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New Ideas on Epidemic Virus Infections
LEADING
THE LANCET LONDON
New Ideas
on
19
NOVEMBER
Epidemic
1960
Virus Infections
MANY of the important epidemic virus diseases of man are transmitted directly from person to person without the intervention of an intermediate or alternate host. Of the factors which influence susceptibility, such as inherent or acquired immunity, some are quite well understood; but the factors affecting virus transmission are much less well defined. Even in such a wellstudied disease as poliomyelitis it is uncertain whether virus from the throat or from the faeces is the more important. In many respiratory infections infected secretions are probably the source of the virus, but we do not really know exactly how and where the virus reaches its next host. We would expect to find that such virus infections are more readily transmitted when people live under crowded conditions, and when standards of hygiene are low; and this seems to be true for poliomyelitis and the common acute respiratory virus infections. It is well known, however, that some virus diseases tend to become epidemic in the summer and others in the winter. ANDREWES1 has pointed out that, although Asian influenza was seeded widely in many countries by modern means of travel, yet in most places epidemics developed only when the cold season came on. Temperature could not determine the " winter factor ", for otherwise " the tropics would never get epidemics at all"; and he suggested that in winter the main change was that people were more crowded where they lived and worked-a change which applies particularly to children who go back to school in the autumn, and who often get colds then. HOPE-SIMPSON2 found an astonishingly close correspondence between increase of outdoor temperature and decrease in the number of patients who consulted him on account of colds. In another study he showed over a three-year period in a group of volunteers that there was a similar correlation between the appearance of symptoms of colds and decrease of temperature 1 ft. below the surface of the earth. He suggested that the reason for these correlations is that in cold weather we heat our rooms and thus reduce the relative humidity of the air; and he found that switching on a one-bar electric fire in an averagesize room with the window and door open reduced the relative humidity from over 80% to about 50% as the temperature rose from 20° to 30°C. This drier air, by drying the mucous membranes of the respiratory tract, 1. 2.
ARTICLES
WADDY3 may increase susceptibility to infection. earlier proposed that low absolute humidity could act in this way to aid the spread of airborne disease; and one of the illustrations he used to support his view was the influenza pandemic of 1918-19. Nevertheless, when volunteers are inoculated with cold viruses at a
wide range of humidities and temperatures the frequency with which colds develop does not seem to
vary.45 Polioviruses, by
contrast, are more prevalent in the later summer months; and the explanations of this have run on the same lines as those of changes in the prevalence of other infectious agents found in the fæcesi.e., greater frequency of faecal-feeding flies, and the larger consumption of uncooked food. These factors must be assumed to overcome the effect of larger amounts of light and higher temperatures, which would tend to reduce the amount of surviving virus. Humidity is not generally regarded as an important influence on the transmission of polioviruses. Laboratory experiments by HEMMES et al.6s in Utrecht may cause us to revise our thinking, and may reconcile some apparent conflicts. These workers prepared from virus suspensions aerosols which they held in a closed system, measuring the rate at which virus infectivity was lost. Temperature and absolute humidity had little effect on this rate; but it was strongly influenced by relative humidity, and there seemed to be a sharp distinction between results obtained at a relative humidity of 40% or lower and one of 50% or higher. In the case of influenza virus (PR8 strain) inactivation of infectivity was slow in the drier conditions and over 10 times more rapid in the moister conditions. The reverse held for a strain of poliovirus type 1, which survived well at relative humidities above 50%, but which at 40% or lower was inactivated so quickly that no virus could be recovered from an aerosol 30 seconds after spraying. Experiments of this sort have many technical snags: some of the aerosol may be lost on the wall of the container, and the composition of the suspending medium or the medium in which samples were collected may greatly affect the survival of viruses. But it is very unlikely that such technical difficulties would alter the relatively greater rate of inactivation of influenza virus in humid air and of poliomyelitis in drier air. In fact the observations with influenza have been confirmed independently7 in experiments conducted by a somewhat different technique. HEMMES et al. point to the correlation between low indoor relative humidity and increased prevalence of influenza, and between high indoor humidity and increased prevalence of poliomyelitis. Their calculations suggest that in the colder months the relative humidity indoors drops below the critical zone of 40-50% which was found in their experiments. Their hypothesis, then, is that seasonal variations in the
6.
