1034
monitoring neurologist, the evaluating neurologist classified 17 of these patients as only requiring a frame.4 This is puzzling since in instances the two observations were simultaneous. Certain categories of patient respond better to cyclophosphamide plus steroids than others. 60 % of the cyclophosphamide group and more than 50% of the study group as a whole had a purely progressive illness unaccompanied by relapse. Purely progressive MS may represent a distinct subcategory of the disease.5,6 The Northeast Cooperative Treatment Group trial suggests that the purely progressive form may be more refractory to immunosuppressive treatment than the relapsing-progressive form and that age is an important factor. The average age of patients in the Canadian trial was greater than in some earlier studies demonstrating efficacy of cyclophosphamide regimens.7,8 The Canadian cyclophosphamide plus steroids regimen differed from that in earlier studies. The dose of cyclophosphamide may not have been sufficient. The dose was chosen to result in a nadir white cell count of 1000-2000/0 yet 20% of patients did not have a count below 2000. The Canadian study did show a trend in favour of both the cyclophosphamide and plasma exchange at 6 and 12 months, and at 12 months, if one combines the two immunosuppressive treatment arms and compares them with the placebo arm, the results show an almost significant effect in favour of immunosuppression most
(p= 0-058,).
non-specific immunosuppression is beneficial in multiple sclerosis". The Canadian trial investigated whether five to nine treatments given every other day for about 2 weeks could affect progressive MS over a 30 month period and did in fact support a benefit at 12 months.
Cyclophosphamide has major limitations, and we feel that the major focus on immunotherapy in MS should be the development of non-toxic and, to the extent possible, antigen-specific treatments that can be given early in the course of the disease. We and others are involved in testing such approaches including the use of copolymer, 0-interferon, T-cell receptor vaccination, and oral tolerisation to myelin antigens, and less toxic immunosuppressants such as methotrexate are being tested in MS by ourselves and others.
Harvard Medical School, Boston, Massachusetts 02115, USA
Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis, a randomized, double-blinded, placebo-controlled
clinical trial. Ann Neurol 1990; 27: 591-605. SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis: a randomized, three-arm study of high-dose cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 1983, 308: 173-80. 3. Mackin GA, Weiner HL, Orav J, et al. IV cyclophosphamide ACTH plus maintenance cyclophosphamide boosters in progressive MS final report of the Northeast Cooperative Treatment Group. Neurology 1991, 41 (suppl 1): 147. 4. Noseworthy JH, Vandervoort MK, Wong CJ, Ebers GC, and the Canadian Cooperative MS Group. Interrater variability with the expanded disability status scale (EDSS) and functional systems (FS) in multiple sclerosis clinical trial Neurology 1990; 40: 971-75. 5. Thompson AJ, Kermode AG, Wicks D, et al. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 1991; 29: 53-62 6. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 1989; 86: 7113-17. 7. Hommes OR, Lamer KJB, Reekers P. Prognostic factors in intensive immunosuppressive treatment of chronic progressive MS. In: Bauer HJ, Poser S, Ritter G, eds. Progress in multiple sclerosis research. Berlin: Springer-Verlag, 1980: 396-440. 8. Carter JL, Hafler DA, Dawson DM, Orav J, Weiner HL. Immunosuppression with high-dose cyclophosphamide and ACTH in progressive multiple sclerosis cumulative 6-year experience in 164 patients. Neurology 1988, 38 (suppl 2) 9-14. 9. Likosky WH. Experience with cyclophosphamide in multiple sclerosis, the cons Neurology 1988; 38 (suppl 2): 14-19. 2. Hauser
SIR,-What the Canadian
group may have found is that there effect of cyclophosphamide given in an intravenous-burst fashion and plasmapheresis which starts at 6 months and which persists for 18 months (fig 1).That is essentially the same as we and others have found.1 Cyclophosphamide given regularly in large intravenous doses will have a beneficial effect and will hold multiple sclerosis in check for about as long as the life of the lymphocytes that it affects. It cannot be expected to last 30 months after a single burst. However, it is not a good drug for the treatment of multiple sclerosis. We should have added to the title of our abstract, "... and it makes most people so sick that they don’t want to continue taking it". was an
In our 1983 report2 on short-term cyclophosphamide we noted that disease stabilisation was transient, and that progression of disease returned in most patients followed up beyond 12 months. We hypothesised that periodic re-treatment or chronic immunosuppression may be required. In the Northeast Cooperative Treatment Group trial bimonthly outpatient cyclophosphamide boosters were administered over a two year period to half the patients. Unpublished results of this randomised, single-blind trial of over 200 patients demonstrate a significant effect of boosters on progression at 24 and 30 months.3 We are now involved in a more intensive 3-year booster programme with cyclophosphamide plus methylprednisolone. The Canadian trial apart, studies of cyclophosphamide plus corticosteroids have lacked a placebo control. Side-effects make it difficult to design a truly blinded placebo-controlled trial. In the Canadian study the placebo group was not strictly "untreated" because the sham plasma exchanges may have led to repeated stimulation of endogenous corticoid secretion via volume change or stress, and some patients were treated with steroids. The emphasis on the negative results of the only previous masked placebo-controlled study of cyclophosphamide,9 is inappropriate since that study did not employ corticotropin or prednisone, used a different dose of cyclophosphamide, did not observe progression in the placebo group, and has only been reported in preliminary form. The study carries an important warning against the unselective use of cyclophosphamide plus steroids in MS, but it would be wrong to conclude that such regimens have no effect and to accept the generalisation that the study was designed "to find out whether
Brigham and Women’s Hospital and Massachusetts General Hospital,
1.
