98 LIVE VARICELLA VACCINE
that barometric pressure is increased in humid weather. Pressure is usually low in such conditions, and therefore this cannot be accepted as an explanation of the association between arthritic pain and humid weather. Hairmyres Hospital, East Kilbride, Glasgow G75 8RG.
SIR,-The administration of a live varicella vaccine to children at this point in time appears to be ill advised. The statement of Dr Takahashi and his colleagues (Nov. 30, p. 1288) that " an attenuated vaccine virus is unlikely to become virulent and cause herpes zoster " is unsupported by data. At present, there is insufficient knowledge concerning the factors which modulate virus latency to intelligently select virus strains for vaccine production. There is no information to suggest, for instance, that viral genes for " attenuation " are linked with those determining persistent infection. Efficacy of any vaccine is judged by comparing the morbidity produced by the natural illness with that resulting from the vaccine. Varicella is usually a relatively mild disease in normal children. As the authors indicate, it can be rather severe in certain types of patients. These patients, however, are usually readily identifiable and can be protected by passive immunisation with zoster immune globulin. During the past decade there have been only approximately 130 deaths annually resulting from varicellai.e., about 4 per 100,000 cases in the United States. It would appear, therefore, that the morbidity produced by varicella is minimal and there exists a means for decreasing it even further. In assessing the morbidity resulting from a live vaccine, one must determine the incidence and severity of zoster as well as varicella. Since there is no way of predicting whether a given vaccine strain might produce zoster more frequently or in a more severe form than the natural disease, one can only carry out the experiment and observe the results. Since zoster usually occurs decades after varicella, the investigators may never learn the outcome of their experiment. One wonders, considering the mildness of varicella and the existing alternative methods of modification, whether the vaccine is worth the trouble and the risk.
B. A. WOODGER.
ASSESSMENT OF THE APGAR SCORE SIR,-Mr Chamberlain and Mr Bank (Nov. 23, p. 1225) have demonstrated courage in their studies of the importance of the various components of the Apgar score. Our own studies showed that the immediate newborn tends to have heart-rates either below 104 or above 144 beats per minute. Since the latter group represents those newborns who have taken their first breath, we likewise concluded that the heart-rate should be given much more emphasis in the evaluation of the immediate newborn infant. In addition to the Apgar score, we would favour the development of a scoring system for the newborn infant’s heart-rate which would discern specific temporal patterns for interpretation. Such a score would be a logical continuation of our present internal and external fetal monitoring. We hope clinicians and investigators will undertake studies similar to those of Mr Chamberlain and Mr Bank. Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, California 95128, U.S.A.
ROBERT C. GOODLIN JAMES R. HARROD.
RATES OF XYY GENOTYPE IN PENAL AND MENTAL SETTINGS
SIR,-Your editorial (Nov. 30, p. 1297) on the XYY male suggests that those detained in maximum-security hospitals do not manifest one end of a continuous spectrum of behavioural problems associated with the genotype, and cites, in support, studies of various delinquent groups, unselected for mental illness or retardation, in which relatively low rates of XYY men were found. While the rates are lower in such exclusively penal settings than in mental-penal settings, they are, however, still higher than the background newborn rate of about 1/900 to 1/1000. In data reviewed at the end of 1972,1 there were 5805 males (unselected for height) in 16 exclusively penal settings who had been studied; 26 XYYs were found yielding a rate of 1/225 affected, about four times " background ". In those five settings studied in the United Kingdom there were 7 XYYs in 2613 males or about 1 in 375 affected. Of interest, the rate of XXY Klinefelter males was also increased over the newborn rate of this genotype (about 1/900) in these institutions but not to the same extent. There were 18 XYYs in all 16 settings (1/322), 5 in the U.K. studies (1/522). (With regard to exclusively mental settings-e.g., mental hospitals without a security requirement-in 2526 males in such 9 settings were there 8 XYYs [1/316] and 10 XXYs [1/253].) These data do not " support the absence of spectrum " of behavioural for either genotype. The 1% risk of an XYY difficulty eventually appearing in a mental-penal setting calculated in your editorial cannot be assumed to be the entire measure of the increased likelihood of future behavioural problems.
New York University Medical Center, 550 First Avenue, New York, New York 10016, U.S.A.
