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.
1036
Claims for the safety of any preparation of vaccinia virus, attenuated recombinant, might be advanced with caution after, say, 100 000 vaccinations with no untoward effects, but certainly not after the 18 reported by Cooney et al. It may be that the benefit of an effective vaccinia-HIV preparation would far outweigh the risk of neuroparalytic accidents, but if that is the justification for its use, let it be stated in those terms, rather than make claims for safety based on scant evidence. In view of the risks from vaccinia, however small, it might be better to explore the use of adenovirus as a vector; this DNA virus has a usefully large genome and has not been associated with
or
demyelinating encephalomyelitis.3 8 Peto Place,
L. H. COLLIER
London NW1 4DT, UK
Rooyen CE, Rhodes AJ. Postvaccinal encephalitis Virus diseases of man. New York: Thomas Nelson & Sons, 1948: 393-429. 2 Dixon CW Smallpox. London: Churchill, 1962. 3. Longson M. Virus infections of the central nervous system. In: Collier LH, Timbury MC, eds. Topley and Wilson’s principles of bactenology, virology and immunity, 8th ed: vol IV, virology. London: Edward Arnold, 1990: 451-78. 1. Van
Cutaneous
sensitivity to thiacetazone
SIR,-Over the past ten months we have seen 7 cases of severe hypersensitivity reactions to thiacetazone in patients being treated for pulmonary tuberculosis with isoniazid, thiacetazone, and streptomycin. We found a similar clinical pattern to that reported by Dr Nunn and colleagues (March 16, p 627). We did not know our patients’ HIV status although the prevalence of HIV infection is still low in Nepal. All skin reactions began with a maculopapular rash that was accompanied by constitutional symptoms with eventual mucosal involvement. Only 4 patients had Stevens-Johnson syndrome, but all 7 were very ill. Those patients with Stevens-Johnson syndrome were started immediately on steroids by junior hospital staff, whereas other patients experienced a delay. We believe that the term Stevens-Johnson syndrome should be abandoned in favour of severe bullous erythema multiforme.1 This simplification of terminology would help the young clinicians to appreciate that these reactions represent a range of severity of the same pathological process, and that prompt cutaneous
administration of steroids is indicated despite the absence of severe mucosal involvement. Eastern
Regional Hospital,
Dharan, Sunsari, Nepal 1.
DAVID FEGAN JACQUELINE GLENNON
Champion RH. Disorders affecting small blood vessels: erythema and telangiectasia. In: Rook A, Wilkinson DS, Ebling FJG, eds. Textbook of dermatology, 2nd ed. London: Blackwell, 1972: 890.
antibody HA-1A for gram-negative shock
Monoclonal
SIR,-In your March 9 editorial (p 588) you discuss the use of the monoclonal antibody HA-IA in the treatment of gram-negative shock.l The results of this studyl are encouraging, in that there was a clear reduction in mortality in patients later confirmed to have gram-negative bacteraemia. However, we are concerned that your comments might be misinterpreted as suggesting that the reduction in mortality from 49% to 30% was seen in all 543 patients entered into the study; this is not so. Ziegler et all had pointed out that, by design, they focused their analysis on patients with proven gram-negative bacteraemia, reasoning that this was the group most likely to show benefit from the antibody treatment. In the event, 200 of the 543 patients given the antibody proved to have gram-negative bacteraemia, and it was in this group that the reduction in mortality from 49% to 30% was seen. The remaining 243 patients had mainly non-bacteraemic gram-negative infection or gram-positive infection, or no infection could be documented. In this group, as indeed in the entire study group, administration of the antibody had no measureable effect. It should be emphasised that the results of the HA-1A study do not provide direct evidence of the mode of action of this antibody.
