31
by the absence of antibodies to it in a large proportion (90% or more) of the population under 50 years of age. Secondly, on three previous occasions the
indicated
Points of View
recovery from SWINE INFLUENZA VIRUS IN MAN
Zoonosis
or
Human Pandemic?
CHARLES STUART-HARRIS
Faculty of Medicine, University of Sheffield Medical School,
Sheffield S10 2RX ANNOUNCEMENTS in the United States about human infection by an influenza virus bearing the surface antigens of the Swine influenza virus of Shope and the subsequent decision to offer influenza vaccine to the population of the United States have greatly surprised British workers. The suggestion, based perhaps on circumstantial evidence linking Shope’s virus with the 1918 pandemic of influenza, that the world is now threatened by a fearful mortality on the scale of 1918 is of immense importance. Present facts and future possibilities must be examined in full so that wise decisions may be made for possible preventive action. The outbreak of influenza from which strains of virus antigenically similar to the Swine virus recovered by Shope in 1931 (Hsw1.NI) occurred in January, 1976, in a large military establishment in Fort Dix, New Jersey, concerned with the primary training of recruits.2 The outbreak was clinically typical of influenza, but a fatal pneumonia in a young serviceman aroused suspicion of an unusual event. For the first time since the recovery of human influenza virus in London,3 two influenza A viruses with entirely dissimilar antigens were recovered from different individual patients during the same outbreak. One was the A/Victoria/75 virus which was then causing widespread influenza in the United States and Europe, including Britain. The other was the virus resembling A/Swine/30 virus which was found in similar cases of influenza and in the one fatal case. No further isolations of Swine-like virus have been reported from Fort Dix after this outbreak. However, the Center for Disease Control, Atlanta, has collected evidence of certain sporadic infections in the United States, widely spaced in time and due to the same Swine-like virus, beginning with the recovery in 1974 of virus from the lung of a patient who died of Hodgkin’s disease at the Mayo Clinic.4 In this and most other sporadic cases, the patient had been in contact with swine. No direct contact with pigs was known at Fort Dix, though some of the recruits had been in contact with swine in their home environment. The total number of cases of infection by Swine-like virus at Fort Dix was estimated serologically as 500, although the camp held 12 000 persons. Thus the infection by Swine-like virus ceased long before all those who were serologically susceptible to it had been infected. The possibility of interference between the two influenza A viruses existed, but could not be evaluated. THE FUTURE
important arguments concern the likelihood of further outbreaks of influenza due to the New Jersey Swine-like virus in the United States or elsewhere. First, there is the probable human susceptibility to the virus, Two
man
of
influenza A virus with either both haemagglutinin (H) and
an
haemagglutinin (H) or neuraminidase (N) antigens having no significant relationship to those of the A virus previously current in the population has led to further epidemics or a pandemic. In 1946-47, the pace of spread of the Al (H1N1) virus was relatively slow and localised outbreaks preceded for some time the major epidemic of 1949. In 1957, the Asian A2 virus (H2N2) caused both immediate and delayed widespread explosive outbreaks throughout the world. Again, in 1968, the Hong Kong (H3N2) virus caused a similar though less extensive pandemic. Minor variants of the influenza A virus possessing some degree of antigenic overlap with previous strains of human virus have sometimes passed round the world, as exemplified by the several variants including the A/Victoria/75 derived from the A/Hong Kong strain. At other times such variants have been less successful spreaders and the B/Taiwan/62 virus caused only the one out5