HOWARD L. WEINER STEPHEN L. HAUSER DAVID M. DAWSON DAVID A. HAFLER GLENN A. MACKIN E. JOHN ORAV
Department of Neurology, School of Medicine,
University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
ROBERT D. CURRIER ARMIN F. HAERER JOE C. FILES FRANCIS S. MORRISON
AF, Currier RD, Files JC, Morrison FS. Monthly intravenous cyclophosphamide for MS works, but it doesn’t last. Neurology 1987; 37 (suppl 1)
1 Haerer
289 (abstr).
Vaccinia from recombinant virus expressing HIV genes SIR,-HIV gene expression in live recombinant vaccinia viruses is an attractive candidate for a vaccine in HIV-seronegative individuals. Picard et aP have reported a clinical study of immunotherapy in HIV-infected patients with paraformaldehydefixed autologous lymphocytes previously infected in vitro by such a recombinant vaccinia virus. They reported no serious adverse reactions. We have seen two patients with HIV infection (CDC group IVC1) and CD4 cell counts below 50/)il in whom severe necrotic skin lesions developed. We suspected vaccinia a few months later, after the patients had died, when we learned that they had received vaccinia virus-containing cells. A 36-year-old man, 13 days after the first injections of immunotherapy on April 28, 1990, had a high fever and an erythematous plaque centred around the subcutaneous injection site. The symptoms worsened and a skin lesion appeared on his neck. We saw him when he was referred to Hopital Tenon, Paris, for hypovolaemic acute renal failure on June 16. He was acutely ill and febrile. Two necrotic plaques with raised borders and surrounded by a few umbilicus-like pustules were noted on the abdominal wall and on the neck (fig 1). The abdominal lesion, 20 cm in diameter, was on a huge area of oedema that extended to the right buttock and thigh. No clinical signs of visceral involvement were seen. Biopsy from the neck lesion revealed complete epidermal and partial dermal necrosis. He was sent back to the referring hospital after correction of hypovolaemia 48 h after admission. He died a few davss later, but we have no information on the cause of death.
1035
antigens and histological signs of viral infection within keratinocytes that are not able to phagocytose infected lymphocytes. The clinical diagnosis of vaccinia may be delayed, as in our patients, since physicians are no longer experienced in recognising this these
disease. HIV infected patients7-just as immunocompromised patients when smallpox vaccination was widely used-are at high risk of complications from this vaccine. Our observations suggest that, unless there are improvements, use of the technique described by Picard et al should be discouraged in such patients. Moreover, the risk of vaccinia should be kept in mind in mass-vaccination programmes that use recombinant vaccinia virus expressing HIV genes,l especially in countries of high frequency of HIVseropositivity and low development, such as those in Africa, where exclusion of seropositive patients before vaccination would cause insurmountable logistic difficulties and costs. were
Hôpital Henri Mondor, Créteil 1: pustules lesion located on neck.