Waddy, B. B. Lancet, 1952, ii, 674. Andrewes, C. H. ibid. 1949, i, 71. Dowling, H. F., Jackson, G. G., Spiesman, I. G., Inouye, T. Amer. J. Hyg. 1958, 66, 59. Hemmes, J. H., Winkler, K. C., Kool, S. M. Nature, Lond. 1960, 188,
7.
Harper,
3. 4. 5.
Andrewes, C. H. J. roy. Soc. Hlth, 1958, 78, 533.
Hope-Simpson,
R. E. ibid. p. 593.
1125
430.
G. L.
Unpublished.
1126
exophthalmos, while the otherfound some evidence suggesting that T.s.H. might occasionally be increased with severe exophthalmos. ADAMS and PunvES8 pointed out that T.s.H. is normally present in high concentration This hypothesis has the great virtue that it can be in the serum of patients with myxoedema and that it is readily tested. Many different viruses are now known suppressed by treatment with thyroid hormone. They suggested that the presence of normal amounts in the to cause respiratory disease in winter; while many other members of the enterovirus group tend, like polio- serum of thyrotoxic patients is surprising and may viruses, to be found in summer. It should not be indicate a failure in the mechanism for its suppression-
of these two virus infections result from variations in the relative humidity indoors, which in turn affect the chances of survival of the viruses in the dried state.
prevalence
difficult to compare the survival of some of these viruses at high and low relative humidities with the known facts of their epidemiology, and thus to substantiate or refute this interesting suggestion.
Endocrine
Exophthalmos
failure that may be the cause of Graves’ disease. There is no good evidence, however, that T.S.H. is the cause of exophthalmos. In 1954 DOBYNS and WILSON,9 using the minnow, demonstrated E.p.s. in the serum of 6 patients with exophthalmos and suggested that the degree of response in the fish was correlated with the severity of the exophthalmos. This work has been extended by MCGILL 10 using the goldfish, Carassium auratus, and by DER KINDEREN et al.11 using the carp, Cyprinus carpio. Both groups developed reasonably satisfactory quantitative procedures and found evidence suggesting that the active principle causing exophthalmos was the same in serum and in pituitary extracts. They both examined the serum from a large series of people and detected an abnormally high level in patients with progressing exophthalmos, a normal level in those with stationary or regressing exophthalmos or with myxoedema, and a low level in those with pituitary failure. There is therefore clinical evidence to support the claim that exophthalmos is caused by increased secretion of E.P.S.
a
exophthalmos associated with Graves’ disease is commonly of minor importance compared with the thyrotoxicosis: it is usually mild and rarely accompanied by paralysis of the external ocular muscles. By contrast, in the exophthalmos associated with exophthalmic ophthalmoplegia,l thyrotoxicosis is usually mild or has been relieved by treatment or replaced by frank myxoedema, but the paralysis of external ocular muscles is often pronounced and may become complete and vision may be jeopardised by secondary infection or vascular thrombosis. These two clinically different types have been termed thyrotoxic and thyrotrophic exophthalmos respectively, implying that the former results from increased secretion of thyroid hormone and the latter from increased secretion of thyroid-stimulating hormone RUNDLE and POCHIN 12 and DOBYNS 13 showed that (T.S.H.). These terms are wholly misleading since every of the eyeball is the result of an increase in gradation between the two syndromes can be found, the protrusion the bulk of the retrobulbar tissues. The amount of fat pathological anatomy is essentially the same, and there in the fat depots is much increased, and the extraocular is no evidence that increased secretion of either the muscles are greatly enlarged and their fat content may thyroid hormone or T.s.H. plays a major part. There is, be doubled. DOBYNS claimed that in the laboratory however, experimental evidence that exophthalmos is animal the fat is is and infiltrated unusually gelatinous produced more easily in the hypothyroid animal 2-- with leucocytes, lymphocytes, and tissue macrophages; an observation which may be relevant to the severity and the amount of fat in the muscles is closely correlated of eye signs in exophthalmic ophthalmoplegia and their with muscular weakness. Similar but less severe changes mildness in Graves’ disease. may affect skeletal and cardiac muscle; and large amounts The principal agent responsible for experimental of fat are found in the liver, kidneys, and epithelium proptosis was found to be present in extracts of pituitary besides large phagocytic cells in the lungs, spleen, and tissue,34 and in 1953 DOBYNS and STEELMAN5 separated lymphnodes. Evidently the effect of E.p.s. is widespread, the exophthalmos-producing substance (E.P.S.) from and indeed it is highly improbable that the pituitary T.S.H. by differential solubility in trichloracetic acid. gland would produce a hormone which specifically They tested it by its capacity to produce exophthalmos caused exophthalmos. It is more likely, as MCGILL in the minnow, Fundulus heteroclitus. Clinical evidence suggests, to be a general metabolic hormone, possibly in support of the experimental work has been accumuinfluencing water partition in fat deposits, and giving lating. In 1956 two groups 6described their work on rise to ocular protrusion only when secreted in the measurement of T.S.H. in serum in a total of 35 THE
excess.