break from which it was recovered. A different circumstance exists, however, in the case of the New Jersey virus. Although the origin of the virus has not been proved, its close relation to Swine influenza virus recovered in the United States from 1931 until as recently as 19736suggests that both human and swine viruses belong to the same stock. The possibility, therefore, exists that the large herds of pigs in the Middle West in which influenza occurs seasonally in the winter now harbour a virus which has become pathogenic for man both by causing sporadic cases of infection and the Fort Dix epidemic. This hidden virus reservoir in the Middle West could, therefore, give rise to further human cases of influenza and, in the presence of an adequate number of susceptible persons, might lead to a new pandemic. Against this possibility must be set the viewpoint that the Swine viruses of the Middle West may have ventured into man from time to time and thus have been the cause of previous undetected human infections without an actual epidemic. That at Fort Dix may, according to this view, be an isolated occurrence-a zoonosiswhich may not necessarily recur. Only the future will decide which of these possibilities is correct and forecasts at the present time are unreliable. What are the likely characters of a future outbreak of Swine-like virus influenza, should it occur? It has been suggested that the virus, being the progeny of a virus which may have caused the 1918 pandemic, may again cause a virulent outbreak. Even though the Fort Dix infections were clinically mild, a returning outbreak might be more lethal because the virulence of influenza virus for an animal host can be readily enhanced by laboratory passage. This view ignores the fact that in the past 40 years epidemics of human influenza have shown remarkably little variation in virulence having regard to the prevalence of the infection. Kilbourne7 indeed stated his belief that the virulence of the influenza virus in nature for man was relatively unvarying. He attributed the mortality of the 1918 epidemic to a virus producing very high morbidity-rates and to conditions favouring secondary bacterial pneumonia. Francis8 described the 1918 epidemic as a unique phenomenon, in which the mortality of people aged 20-40 was only apparently
32
excessive. Francis believed the mortality to be a reflection of the very high attack-rate upon the young adults, those of older age being spared by reason of being less susceptible, perhaps from previous encounter with a similar virus. On the other hand, many experienced bacteriologists at the time of the 1918 epidemic thought that bacterial pneumonia was not the only factor in mortality and that it was aided significantly by the action of the then unknown virus upon the lung. Mulder and Hers9 have indeed illustrated histological changes in the sterile lungs of cases of Asian influenzal pneumonia which are similar to those recorded in 1918. It would thus appear safer to regard the 1918 influenza virus as one possessing unusual pneumotropic potential rather than to blame bacteria for the havoc. The question now needing consideration is whether the Swine-like virus of the New Jersey epidemic has, or is likely in the future to acquire, an excessive pneumotropism for the human lung. The only valid grounds on which to base the answer to this question is that experience of the past 40 years of known virus epidemics and particularly that of the Asian virus whose surface antigens (H2N2) were completely different from those of its precursor (H1N1). The mortality by age in 1957-58 in the United Kingdom was primarily in the older section of the population,1O 63% of deaths were in those over 64 during the autumn epidemic and it was only in the first four weeks of this outbreak in Britain that there were numbers of deaths in younger persons, probably because the latter bore the brunt of the initial attack. There was certainly no suggestion of enhanced virulence in the second and third outbreaks in 1959 and 1961. From first to last of the original Asian pandemic, the virus remained as unchanged antigenically as in its virulence, and even the populations of the developing countries of Asia and Africa exhibited no unusual mortality from its onslaught. This experience of pandemic influenza due to a virus of antigenic composition completely different from its precursors thus gives no ground for a belief that the Swine-like virus will behave in an unusually virulent way. Nor can the human population of 1976 be regarded as analogous to that of the Western World of 1918 after 4 years of an exhausting war. THE
QUESTION
OF IMMUNISATION
Inactivated influenza vaccine is capable of affording short-term protection against an influenza virus similar antigenically to that contained in the vaccine. Its mass use has never before been advocated in an attempt to control epidemic spread in the community, partly because of doubts concerning its capacity to achieve this unless all children were also immunised. The inevitable need to repeat the inoculation one or two years later and at intervals thereafter has also been a powerful deterrent to mass use of this vaccine. The American proposal is therefore unprecedented and the outcome will be of great interest, should the New Jersey virus return. Should other countries follow suit? Canada has declared its intention to immunise those under 50, though not to offer vaccine to children because of their liability to adverse reactions. The report of a W.H.O. Advisory Group meeting" suggests that countries should strengthen their surveillance and means of detection of influenza virus in an effort to identify as early as pos-