Gram-negative septicaemia and endotoxaemia are not synonymous Patients with the "sepsis syndrome" may have endotoxaerma despite negative blood cultures, and, conversely, not all patients with septicaemia have endotoxaemia.2It would be of considerable interest to know what proportion of the 543 patients had endotoxm in their plasma on entry to the study, and whether this was an important variable in the determination of response to antibody. These concerns should not negate the striking improvement in mortality seen when HA-IA is given to patients with sepsis and gram-negative bacteraemia. The difficulty facing the clinician is how to identify those individuals most likely to benefit Distinguishing shock caused by gram-positive organisms (which is unlikely to respond to anti-endotoxin) from that caused by gram-negative bacteria is notoriously difficult, and up to 50% of community acquired bacteraemias may be gram-positive in origm.J Even with the criteria developed by the HA-1A study group, only 37% of the patients enrolled had gram-negative bacteraemia, and those criteria are probably too cumbersome to be used in everyday clinical practice. Monoclonal antibodies to endotoxin are an exciting and important development in the management of serious gramnegative infection, but many questions-both scientific and practical-remain unanswered. As you say, the pressures to use the drug "in any patients at risk" will be high; it would be a pity if you were seen to endorse a strategy whose benefits have not yet been shown to be tangible or cost-effective. Infectious Diseases Unit, Department of Medicine, Royal Postgraduate Medical School, London W12 0NN, UK 1.
PAUL LEHNER
JONATHAN COHEN
Ziegler EJ, Fisher CJ Jr, Sprung CL, et al. Treatment of gram negative bacteraemia and septic shock with HA-1A human monoclonal antibody against endotoxin a randomised, double-blind, placebo-controlled trial N Engl J Med 1991, 324:
429-36. 2. Parillo JE. Septic shock in humans advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy. Ann Intern Med 1990, 113: 227-42 3. Rayner BL, Willcox PA. Community-acquired bacteraemia; a prospective surv ey of 239 cases. Q J Med 1988; 69: 907-19.
SIR,-You cite a study by Tracey et al on recombinant human cachectin. This was published in Science, not Nature, and the work was done in rats, not baboons. Interested readers will find it difficult to locate the reference in Nature. Furthermore, although the article is important in emphasising the significance of monoclonal antibodies to tumour necrosis factor, stating that the study was done in baboons when it was in a non-primate species, may imply a greater relevance to man. There is, however, a study demonstrating efficacy of anti-cachectin antibodies in baboons by Tracey et al, published in Nature in 1987.2This reference, if included, would have rendered the editorial not so wide of the mark, and enhanced its relevance to man. Division of Infectious Diseases, Maimonides Medical Center, Brooklyn, NY 11219, USA
EDWARD K. CHAPNICK LARRY I. LUTWICK
et al Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234: 470-74. 2. Tracey KJ, Fong Y, Hesse DG, et al Anti-cachectin TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 1987, 330: 662-64
1. Tracey KJ, Berther B, Lowry SF,
SiR,—Your leading article misrepresents the result of the HA- 1A antibody triaJ.1 In the intention-to-treat population of 543 cases with sepsis, there was no significant benefit from HA-1A anubodB. The "benefit" was seen only in a subset analysis of cases shown or. blood culture to have sepsis caused by gram-negative rods. This group accounted for only one-third of the total study population. and cannot be identified until long after the treatment has beer given. Since the subset who may benefit cannot be identified the only valid analysis is that based on the intention-to-treat data from all cases enrolled; this showed no difference. From both this result and the findings of the subse: analysis, one may ask what harm the HA-1 A treatment did in 0.: subset who did not have organisms that HA-1 A recognises ?%
prospectively,
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.
1036
Claims for the safety of any preparation of vaccinia virus, attenuated recombinant, might be advanced with caution after, say, 100 000 vaccinations with no untoward effects, but certainly not after the 18 reported by Cooney et al. It may be that the benefit of an effective vaccinia-HIV preparation would far outweigh the risk of neuroparalytic accidents, but if that is the justification for its use, let it be stated in those terms, rather than make claims for safety based on scant evidence. In view of the risks from vaccinia, however small, it might be better to explore the use of adenovirus as a vector; this DNA virus has a usefully large genome and has not been associated with
or
demyelinating encephalomyelitis.3 8 Peto Place,
L. H. COLLIER
London NW1 4DT, UK
Rooyen CE, Rhodes AJ. Postvaccinal encephalitis Virus diseases of man. New York: Thomas Nelson & Sons, 1948: 393-429. 2 Dixon CW Smallpox. London: Churchill, 1962. 3. Longson M. Virus infections of the central nervous system. In: Collier LH, Timbury MC, eds. Topley and Wilson’s principles of bactenology, virology and immunity, 8th ed: vol IV, virology. London: Edward Arnold, 1990: 451-78. 1. Van
Cutaneous
sensitivity to thiacetazone
SIR,-Over the past ten months we have seen 7 cases of severe hypersensitivity reactions to thiacetazone in patients being treated for pulmonary tuberculosis with isoniazid, thiacetazone, and streptomycin. We found a similar clinical pattern to that reported by Dr Nunn and colleagues (March 16, p 627). We did not know our patients’ HIV status although the prevalence of HIV infection is still low in Nepal. All skin reactions began with a maculopapular rash that was accompanied by constitutional symptoms with eventual mucosal involvement. Only 4 patients had Stevens-Johnson syndrome, but all 7 were very ill. Those patients with Stevens-Johnson syndrome were started immediately on steroids by junior hospital staff, whereas other patients experienced a delay. We believe that the term Stevens-Johnson syndrome should be abandoned in favour of severe bullous erythema multiforme.1 This simplification of terminology would help the young clinicians to appreciate that these reactions represent a range of severity of the same pathological process, and that prompt cutaneous
administration of steroids is indicated despite the absence of severe mucosal involvement. Eastern
Regional Hospital,
Dharan, Sunsari, Nepal 1.