% * Some of the points raised by Dr. Brunell were discussed in an editorial (Nov. 30, p. 1300).-ED. L. SiR,—The report by Takahashi et al.1 on the use of a live varicella-zoster virus vaccine was thought-provoking. While in theory the conquest of viral diseases probably lies in the development of attenuated live-virus vaccines, the effect of this particular vaccine is questionable for a number of reasons. It is unclear whether the vaccine was attenuated or even specifically immunogenic, because of the circumstances under which the vaccine was given. The children who were already immune to varicella were not eliminated from the study group by appropriate serological testing. Neither
history
Birth Defects Institute, New York State Department of ’
Health, Albany, New York 12237, U.S.A., and Department of Pediatrics, Albany Medical College.
ERNEST B. HOOK.
Hook, E. B. Science, 1973, 179, 139.
nor
complement-fixation
tests
are
adequate
to
determine immune status to varicella.2 If the vaccine were administered to immune children one might expect a boost in antibody titre and no evidence of clinical illness. Furthermore, of the 23 immunised children, 2 developed evidence of varicella and it is unclear whether the disease was due to their exposure to chickenpox or to the vaccinaSince not all immunocompromised tion they received. children who contract varicella become severely ill, one cannot conclude that the disease was vaccine-induced because it was mild. In addition, because it is not possible to separate varicella-zoster virus from cell proteins, anti1. 2.
1.
PHILIP A. BRUNELL.
Takahashi, M., Otsuka, T., Okuno, Y., Asano, Y., Yazaki, T., Isomura, S. Lancet, 1974, ii, 1288. Williams, V., Gershon, A., Brunell, P. A. J. infect. Dis. 1974, 130, 669.
99 cell antibodies may appear after immunisation with virus in tissue-culture. Such antibodies would be difficult to distinguish from antiviral antibodies. Until a varicella-zoster vaccine has been used in proven susceptibles and a persistent specific immune response can be documented, it is difficult to assess the effect of vaccination against varicella. Meanwhile zoster immune globulin can be used to protect high-risk susceptibles who are inadvertently exposed to varicella; this preparation is effective and non-toxic.3
COUNTER ELECTROPHORESIS AND DETECTION OF VIRUSES
propagated
Department of Pediatrics, New York University Medical Center, 550 First Avenue, New York, N.Y. 10016, U.S.A.
ANNE A. GERSHON.
HUMAN PLACENTAL LACTOGEN AND FETAL ABNORMALITY
SIR,-Your editorial on microbial antigen detection (July 20, p. 138) and the letters by Balfour and Edelman (Nov. 23, p. 1267) and by Churdboonchart and others (Oct. 5, p. 841) indicated the general usefulness of counter electrophoresis (c.E.P.). For several years we have been engaged in field studies of the California encephalitis virus (c.E.v.) group of arboviruses, using standard arbovirus techniques. 1,2 As an adjunct to the complement-fixation (c.F.) test we have used C.E.P. to identify c.E.v. isolates and to screen sentinel animal sera for C.E.v. antibody.3 We are in general agreement with Balfour and Edelman that rabbit antiserum to C.E.V. is more homotypic than hyperimmune mouse ascitic fluid. Our experience is that hamster antiserum to c.E.v. is more BLIND STUDY FOR DETECTION OF C.E.V.
(KEYSTONE AR 5241)
BY
S.C.E.P.
Gau and Dr Cadle
SIR,-Dr (Sept. 28, p. 775) suggest that low serum-human-placental-lactogen (H.P.L.) levels may be associated with fetal congenital anomalies. This is in contrast to the data from Singer et al. and Spellacy et a!.5 By expanding the series, it has been possible to measure serum-H.p.L. levels in 113 serum samples from
homotypic than rabbit antiserum and is therefore superior for subtyping c.E.v. isolates by the C.E.P. technique. For screening sentinel animal sera for antibody to C.E.V. we recommend use of local c.E.v. isolates plus the c.E.v. prototype BFS-283 which has wide cross-reactivity with antisera to other C.E.v. subtypes. We have modified the C.E.P. technique by conducting a second electrophoresis using antiglobulin specific for the globulin of the species used as a source of the c.E.v. antibody. This antiglobulin is placed in the antibody (anodal) well and a second electrophoresis conducted. This technique increases the sensitivity of the test, since weak precipitin reactions that do not produce a visible line of precipitate may now be displayed by sandwiching " the antiglobulin to the invisible antigen-antibody complex. Using this " sandwich " counter electrophoresis (S.C.E.P.) we have been able to detect circulating c.E.v. (Keystone AR 5241) in virsemic rabbits and hamsters, in positive wild mosquito pools, and in single mosquitoes infected in the laboratory. In our evaluation of this technique we conducted a blind study, giving the technologist who conducted "
H.P.L. levels in 113 serum samples taken during normal gestations of fetuses with congenital anomalies.
with
normal pregnancy but where the fetus had a congenital anomaly (see accompanying figure). The results did not differ from the values obtained when the fetus was normal.H.P.L. is correlated with fetal weight and, therefore, small infants resulting from congenital anomalies may have proportionately low H.P.L. values.s It seems from this expanded series that H.P.L. is not useful for diagnosing fetal congenital anomalies and that the maternal serum values are generally not lowered by the fetal abnormality.
women
a
Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida 32610, U.S.A. 3.