sible a spread of the New Jersey virus. It was also recommended that the A/New Jersey/1976 virus should be added to the A/Victoria/75 and the B strain of current inactivated vaccines for the protection of those at special risk. All these steps are likely to be taken in Britain where inactivated vaccine has long been advocated for patients at special risk such as those with chronic heart, lung, kidney, and certain metabolic disorders, including diabetes. Persons with a high risk of acquiring infection such as doctors, nurses, and other health workers, children over 8 years of age and elderly persons living in residential institutions are also included. The third recommendation of the W.H.O. group was to stock-pile monovalent A/New Jersey/76 virus vaccine but the size of the stockpile and its possible use was not specified. Clearly, a stockpile suggests an emergency or strategic reserve,12 and such could be used if the maintenance of essential services was threatened by an epidemic of exceptional proportions (say, 20%). All those concerned with the maintenance of law and order, the health, power, and transport services, and so forth could then be offered vaccine. The size of such a strategic reserve need not be colossal; its use would confer individual but not mass protection. It could not be expected to prevent mortality from an exceptionally virulent epidemic and it is indeed highly questionable whether the amount of vaccine required for all those between 20 and 50 years of age should be prepared at the present time for any country, including even the United States, until the shape of things to come can be seen more clearly. Meanwhile, the preparation of a high-yielding seed virus from the New Jersey strain and the development and serological testing of inactivated vaccine in persons of different ages are matters for present action. It is not possible for manufacturers to develop "shadow" factories for the mass production of a biologically prepared vaccine without a greater degree of certainty concerning its eventual use. If ever there was a time for a continual reappraisal of all possibilities rather than for a change of tactics, this time is now. 1. Shope, R. E. Medicine, 1944, 23, 415. 2. Morbidity and Mortality Reports, Center for Disease
Control, 1976, Vol.25. no. 47, p.55. 3. Smith, W., Andrewes, C. H., Laidlow, P. P. Lancet, 1933, ii, 66. 4. Smith, T. F., Burgert, E. O. J., Dowdle, W. R., Noble, G. R., Campbell, R. J., Van Scoy, R. E. New Engl. J. Med. 1976, 294, 708. 5. Green, I. J., Hung, S. C., Yu, P. S., Lee, G. W., Pereira, H. G. Am. J. Hyg. 1964, 79, 107. 6. Nath, D. M., Rodkey, L. S., Minocha, H. C. Archs Virol. 1975, 48, 245. 7. Kilbourne, E. D. in Ciba Foundation, Study Group; no. 4; p. 58. London,
1960. 8. Francis, T. Jr., Ann. intern Med. 1953, 39, 203. 9. Mulder, J., Hers, J. F. P. Influenza. Groningen, 1972. 10. McDonald, J. C. Proc. R. Soc. Med. 1958, 51, 1016. 11. Wld Hlth Org. Wkly Epidem. Rec. 1976, 51, 123. 12. Pereira, H. G. Nature, 1976, 261, 10.
"The doctor’s money is the aspect of medicopolitical discussion which is constantly in the public news. Not the quality of medical service, not the prevention of heart disease, not the use of hospital beds, but money for the doctor, his fees and charges, it beats all the others for the number of column inches or broadcast time devoted to discussing it. By this straight test it is currently the most sensitive and important aspect of the relation between the profession and the community Money and positive social prestige are satisfactory non-aversive behaviour controls. But they are ... to a certain extent reciprocal, so far as Medicine is concerned because money is a material reward and prestige is not obviously so. The more cupidity we doctors show, the less prestige we are accorded, and vice versa. And then, the less prestige, the less professional liberty."-EARLE HACKETT, South Australian
Clinics, 1975, 7, 3.
by the absence of antibodies to it in a large proportion (90% or more) of the population under 50 years of age. Secondly, on three previous occasions the
indicated
Points of View
recovery from SWINE INFLUENZA VIRUS IN MAN
Zoonosis
or
Human Pandemic?