patients with thyrotoxicosis or exophthalmic ophthalmoplegia. They used different techniques, and their results at best were only semiquantitative. Both groups were generally able to detect T.s.H. in the serum of their patients: onefound no correlation with the degree of 1. 2. 3. 4. 5. 6. 7.
Brain, W. R. Lancet, 1936, i, 182. Marine, D., Rosen, S. H. Amer. J. med Sci. 1934, 188, 565. Loeb, L., Friedman, H. Proc. Soc. exp. Biol., N.Y. 1931, 29, 648. Shockaert, J. A. ibid. p. 306. Dobyns, B. M., Steelman, S. L. Endocrinology, 1953, 52, 705. Querido, A., Lameyer, L. D. F. Proc. R. Soc. Med. 1956, 49, 209. Gilliland, I. C. ibid. p. 212.
The treatment of endocrine exophthalmos has been reviewed by BRAIN.14 No specific endocrine therapy has been proved to be uniformly effective. Œstrogens and thyroid extract have been tried extensively, but 8. Adams, D. D., Purves, H. D. Metabolism, 1957, 6, 26. 9. Dobyns, B. M., Wilson, L. A. J. clin. Endocrin. 1954, 14, 1393. 10. McGill, D. A. Quart. J. Med. 1960, 29, 423. 11. der Kinderen, P. J., Houtstra-Lanz, M., Schwarz, F. J. clin. Endocrin. 1960, 20, 712. 12. Rundle, F. F., Pochin, E. E. Clin. Sci. 1944, 5, 51. 13. Dobyns, B. M. Surg. Gynec. Obstet. 1946, 82, 609. 14. Brain, W. R. Lancet, 1959, i, 109.
THE LANCET LONDON
New Ideas
on
19
NOVEMBER
Epidemic
1960
Virus Infections
MANY of the important epidemic virus diseases of man are transmitted directly from person to person without the intervention of an intermediate or alternate host. Of the factors which influence susceptibility, such as inherent or acquired immunity, some are quite well understood; but the factors affecting virus transmission are much less well defined. Even in such a wellstudied disease as poliomyelitis it is uncertain whether virus from the throat or from the faeces is the more important. In many respiratory infections infected secretions are probably the source of the virus, but we do not really know exactly how and where the virus reaches its next host. We would expect to find that such virus infections are more readily transmitted when people live under crowded conditions, and when standards of hygiene are low; and this seems to be true for poliomyelitis and the common acute respiratory virus infections. It is well known, however, that some virus diseases tend to become epidemic in the summer and others in the winter. ANDREWES1 has pointed out that, although Asian influenza was seeded widely in many countries by modern means of travel, yet in most places epidemics developed only when the cold season came on. Temperature could not determine the " winter factor ", for otherwise " the tropics would never get epidemics at all"; and he suggested that in winter the main change was that people were more crowded where they lived and worked-a change which applies particularly to children who go back to school in the autumn, and who often get colds then. HOPE-SIMPSON2 found an astonishingly close correspondence between increase of outdoor temperature and decrease in the number of patients who consulted him on account of colds. In another study he showed over a three-year period in a group of volunteers that there was a similar correlation between the appearance of symptoms of colds and decrease of temperature 1 ft. below the surface of the earth. He suggested that the reason for these correlations is that in cold weather we heat our rooms and thus reduce the relative humidity of the air; and he found that switching on a one-bar electric fire in an averagesize room with the window and door open reduced the relative humidity from over 80% to about 50% as the temperature rose from 20° to 30°C. This drier air, by drying the mucous membranes of the respiratory tract, 1. 2.