W. N. SPELLACY.
Gershon, A., Steinberg, S., Brunell, P. A. New Engl. J. Med., 1974, 290, 243. 4. Singer, W., Desjardins, P., Friesen, H. G. Obstet. Gynec. 1970, 36, 222. 5. Spellacy, W. N., Buhi, W. C., Schram, J. D., Birk, S. A., McCreary, S. A. ibid. 1971, 37, 567. 6. Spellacy, W. N. Clin. Perinatol. 1974, 1, 65.
S.C.E.P. coded specimens some of which contained virus determined by suckling-mouse isolation and other specimens that were negative by suckling-mouse isolation
the as
(see accompanying table). Of the 62 coded test specimens 33 were positive for c.E.v. AR 5241) by suckling-mouse isolation and 28 of these 33 were identified as positive by S.C.E.P. Of the 29 coded specimens negative for c.E.v. (Keystone AR 5241) by suckling-mouse isolation 28 were identified as negative by S.C.E.P. This indicates a sensitivity of 81-8°o and a specificity of 96-5°o for S.c.E.P. compared to suckling-mouse isolation. We have also demonstrated that group-A arboviruses (Western, Eastern, and Venezuelan equine encephalitis), group-B arboviruses (St. Louis encephalitis), and the rhabdoviruses (Hart Park and Flanders) give c.E.P. reactions in homologous antigen-antibody systems.
(Keystone
Kokemot, R. H., Hayes, J., Boyd, K. R., Sullivan, P. S. J. med. Entomol. 1974, 11, 419. 2. McLerran, J., Arlinghouse, R. Virology, 1973, 53, 247. 3. Gocke, D., Howe, J. Immunology, 1970, 104, 1031. 1.
that barometric pressure is increased in humid weather. Pressure is usually low in such conditions, and therefore this cannot be accepted as an explanation of the association between arthritic pain and humid weather. Hairmyres Hospital, East Kilbride, Glasgow G75 8RG.
SIR,-The administration of a live varicella vaccine to children at this point in time appears to be ill advised. The statement of Dr Takahashi and his colleagues (Nov. 30, p. 1288) that " an attenuated vaccine virus is unlikely to become virulent and cause herpes zoster " is unsupported by data. At present, there is insufficient knowledge concerning the factors which modulate virus latency to intelligently select virus strains for vaccine production. There is no information to suggest, for instance, that viral genes for " attenuation " are linked with those determining persistent infection. Efficacy of any vaccine is judged by comparing the morbidity produced by the natural illness with that resulting from the vaccine. Varicella is usually a relatively mild disease in normal children. As the authors indicate, it can be rather severe in certain types of patients. These patients, however, are usually readily identifiable and can be protected by passive immunisation with zoster immune globulin. During the past decade there have been only approximately 130 deaths annually resulting from varicellai.e., about 4 per 100,000 cases in the United States. It would appear, therefore, that the morbidity produced by varicella is minimal and there exists a means for decreasing it even further. In assessing the morbidity resulting from a live vaccine, one must determine the incidence and severity of zoster as well as varicella. Since there is no way of predicting whether a given vaccine strain might produce zoster more frequently or in a more severe form than the natural disease, one can only carry out the experiment and observe the results. Since zoster usually occurs decades after varicella, the investigators may never learn the outcome of their experiment. One wonders, considering the mildness of varicella and the existing alternative methods of modification, whether the vaccine is worth the trouble and the risk.
B. A. WOODGER.
ASSESSMENT OF THE APGAR SCORE SIR,-Mr Chamberlain and Mr Bank (Nov. 23, p. 1225) have demonstrated courage in their studies of the importance of the various components of the Apgar score. Our own studies showed that the immediate newborn tends to have heart-rates either below 104 or above 144 beats per minute. Since the latter group represents those newborns who have taken their first breath, we likewise concluded that the heart-rate should be given much more emphasis in the evaluation of the immediate newborn infant. In addition to the Apgar score, we would favour the development of a scoring system for the newborn infant’s heart-rate which would discern specific temporal patterns for interpretation. Such a score would be a logical continuation of our present internal and external fetal monitoring. We hope clinicians and investigators will undertake studies similar to those of Mr Chamberlain and Mr Bank. Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, California 95128, U.S.A.