CHARLES STUART-HARRIS
Faculty of Medicine, University of Sheffield Medical School,
Sheffield S10 2RX ANNOUNCEMENTS in the United States about human infection by an influenza virus bearing the surface antigens of the Swine influenza virus of Shope and the subsequent decision to offer influenza vaccine to the population of the United States have greatly surprised British workers. The suggestion, based perhaps on circumstantial evidence linking Shope’s virus with the 1918 pandemic of influenza, that the world is now threatened by a fearful mortality on the scale of 1918 is of immense importance. Present facts and future possibilities must be examined in full so that wise decisions may be made for possible preventive action. The outbreak of influenza from which strains of virus antigenically similar to the Swine virus recovered by Shope in 1931 (Hsw1.NI) occurred in January, 1976, in a large military establishment in Fort Dix, New Jersey, concerned with the primary training of recruits.2 The outbreak was clinically typical of influenza, but a fatal pneumonia in a young serviceman aroused suspicion of an unusual event. For the first time since the recovery of human influenza virus in London,3 two influenza A viruses with entirely dissimilar antigens were recovered from different individual patients during the same outbreak. One was the A/Victoria/75 virus which was then causing widespread influenza in the United States and Europe, including Britain. The other was the virus resembling A/Swine/30 virus which was found in similar cases of influenza and in the one fatal case. No further isolations of Swine-like virus have been reported from Fort Dix after this outbreak. However, the Center for Disease Control, Atlanta, has collected evidence of certain sporadic infections in the United States, widely spaced in time and due to the same Swine-like virus, beginning with the recovery in 1974 of virus from the lung of a patient who died of Hodgkin’s disease at the Mayo Clinic.4 In this and most other sporadic cases, the patient had been in contact with swine. No direct contact with pigs was known at Fort Dix, though some of the recruits had been in contact with swine in their home environment. The total number of cases of infection by Swine-like virus at Fort Dix was estimated serologically as 500, although the camp held 12 000 persons. Thus the infection by Swine-like virus ceased long before all those who were serologically susceptible to it had been infected. The possibility of interference between the two influenza A viruses existed, but could not be evaluated. THE FUTURE
important arguments concern the likelihood of further outbreaks of influenza due to the New Jersey Swine-like virus in the United States or elsewhere. First, there is the probable human susceptibility to the virus, Two
man
of
influenza A virus with either both haemagglutinin (H) and
an
haemagglutinin (H) or neuraminidase (N) antigens having no significant relationship to those of the A virus previously current in the population has led to further epidemics or a pandemic. In 1946-47, the pace of spread of the Al (H1N1) virus was relatively slow and localised outbreaks preceded for some time the major epidemic of 1949. In 1957, the Asian A2 virus (H2N2) caused both immediate and delayed widespread explosive outbreaks throughout the world. Again, in 1968, the Hong Kong (H3N2) virus caused a similar though less extensive pandemic. Minor variants of the influenza A virus possessing some degree of antigenic overlap with previous strains of human virus have sometimes passed round the world, as exemplified by the several variants including the A/Victoria/75 derived from the A/Hong Kong strain. At other times such variants have been less successful spreaders and the B/Taiwan/62 virus caused only the one out5