Fig 1-Patient
(arrow)
at
margin of secondary
Dermatology Unit, Hôpital Tenon,
P. SAIAG
75020 Paris, France
32-year-old man had received repeated injections of immunotherapy since July, 1989. In July, 1990, a progressive infiltration of the right buttock on the site of previous intramuscular injections developed, with fever. Intravenous acyclovir was unhelpful. We saw him when he was transferred to the Forcilles Medical Centre for nutrition therapy on Sept 19, 1990. He was cachectic and febrile, and had a single cutaneous lesion, 30 cm in diameter, extending from the right buttock to the abdomen and right thigh. The centre of the lesion was necrotic, with vesicles on the advancing border (fig 2). Biopsy of this border revealed cytopathic changes within numerous keratinocytes. The patient deteriorated rapidly and he died on Oct 1. A
Virus culture from skin lesions was not done but we are convinced that these two patients had vaccinia. The clinical pattern was typical; specific eosinophilic intracytoplasmic inclusions (Guarnieri bodies)’ were found histologically in patient 2 (in patient 1 the epidermis was completely necrotic); and immunohistochemical studies of skin biopsy material, with a polyclonal anti-vaccinia-virus antibody grown in the rabbit and a monoclonal antibody (5B4/2F2), were positive. This monoclonal antibody recognises an epitope located on the outer envelope of vaccinia virus5 (courtesy of R. Drillien, INSERM Unit 74, Strasbourg). Intense binding6 was seen with both antibodies in epidermal cells of patient 2 and in dermal macrophages in both patients. Controls (normal skin from AIDS patients and herpes simplex virus and varicella zoster virus induced skin lesions) were
negative. False positivity due to passive migration of non-infective recombinant vaccinia virus particles from the injection sites seems very unlikely. In patient 1, vaccinia virus antigens were demonstrated in the secondary skin lesion. In patient 2, we found
J. WECHSLER M. C. LESCS
J. C. ROUJEAU
Hôpital Henri Mondor 1.
Cooney EL, Collier AC, Greenburg PD, et al. Safety of and immunological response to a recombinant vaccinia virus expressing HIV envelope glycoprotein. Lancet 1991; 337: 567-72.
2. Picard O, Giral P, Defer MC, et al. AIDS vaccine therapy: phase I trial. Lancet 1990; 336: 179. 3. Fulginiti VA. Smallpox and complications of smallpox vaccination. In: Fitzpatrick TB, et al, eds. Dermatology in general medicine. New York: McGraw-Hill, 1987: 2340-47. 4. Strano AJ. Smallpox. In: Binford CH, Connor DH, eds. Pathology of tropical and extraordinary diseases. Washington DC: Armed Forces Institute of Pathology, 1976: 65-67. 5. Czerby CP, Mahnel H. Structural and functional analysis of orthopoxvirus epitopes with neutralizing monoclonal antibodies.J Gen Virol 1990; 71: 2341-52 6. Cordell JL, Falini B, Erber WN, et al. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) complexes. JHistochem Cytochem 1984; 32: 219-29. 7. Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med 1987; 31: 673-76.
Safety of recombinant vaccinia vaccines SIR,-Like Dr Baxby (April 13, p 913), but for different reasons, concerned about the claims by Dr Cooney and co-workers (March 19, p 567) for the safety of a recombinant vaccinia-HIV I
am
vaccine. The two
important complications of Jennerian vaccination are generalised vaccinia and post-vaccinal encephalomyelitis. It is conceivable-although there is no evidence to support the ideathat an "attenuated" strain of vaccinia might be less liable to generalise in those who are especially susceptible (ie, patients with immunodeficiencies
people
Fig 2-Patient 2: advancing border with umbilicated vesicles.
J. C. GUILLAUME
are
unlikely
or
to
certain skin diseases). In any event, such be offered any preparation containing live
vaccinia. Post-vaccinal encephalomyelitis is another problem altogether. In the days of mass smallpox immunisation, its incidence was about 1 in 10 000 vaccinations, but this figure varied widely in different populations. Although the virus was isolated from the central nervous system in a proportion of cases, it usually could not be found. In this, and in its clinical features and pathology, it resembled acute demyelinating encephalomyelitis due to other viruses. There were reports that the incidence varied with age, sex, place (the Netherlands having an especially high rate), time of year, and history of previous vaccination.1,2 The evidence that it depended on the strain of vacinia used is conflicting and difficult to evaluate because of confounding variables. In short, it seems that post-viral encephalomyelitis has much more to do with an abnormal response of the host, possibly mediated by immunological factors, than with the strain or type of virus involved. There are at present no firm grounds for supposing that a strain of vaccinia attenuated in virulence for the skin would be less liable to cause encephalomyelitis.