ROBERT C. GOODLIN JAMES R. HARROD.
RATES OF XYY GENOTYPE IN PENAL AND MENTAL SETTINGS
SIR,-Your editorial (Nov. 30, p. 1297) on the XYY male suggests that those detained in maximum-security hospitals do not manifest one end of a continuous spectrum of behavioural problems associated with the genotype, and cites, in support, studies of various delinquent groups, unselected for mental illness or retardation, in which relatively low rates of XYY men were found. While the rates are lower in such exclusively penal settings than in mental-penal settings, they are, however, still higher than the background newborn rate of about 1/900 to 1/1000. In data reviewed at the end of 1972,1 there were 5805 males (unselected for height) in 16 exclusively penal settings who had been studied; 26 XYYs were found yielding a rate of 1/225 affected, about four times " background ". In those five settings studied in the United Kingdom there were 7 XYYs in 2613 males or about 1 in 375 affected. Of interest, the rate of XXY Klinefelter males was also increased over the newborn rate of this genotype (about 1/900) in these institutions but not to the same extent. There were 18 XYYs in all 16 settings (1/322), 5 in the U.K. studies (1/522). (With regard to exclusively mental settings-e.g., mental hospitals without a security requirement-in 2526 males in such 9 settings were there 8 XYYs [1/316] and 10 XXYs [1/253].) These data do not " support the absence of spectrum " of behavioural for either genotype. The 1% risk of an XYY difficulty eventually appearing in a mental-penal setting calculated in your editorial cannot be assumed to be the entire measure of the increased likelihood of future behavioural problems.
New York University Medical Center, 550 First Avenue, New York, New York 10016, U.S.A.
% * Some of the points raised by Dr. Brunell were discussed in an editorial (Nov. 30, p. 1300).-ED. L. SiR,—The report by Takahashi et al.1 on the use of a live varicella-zoster virus vaccine was thought-provoking. While in theory the conquest of viral diseases probably lies in the development of attenuated live-virus vaccines, the effect of this particular vaccine is questionable for a number of reasons. It is unclear whether the vaccine was attenuated or even specifically immunogenic, because of the circumstances under which the vaccine was given. The children who were already immune to varicella were not eliminated from the study group by appropriate serological testing. Neither
history
Birth Defects Institute, New York State Department of ’
Health, Albany, New York 12237, U.S.A., and Department of Pediatrics, Albany Medical College.
ERNEST B. HOOK.
Hook, E. B. Science, 1973, 179, 139.
nor
complement-fixation
tests
are
adequate
to
determine immune status to varicella.2 If the vaccine were administered to immune children one might expect a boost in antibody titre and no evidence of clinical illness. Furthermore, of the 23 immunised children, 2 developed evidence of varicella and it is unclear whether the disease was due to their exposure to chickenpox or to the vaccinaSince not all immunocompromised tion they received. children who contract varicella become severely ill, one cannot conclude that the disease was vaccine-induced because it was mild. In addition, because it is not possible to separate varicella-zoster virus from cell proteins, anti1. 2.
1.
PHILIP A. BRUNELL.
Takahashi, M., Otsuka, T., Okuno, Y., Asano, Y., Yazaki, T., Isomura, S. Lancet, 1974, ii, 1288. Williams, V., Gershon, A., Brunell, P. A. J. infect. Dis. 1974, 130, 669.
99 cell antibodies may appear after immunisation with virus in tissue-culture. Such antibodies would be difficult to distinguish from antiviral antibodies. Until a varicella-zoster vaccine has been used in proven susceptibles and a persistent specific immune response can be documented, it is difficult to assess the effect of vaccination against varicella. Meanwhile zoster immune globulin can be used to protect high-risk susceptibles who are inadvertently exposed to varicella; this preparation is effective and non-toxic.3
COUNTER ELECTROPHORESIS AND DETECTION OF VIRUSES
propagated
Department of Pediatrics, New York University Medical Center, 550 First Avenue, New York, N.Y. 10016, U.S.A.
ANNE A. GERSHON.