break from which it was recovered. A different circumstance exists, however, in the case of the New Jersey virus. Although the origin of the virus has not been proved, its close relation to Swine influenza virus recovered in the United States from 1931 until as recently as 19736suggests that both human and swine viruses belong to the same stock. The possibility, therefore, exists that the large herds of pigs in the Middle West in which influenza occurs seasonally in the winter now harbour a virus which has become pathogenic for man both by causing sporadic cases of infection and the Fort Dix epidemic. This hidden virus reservoir in the Middle West could, therefore, give rise to further human cases of influenza and, in the presence of an adequate number of susceptible persons, might lead to a new pandemic. Against this possibility must be set the viewpoint that the Swine viruses of the Middle West may have ventured into man from time to time and thus have been the cause of previous undetected human infections without an actual epidemic. That at Fort Dix may, according to this view, be an isolated occurrence-a zoonosiswhich may not necessarily recur. Only the future will decide which of these possibilities is correct and forecasts at the present time are unreliable. What are the likely characters of a future outbreak of Swine-like virus influenza, should it occur? It has been suggested that the virus, being the progeny of a virus which may have caused the 1918 pandemic, may again cause a virulent outbreak. Even though the Fort Dix infections were clinically mild, a returning outbreak might be more lethal because the virulence of influenza virus for an animal host can be readily enhanced by laboratory passage. This view ignores the fact that in the past 40 years epidemics of human influenza have shown remarkably little variation in virulence having regard to the prevalence of the infection. Kilbourne7 indeed stated his belief that the virulence of the influenza virus in nature for man was relatively unvarying. He attributed the mortality of the 1918 epidemic to a virus producing very high morbidity-rates and to conditions favouring secondary bacterial pneumonia. Francis8 described the 1918 epidemic as a unique phenomenon, in which the mortality of people aged 20-40 was only apparently
32
excessive. Francis believed the mortality to be a reflection of the very high attack-rate upon the young adults, those of older age being spared by reason of being less susceptible, perhaps from previous encounter with a similar virus. On the other hand, many experienced bacteriologists at the time of the 1918 epidemic thought that bacterial pneumonia was not the only factor in mortality and that it was aided significantly by the action of the then unknown virus upon the lung. Mulder and Hers9 have indeed illustrated histological changes in the sterile lungs of cases of Asian influenzal pneumonia which are similar to those recorded in 1918. It would thus appear safer to regard the 1918 influenza virus as one possessing unusual pneumotropic potential rather than to blame bacteria for the havoc. The question now needing consideration is whether the Swine-like virus of the New Jersey epidemic has, or is likely in the future to acquire, an excessive pneumotropism for the human lung. The only valid grounds on which to base the answer to this question is that experience of the past 40 years of known virus epidemics and particularly that of the Asian virus whose surface antigens (H2N2) were completely different from those of its precursor (H1N1). The mortality by age in 1957-58 in the United Kingdom was primarily in the older section of the population,1O 63% of deaths were in those over 64 during the autumn epidemic and it was only in the first four weeks of this outbreak in Britain that there were numbers of deaths in younger persons, probably because the latter bore the brunt of the initial attack. There was certainly no suggestion of enhanced virulence in the second and third outbreaks in 1959 and 1961. From first to last of the original Asian pandemic, the virus remained as unchanged antigenically as in its virulence, and even the populations of the developing countries of Asia and Africa exhibited no unusual mortality from its onslaught. This experience of pandemic influenza due to a virus of antigenic composition completely different from its precursors thus gives no ground for a belief that the Swine-like virus will behave in an unusually virulent way. Nor can the human population of 1976 be regarded as analogous to that of the Western World of 1918 after 4 years of an exhausting war. THE
QUESTION
OF IMMUNISATION