monitoring neurologist, the evaluating neurologist classified 17 of these patients as only requiring a frame.4 This is puzzling since in instances the two observations were simultaneous. Certain categories of patient respond better to cyclophosphamide plus steroids than others. 60 % of the cyclophosphamide group and more than 50% of the study group as a whole had a purely progressive illness unaccompanied by relapse. Purely progressive MS may represent a distinct subcategory of the disease.5,6 The Northeast Cooperative Treatment Group trial suggests that the purely progressive form may be more refractory to immunosuppressive treatment than the relapsing-progressive form and that age is an important factor. The average age of patients in the Canadian trial was greater than in some earlier studies demonstrating efficacy of cyclophosphamide regimens.7,8 The Canadian cyclophosphamide plus steroids regimen differed from that in earlier studies. The dose of cyclophosphamide may not have been sufficient. The dose was chosen to result in a nadir white cell count of 1000-2000/0 yet 20% of patients did not have a count below 2000. The Canadian study did show a trend in favour of both the cyclophosphamide and plasma exchange at 6 and 12 months, and at 12 months, if one combines the two immunosuppressive treatment arms and compares them with the placebo arm, the results show an almost significant effect in favour of immunosuppression most
(p= 0-058,).
non-specific immunosuppression is beneficial in multiple sclerosis". The Canadian trial investigated whether five to nine treatments given every other day for about 2 weeks could affect progressive MS over a 30 month period and did in fact support a benefit at 12 months.
Cyclophosphamide has major limitations, and we feel that the major focus on immunotherapy in MS should be the development of non-toxic and, to the extent possible, antigen-specific treatments that can be given early in the course of the disease. We and others are involved in testing such approaches including the use of copolymer, 0-interferon, T-cell receptor vaccination, and oral tolerisation to myelin antigens, and less toxic immunosuppressants such as methotrexate are being tested in MS by ourselves and others.
Harvard Medical School, Boston, Massachusetts 02115, USA
Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis, a randomized, double-blinded, placebo-controlled
clinical trial. Ann Neurol 1990; 27: 591-605. SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis: a randomized, three-arm study of high-dose cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 1983, 308: 173-80. 3. Mackin GA, Weiner HL, Orav J, et al. IV cyclophosphamide ACTH plus maintenance cyclophosphamide boosters in progressive MS final report of the Northeast Cooperative Treatment Group. Neurology 1991, 41 (suppl 1): 147. 4. Noseworthy JH, Vandervoort MK, Wong CJ, Ebers GC, and the Canadian Cooperative MS Group. Interrater variability with the expanded disability status scale (EDSS) and functional systems (FS) in multiple sclerosis clinical trial Neurology 1990; 40: 971-75. 5. Thompson AJ, Kermode AG, Wicks D, et al. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 1991; 29: 53-62 6. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 1989; 86: 7113-17. 7. Hommes OR, Lamer KJB, Reekers P. Prognostic factors in intensive immunosuppressive treatment of chronic progressive MS. In: Bauer HJ, Poser S, Ritter G, eds. Progress in multiple sclerosis research. Berlin: Springer-Verlag, 1980: 396-440. 8. Carter JL, Hafler DA, Dawson DM, Orav J, Weiner HL. Immunosuppression with high-dose cyclophosphamide and ACTH in progressive multiple sclerosis cumulative 6-year experience in 164 patients. Neurology 1988, 38 (suppl 2) 9-14. 9. Likosky WH. Experience with cyclophosphamide in multiple sclerosis, the cons Neurology 1988; 38 (suppl 2): 14-19. 2. Hauser
SIR,-What the Canadian
group may have found is that there effect of cyclophosphamide given in an intravenous-burst fashion and plasmapheresis which starts at 6 months and which persists for 18 months (fig 1).That is essentially the same as we and others have found.1 Cyclophosphamide given regularly in large intravenous doses will have a beneficial effect and will hold multiple sclerosis in check for about as long as the life of the lymphocytes that it affects. It cannot be expected to last 30 months after a single burst. However, it is not a good drug for the treatment of multiple sclerosis. We should have added to the title of our abstract, "... and it makes most people so sick that they don’t want to continue taking it". was an
In our 1983 report2 on short-term cyclophosphamide we noted that disease stabilisation was transient, and that progression of disease returned in most patients followed up beyond 12 months. We hypothesised that periodic re-treatment or chronic immunosuppression may be required. In the Northeast Cooperative Treatment Group trial bimonthly outpatient cyclophosphamide boosters were administered over a two year period to half the patients. Unpublished results of this randomised, single-blind trial of over 200 patients demonstrate a significant effect of boosters on progression at 24 and 30 months.3 We are now involved in a more intensive 3-year booster programme with cyclophosphamide plus methylprednisolone. The Canadian trial apart, studies of cyclophosphamide plus corticosteroids have lacked a placebo control. Side-effects make it difficult to design a truly blinded placebo-controlled trial. In the Canadian study the placebo group was not strictly "untreated" because the sham plasma exchanges may have led to repeated stimulation of endogenous corticoid secretion via volume change or stress, and some patients were treated with steroids. The emphasis on the negative results of the only previous masked placebo-controlled study of cyclophosphamide,9 is inappropriate since that study did not employ corticotropin or prednisone, used a different dose of cyclophosphamide, did not observe progression in the placebo group, and has only been reported in preliminary form. The study carries an important warning against the unselective use of cyclophosphamide plus steroids in MS, but it would be wrong to conclude that such regimens have no effect and to accept the generalisation that the study was designed "to find out whether
Brigham and Women’s Hospital and Massachusetts General Hospital,
1.