HUMAN PLACENTAL LACTOGEN AND FETAL ABNORMALITY
SIR,-Your editorial on microbial antigen detection (July 20, p. 138) and the letters by Balfour and Edelman (Nov. 23, p. 1267) and by Churdboonchart and others (Oct. 5, p. 841) indicated the general usefulness of counter electrophoresis (c.E.P.). For several years we have been engaged in field studies of the California encephalitis virus (c.E.v.) group of arboviruses, using standard arbovirus techniques. 1,2 As an adjunct to the complement-fixation (c.F.) test we have used C.E.P. to identify c.E.v. isolates and to screen sentinel animal sera for C.E.v. antibody.3 We are in general agreement with Balfour and Edelman that rabbit antiserum to C.E.V. is more homotypic than hyperimmune mouse ascitic fluid. Our experience is that hamster antiserum to c.E.v. is more BLIND STUDY FOR DETECTION OF C.E.V.
(KEYSTONE AR 5241)
BY
S.C.E.P.
Gau and Dr Cadle
SIR,-Dr (Sept. 28, p. 775) suggest that low serum-human-placental-lactogen (H.P.L.) levels may be associated with fetal congenital anomalies. This is in contrast to the data from Singer et al. and Spellacy et a!.5 By expanding the series, it has been possible to measure serum-H.p.L. levels in 113 serum samples from
homotypic than rabbit antiserum and is therefore superior for subtyping c.E.v. isolates by the C.E.P. technique. For screening sentinel animal sera for antibody to C.E.V. we recommend use of local c.E.v. isolates plus the c.E.v. prototype BFS-283 which has wide cross-reactivity with antisera to other C.E.v. subtypes. We have modified the C.E.P. technique by conducting a second electrophoresis using antiglobulin specific for the globulin of the species used as a source of the c.E.v. antibody. This antiglobulin is placed in the antibody (anodal) well and a second electrophoresis conducted. This technique increases the sensitivity of the test, since weak precipitin reactions that do not produce a visible line of precipitate may now be displayed by sandwiching " the antiglobulin to the invisible antigen-antibody complex. Using this " sandwich " counter electrophoresis (S.C.E.P.) we have been able to detect circulating c.E.v. (Keystone AR 5241) in virsemic rabbits and hamsters, in positive wild mosquito pools, and in single mosquitoes infected in the laboratory. In our evaluation of this technique we conducted a blind study, giving the technologist who conducted "
H.P.L. levels in 113 serum samples taken during normal gestations of fetuses with congenital anomalies.
with
normal pregnancy but where the fetus had a congenital anomaly (see accompanying figure). The results did not differ from the values obtained when the fetus was normal.H.P.L. is correlated with fetal weight and, therefore, small infants resulting from congenital anomalies may have proportionately low H.P.L. values.s It seems from this expanded series that H.P.L. is not useful for diagnosing fetal congenital anomalies and that the maternal serum values are generally not lowered by the fetal abnormality.
women
a
Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida 32610, U.S.A. 3.
W. N. SPELLACY.
Gershon, A., Steinberg, S., Brunell, P. A. New Engl. J. Med., 1974, 290, 243. 4. Singer, W., Desjardins, P., Friesen, H. G. Obstet. Gynec. 1970, 36, 222. 5. Spellacy, W. N., Buhi, W. C., Schram, J. D., Birk, S. A., McCreary, S. A. ibid. 1971, 37, 567. 6. Spellacy, W. N. Clin. Perinatol. 1974, 1, 65.
S.C.E.P. coded specimens some of which contained virus determined by suckling-mouse isolation and other specimens that were negative by suckling-mouse isolation
the as
(see accompanying table). Of the 62 coded test specimens 33 were positive for c.E.v. AR 5241) by suckling-mouse isolation and 28 of these 33 were identified as positive by S.C.E.P. Of the 29 coded specimens negative for c.E.v. (Keystone AR 5241) by suckling-mouse isolation 28 were identified as negative by S.C.E.P. This indicates a sensitivity of 81-8°o and a specificity of 96-5°o for S.c.E.P. compared to suckling-mouse isolation. We have also demonstrated that group-A arboviruses (Western, Eastern, and Venezuelan equine encephalitis), group-B arboviruses (St. Louis encephalitis), and the rhabdoviruses (Hart Park and Flanders) give c.E.P. reactions in homologous antigen-antibody systems.
(Keystone
Kokemot, R. H., Hayes, J., Boyd, K. R., Sullivan, P. S. J. med. Entomol. 1974, 11, 419. 2. McLerran, J., Arlinghouse, R. Virology, 1973, 53, 247. 3. Gocke, D., Howe, J. Immunology, 1970, 104, 1031. 1.
