1 patient died of resistant congestive cardiac failure three months after completing a course of cobalt. Suspecting a cardiomyopathy due to cobalt toxicity, CURTIs et al. measured the myocardial cobalt concentration (by neutron activation analysis) in this patient and it was 25-80 times greater than that in 2 other dialysis patients who had never received cobalt and in 2 other patients who had not had renal failure. In addition, whole-blood cobalt concentrations (neutron activation analysis) in dialysis patients who had been treated 13-20 months previously with cobalt were significantly higher than in dialysis patients who had not received 30. Edwards, M. S., Curtis, J. R. Lancet, 1971, ii, 582. 31. Bowie, E. A., Hurley, P. J. Aust. N.Z.J. Med. 1975, 5, 306. 32. Duckham, J. M., Lee, H. A. Q.Jl Med. 1976, 45, 277. 33. Curtis, J. R., Goode, G. C., Herrington, J., Urdaneta, L. E. Clin.
1976, 5, 61.
Nephrol