HOWARD L. WEINER STEPHEN L. HAUSER DAVID M. DAWSON DAVID A. HAFLER GLENN A. MACKIN E. JOHN ORAV
Department of Neurology, School of Medicine,
University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
ROBERT D. CURRIER ARMIN F. HAERER JOE C. FILES FRANCIS S. MORRISON
AF, Currier RD, Files JC, Morrison FS. Monthly intravenous cyclophosphamide for MS works, but it doesn’t last. Neurology 1987; 37 (suppl 1)
1 Haerer
289 (abstr).
Vaccinia from recombinant virus expressing HIV genes SIR,-HIV gene expression in live recombinant vaccinia viruses is an attractive candidate for a vaccine in HIV-seronegative individuals. Picard et aP have reported a clinical study of immunotherapy in HIV-infected patients with paraformaldehydefixed autologous lymphocytes previously infected in vitro by such a recombinant vaccinia virus. They reported no serious adverse reactions. We have seen two patients with HIV infection (CDC group IVC1) and CD4 cell counts below 50/)il in whom severe necrotic skin lesions developed. We suspected vaccinia a few months later, after the patients had died, when we learned that they had received vaccinia virus-containing cells. A 36-year-old man, 13 days after the first injections of immunotherapy on April 28, 1990, had a high fever and an erythematous plaque centred around the subcutaneous injection site. The symptoms worsened and a skin lesion appeared on his neck. We saw him when he was referred to Hopital Tenon, Paris, for hypovolaemic acute renal failure on June 16. He was acutely ill and febrile. Two necrotic plaques with raised borders and surrounded by a few umbilicus-like pustules were noted on the abdominal wall and on the neck (fig 1). The abdominal lesion, 20 cm in diameter, was on a huge area of oedema that extended to the right buttock and thigh. No clinical signs of visceral involvement were seen. Biopsy from the neck lesion revealed complete epidermal and partial dermal necrosis. He was sent back to the referring hospital after correction of hypovolaemia 48 h after admission. He died a few davss later, but we have no information on the cause of death.
1035
antigens and histological signs of viral infection within keratinocytes that are not able to phagocytose infected lymphocytes. The clinical diagnosis of vaccinia may be delayed, as in our patients, since physicians are no longer experienced in recognising this these
disease. HIV infected patients7-just as immunocompromised patients when smallpox vaccination was widely used-are at high risk of complications from this vaccine. Our observations suggest that, unless there are improvements, use of the technique described by Picard et al should be discouraged in such patients. Moreover, the risk of vaccinia should be kept in mind in mass-vaccination programmes that use recombinant vaccinia virus expressing HIV genes,l especially in countries of high frequency of HIVseropositivity and low development, such as those in Africa, where exclusion of seropositive patients before vaccination would cause insurmountable logistic difficulties and costs. were
Hôpital Henri Mondor, Créteil 1: pustules lesion located on neck.