Inactivated influenza vaccine is capable of affording short-term protection against an influenza virus similar antigenically to that contained in the vaccine. Its mass use has never before been advocated in an attempt to control epidemic spread in the community, partly because of doubts concerning its capacity to achieve this unless all children were also immunised. The inevitable need to repeat the inoculation one or two years later and at intervals thereafter has also been a powerful deterrent to mass use of this vaccine. The American proposal is therefore unprecedented and the outcome will be of great interest, should the New Jersey virus return. Should other countries follow suit? Canada has declared its intention to immunise those under 50, though not to offer vaccine to children because of their liability to adverse reactions. The report of a W.H.O. Advisory Group meeting" suggests that countries should strengthen their surveillance and means of detection of influenza virus in an effort to identify as early as pos-
sible a spread of the New Jersey virus. It was also recommended that the A/New Jersey/1976 virus should be added to the A/Victoria/75 and the B strain of current inactivated vaccines for the protection of those at special risk. All these steps are likely to be taken in Britain where inactivated vaccine has long been advocated for patients at special risk such as those with chronic heart, lung, kidney, and certain metabolic disorders, including diabetes. Persons with a high risk of acquiring infection such as doctors, nurses, and other health workers, children over 8 years of age and elderly persons living in residential institutions are also included. The third recommendation of the W.H.O. group was to stock-pile monovalent A/New Jersey/76 virus vaccine but the size of the stockpile and its possible use was not specified. Clearly, a stockpile suggests an emergency or strategic reserve,12 and such could be used if the maintenance of essential services was threatened by an epidemic of exceptional proportions (say, 20%). All those concerned with the maintenance of law and order, the health, power, and transport services, and so forth could then be offered vaccine. The size of such a strategic reserve need not be colossal; its use would confer individual but not mass protection. It could not be expected to prevent mortality from an exceptionally virulent epidemic and it is indeed highly questionable whether the amount of vaccine required for all those between 20 and 50 years of age should be prepared at the present time for any country, including even the United States, until the shape of things to come can be seen more clearly. Meanwhile, the preparation of a high-yielding seed virus from the New Jersey strain and the development and serological testing of inactivated vaccine in persons of different ages are matters for present action. It is not possible for manufacturers to develop "shadow" factories for the mass production of a biologically prepared vaccine without a greater degree of certainty concerning its eventual use. If ever there was a time for a continual reappraisal of all possibilities rather than for a change of tactics, this time is now. 1. Shope, R. E. Medicine, 1944, 23, 415. 2. Morbidity and Mortality Reports, Center for Disease
Control, 1976, Vol.25. no. 47, p.55. 3. Smith, W., Andrewes, C. H., Laidlow, P. P. Lancet, 1933, ii, 66. 4. Smith, T. F., Burgert, E. O. J., Dowdle, W. R., Noble, G. R., Campbell, R. J., Van Scoy, R. E. New Engl. J. Med. 1976, 294, 708. 5. Green, I. J., Hung, S. C., Yu, P. S., Lee, G. W., Pereira, H. G. Am. J. Hyg. 1964, 79, 107. 6. Nath, D. M., Rodkey, L. S., Minocha, H. C. Archs Virol. 1975, 48, 245. 7. Kilbourne, E. D. in Ciba Foundation, Study Group; no. 4; p. 58. London,
1960. 8. Francis, T. Jr., Ann. intern Med. 1953, 39, 203. 9. Mulder, J., Hers, J. F. P. Influenza. Groningen, 1972. 10. McDonald, J. C. Proc. R. Soc. Med. 1958, 51, 1016. 11. Wld Hlth Org. Wkly Epidem. Rec. 1976, 51, 123. 12. Pereira, H. G. Nature, 1976, 261, 10.
"The doctor’s money is the aspect of medicopolitical discussion which is constantly in the public news. Not the quality of medical service, not the prevention of heart disease, not the use of hospital beds, but money for the doctor, his fees and charges, it beats all the others for the number of column inches or broadcast time devoted to discussing it. By this straight test it is currently the most sensitive and important aspect of the relation between the profession and the community Money and positive social prestige are satisfactory non-aversive behaviour controls. But they are ... to a certain extent reciprocal, so far as Medicine is concerned because money is a material reward and prestige is not obviously so. The more cupidity we doctors show, the less prestige we are accorded, and vice versa. And then, the less prestige, the less professional liberty."-EARLE HACKETT, South Australian
Clinics, 1975, 7, 3.