ARTICLES
WADDY3 may increase susceptibility to infection. earlier proposed that low absolute humidity could act in this way to aid the spread of airborne disease; and one of the illustrations he used to support his view was the influenza pandemic of 1918-19. Nevertheless, when volunteers are inoculated with cold viruses at a
wide range of humidities and temperatures the frequency with which colds develop does not seem to
vary.45 Polioviruses, by
contrast, are more prevalent in the later summer months; and the explanations of this have run on the same lines as those of changes in the prevalence of other infectious agents found in the fæcesi.e., greater frequency of faecal-feeding flies, and the larger consumption of uncooked food. These factors must be assumed to overcome the effect of larger amounts of light and higher temperatures, which would tend to reduce the amount of surviving virus. Humidity is not generally regarded as an important influence on the transmission of polioviruses. Laboratory experiments by HEMMES et al.6s in Utrecht may cause us to revise our thinking, and may reconcile some apparent conflicts. These workers prepared from virus suspensions aerosols which they held in a closed system, measuring the rate at which virus infectivity was lost. Temperature and absolute humidity had little effect on this rate; but it was strongly influenced by relative humidity, and there seemed to be a sharp distinction between results obtained at a relative humidity of 40% or lower and one of 50% or higher. In the case of influenza virus (PR8 strain) inactivation of infectivity was slow in the drier conditions and over 10 times more rapid in the moister conditions. The reverse held for a strain of poliovirus type 1, which survived well at relative humidities above 50%, but which at 40% or lower was inactivated so quickly that no virus could be recovered from an aerosol 30 seconds after spraying. Experiments of this sort have many technical snags: some of the aerosol may be lost on the wall of the container, and the composition of the suspending medium or the medium in which samples were collected may greatly affect the survival of viruses. But it is very unlikely that such technical difficulties would alter the relatively greater rate of inactivation of influenza virus in humid air and of poliomyelitis in drier air. In fact the observations with influenza have been confirmed independently7 in experiments conducted by a somewhat different technique. HEMMES et al. point to the correlation between low indoor relative humidity and increased prevalence of influenza, and between high indoor humidity and increased prevalence of poliomyelitis. Their calculations suggest that in the colder months the relative humidity indoors drops below the critical zone of 40-50% which was found in their experiments. Their hypothesis, then, is that seasonal variations in the
6.
Waddy, B. B. Lancet, 1952, ii, 674. Andrewes, C. H. ibid. 1949, i, 71. Dowling, H. F., Jackson, G. G., Spiesman, I. G., Inouye, T. Amer. J. Hyg. 1958, 66, 59. Hemmes, J. H., Winkler, K. C., Kool, S. M. Nature, Lond. 1960, 188,
7.
Harper,
3. 4. 5.
Andrewes, C. H. J. roy. Soc. Hlth, 1958, 78, 533.
Hope-Simpson,
R. E. ibid. p. 593.
1125
430.
G. L.
Unpublished.
1126
exophthalmos, while the otherfound some evidence suggesting that T.s.H. might occasionally be increased with severe exophthalmos. ADAMS and PunvES8 pointed out that T.s.H. is normally present in high concentration This hypothesis has the great virtue that it can be in the serum of patients with myxoedema and that it is readily tested. Many different viruses are now known suppressed by treatment with thyroid hormone. They suggested that the presence of normal amounts in the to cause respiratory disease in winter; while many other members of the enterovirus group tend, like polio- serum of thyrotoxic patients is surprising and may viruses, to be found in summer. It should not be indicate a failure in the mechanism for its suppression-
of these two virus infections result from variations in the relative humidity indoors, which in turn affect the chances of survival of the viruses in the dried state.
prevalence
difficult to compare the survival of some of these viruses at high and low relative humidities with the known facts of their epidemiology, and thus to substantiate or refute this interesting suggestion.
Endocrine
Exophthalmos
failure that may be the cause of Graves’ disease. There is no good evidence, however, that T.S.H. is the cause of exophthalmos. In 1954 DOBYNS and WILSON,9 using the minnow, demonstrated E.p.s. in the serum of 6 patients with exophthalmos and suggested that the degree of response in the fish was correlated with the severity of the exophthalmos. This work has been extended by MCGILL 10 using the goldfish, Carassium auratus, and by DER KINDEREN et al.11 using the carp, Cyprinus carpio. Both groups developed reasonably satisfactory quantitative procedures and found evidence suggesting that the active principle causing exophthalmos was the same in serum and in pituitary extracts. They both examined the serum from a large series of people and detected an abnormally high level in patients with progressing exophthalmos, a normal level in those with stationary or regressing exophthalmos or with myxoedema, and a low level in those with pituitary failure. There is therefore clinical evidence to support the claim that exophthalmos is caused by increased secretion of E.P.S.