Fig 1-Patient
(arrow)
at
margin of secondary
Dermatology Unit, Hôpital Tenon,
P. SAIAG
75020 Paris, France
32-year-old man had received repeated injections of immunotherapy since July, 1989. In July, 1990, a progressive infiltration of the right buttock on the site of previous intramuscular injections developed, with fever. Intravenous acyclovir was unhelpful. We saw him when he was transferred to the Forcilles Medical Centre for nutrition therapy on Sept 19, 1990. He was cachectic and febrile, and had a single cutaneous lesion, 30 cm in diameter, extending from the right buttock to the abdomen and right thigh. The centre of the lesion was necrotic, with vesicles on the advancing border (fig 2). Biopsy of this border revealed cytopathic changes within numerous keratinocytes. The patient deteriorated rapidly and he died on Oct 1. A
Virus culture from skin lesions was not done but we are convinced that these two patients had vaccinia. The clinical pattern was typical; specific eosinophilic intracytoplasmic inclusions (Guarnieri bodies)’ were found histologically in patient 2 (in patient 1 the epidermis was completely necrotic); and immunohistochemical studies of skin biopsy material, with a polyclonal anti-vaccinia-virus antibody grown in the rabbit and a monoclonal antibody (5B4/2F2), were positive. This monoclonal antibody recognises an epitope located on the outer envelope of vaccinia virus5 (courtesy of R. Drillien, INSERM Unit 74, Strasbourg). Intense binding6 was seen with both antibodies in epidermal cells of patient 2 and in dermal macrophages in both patients. Controls (normal skin from AIDS patients and herpes simplex virus and varicella zoster virus induced skin lesions) were
negative. False positivity due to passive migration of non-infective recombinant vaccinia virus particles from the injection sites seems very unlikely. In patient 1, vaccinia virus antigens were demonstrated in the secondary skin lesion. In patient 2, we found
J. WECHSLER M. C. LESCS
J. C. ROUJEAU
Hôpital Henri Mondor 1.
Cooney EL, Collier AC, Greenburg PD, et al. Safety of and immunological response to a recombinant vaccinia virus expressing HIV envelope glycoprotein. Lancet 1991; 337: 567-72.
2. Picard O, Giral P, Defer MC, et al. AIDS vaccine therapy: phase I trial. Lancet 1990; 336: 179. 3. Fulginiti VA. Smallpox and complications of smallpox vaccination. In: Fitzpatrick TB, et al, eds. Dermatology in general medicine. New York: McGraw-Hill, 1987: 2340-47. 4. Strano AJ. Smallpox. In: Binford CH, Connor DH, eds. Pathology of tropical and extraordinary diseases. Washington DC: Armed Forces Institute of Pathology, 1976: 65-67. 5. Czerby CP, Mahnel H. Structural and functional analysis of orthopoxvirus epitopes with neutralizing monoclonal antibodies.J Gen Virol 1990; 71: 2341-52 6. Cordell JL, Falini B, Erber WN, et al. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) complexes. JHistochem Cytochem 1984; 32: 219-29. 7. Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med 1987; 31: 673-76.
Safety of recombinant vaccinia vaccines SIR,-Like Dr Baxby (April 13, p 913), but for different reasons, concerned about the claims by Dr Cooney and co-workers (March 19, p 567) for the safety of a recombinant vaccinia-HIV I
am
vaccine. The two
important complications of Jennerian vaccination are generalised vaccinia and post-vaccinal encephalomyelitis. It is conceivable-although there is no evidence to support the ideathat an "attenuated" strain of vaccinia might be less liable to generalise in those who are especially susceptible (ie, patients with immunodeficiencies
people
Fig 2-Patient 2: advancing border with umbilicated vesicles.
J. C. GUILLAUME
are
unlikely
or
to
certain skin diseases). In any event, such be offered any preparation containing live
vaccinia. Post-vaccinal encephalomyelitis is another problem altogether. In the days of mass smallpox immunisation, its incidence was about 1 in 10 000 vaccinations, but this figure varied widely in different populations. Although the virus was isolated from the central nervous system in a proportion of cases, it usually could not be found. In this, and in its clinical features and pathology, it resembled acute demyelinating encephalomyelitis due to other viruses. There were reports that the incidence varied with age, sex, place (the Netherlands having an especially high rate), time of year, and history of previous vaccination.1,2 The evidence that it depended on the strain of vacinia used is conflicting and difficult to evaluate because of confounding variables. In short, it seems that post-viral encephalomyelitis has much more to do with an abnormal response of the host, possibly mediated by immunological factors, than with the strain or type of virus involved. There are at present no firm grounds for supposing that a strain of vaccinia attenuated in virulence for the skin would be less liable to cause encephalomyelitis.