a
exophthalmos associated with Graves’ disease is commonly of minor importance compared with the thyrotoxicosis: it is usually mild and rarely accompanied by paralysis of the external ocular muscles. By contrast, in the exophthalmos associated with exophthalmic ophthalmoplegia,l thyrotoxicosis is usually mild or has been relieved by treatment or replaced by frank myxoedema, but the paralysis of external ocular muscles is often pronounced and may become complete and vision may be jeopardised by secondary infection or vascular thrombosis. These two clinically different types have been termed thyrotoxic and thyrotrophic exophthalmos respectively, implying that the former results from increased secretion of thyroid hormone and the latter from increased secretion of thyroid-stimulating hormone RUNDLE and POCHIN 12 and DOBYNS 13 showed that (T.S.H.). These terms are wholly misleading since every of the eyeball is the result of an increase in gradation between the two syndromes can be found, the protrusion the bulk of the retrobulbar tissues. The amount of fat pathological anatomy is essentially the same, and there in the fat depots is much increased, and the extraocular is no evidence that increased secretion of either the muscles are greatly enlarged and their fat content may thyroid hormone or T.s.H. plays a major part. There is, be doubled. DOBYNS claimed that in the laboratory however, experimental evidence that exophthalmos is animal the fat is is and infiltrated unusually gelatinous produced more easily in the hypothyroid animal 2-- with leucocytes, lymphocytes, and tissue macrophages; an observation which may be relevant to the severity and the amount of fat in the muscles is closely correlated of eye signs in exophthalmic ophthalmoplegia and their with muscular weakness. Similar but less severe changes mildness in Graves’ disease. may affect skeletal and cardiac muscle; and large amounts The principal agent responsible for experimental of fat are found in the liver, kidneys, and epithelium proptosis was found to be present in extracts of pituitary besides large phagocytic cells in the lungs, spleen, and tissue,34 and in 1953 DOBYNS and STEELMAN5 separated lymphnodes. Evidently the effect of E.p.s. is widespread, the exophthalmos-producing substance (E.P.S.) from and indeed it is highly improbable that the pituitary T.S.H. by differential solubility in trichloracetic acid. gland would produce a hormone which specifically They tested it by its capacity to produce exophthalmos caused exophthalmos. It is more likely, as MCGILL in the minnow, Fundulus heteroclitus. Clinical evidence suggests, to be a general metabolic hormone, possibly in support of the experimental work has been accumuinfluencing water partition in fat deposits, and giving lating. In 1956 two groups 6described their work on rise to ocular protrusion only when secreted in the measurement of T.S.H. in serum in a total of 35 THE
excess.
patients with thyrotoxicosis or exophthalmic ophthalmoplegia. They used different techniques, and their results at best were only semiquantitative. Both groups were generally able to detect T.s.H. in the serum of their patients: onefound no correlation with the degree of 1. 2. 3. 4. 5. 6. 7.
Brain, W. R. Lancet, 1936, i, 182. Marine, D., Rosen, S. H. Amer. J. med Sci. 1934, 188, 565. Loeb, L., Friedman, H. Proc. Soc. exp. Biol., N.Y. 1931, 29, 648. Shockaert, J. A. ibid. p. 306. Dobyns, B. M., Steelman, S. L. Endocrinology, 1953, 52, 705. Querido, A., Lameyer, L. D. F. Proc. R. Soc. Med. 1956, 49, 209. Gilliland, I. C. ibid. p. 212.
The treatment of endocrine exophthalmos has been reviewed by BRAIN.14 No specific endocrine therapy has been proved to be uniformly effective. Œstrogens and thyroid extract have been tried extensively, but 8. Adams, D. D., Purves, H. D. Metabolism, 1957, 6, 26. 9. Dobyns, B. M., Wilson, L. A. J. clin. Endocrin. 1954, 14, 1393. 10. McGill, D. A. Quart. J. Med. 1960, 29, 423. 11. der Kinderen, P. J., Houtstra-Lanz, M., Schwarz, F. J. clin. Endocrin. 1960, 20, 712. 12. Rundle, F. F., Pochin, E. E. Clin. Sci. 1944, 5, 51. 13. Dobyns, B. M. Surg. Gynec. Obstet. 1946, 82, 609. 14. Brain, W. R. Lancet, 1959, i, 109.