DAVID FEGAN JACQUELINE GLENNON
Champion RH. Disorders affecting small blood vessels: erythema and telangiectasia. In: Rook A, Wilkinson DS, Ebling FJG, eds. Textbook of dermatology, 2nd ed. London: Blackwell, 1972: 890.
antibody HA-1A for gram-negative shock
Monoclonal
SIR,-In your March 9 editorial (p 588) you discuss the use of the monoclonal antibody HA-IA in the treatment of gram-negative shock.l The results of this studyl are encouraging, in that there was a clear reduction in mortality in patients later confirmed to have gram-negative bacteraemia. However, we are concerned that your comments might be misinterpreted as suggesting that the reduction in mortality from 49% to 30% was seen in all 543 patients entered into the study; this is not so. Ziegler et all had pointed out that, by design, they focused their analysis on patients with proven gram-negative bacteraemia, reasoning that this was the group most likely to show benefit from the antibody treatment. In the event, 200 of the 543 patients given the antibody proved to have gram-negative bacteraemia, and it was in this group that the reduction in mortality from 49% to 30% was seen. The remaining 243 patients had mainly non-bacteraemic gram-negative infection or gram-positive infection, or no infection could be documented. In this group, as indeed in the entire study group, administration of the antibody had no measureable effect. It should be emphasised that the results of the HA-1A study do not provide direct evidence of the mode of action of this antibody.
Gram-negative septicaemia and endotoxaemia are not synonymous Patients with the "sepsis syndrome" may have endotoxaerma despite negative blood cultures, and, conversely, not all patients with septicaemia have endotoxaemia.2It would be of considerable interest to know what proportion of the 543 patients had endotoxm in their plasma on entry to the study, and whether this was an important variable in the determination of response to antibody. These concerns should not negate the striking improvement in mortality seen when HA-IA is given to patients with sepsis and gram-negative bacteraemia. The difficulty facing the clinician is how to identify those individuals most likely to benefit Distinguishing shock caused by gram-positive organisms (which is unlikely to respond to anti-endotoxin) from that caused by gram-negative bacteria is notoriously difficult, and up to 50% of community acquired bacteraemias may be gram-positive in origm.J Even with the criteria developed by the HA-1A study group, only 37% of the patients enrolled had gram-negative bacteraemia, and those criteria are probably too cumbersome to be used in everyday clinical practice. Monoclonal antibodies to endotoxin are an exciting and important development in the management of serious gramnegative infection, but many questions-both scientific and practical-remain unanswered. As you say, the pressures to use the drug "in any patients at risk" will be high; it would be a pity if you were seen to endorse a strategy whose benefits have not yet been shown to be tangible or cost-effective. Infectious Diseases Unit, Department of Medicine, Royal Postgraduate Medical School, London W12 0NN, UK 1.
PAUL LEHNER
JONATHAN COHEN
Ziegler EJ, Fisher CJ Jr, Sprung CL, et al. Treatment of gram negative bacteraemia and septic shock with HA-1A human monoclonal antibody against endotoxin a randomised, double-blind, placebo-controlled trial N Engl J Med 1991, 324:
429-36. 2. Parillo JE. Septic shock in humans advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy. Ann Intern Med 1990, 113: 227-42 3. Rayner BL, Willcox PA. Community-acquired bacteraemia; a prospective surv ey of 239 cases. Q J Med 1988; 69: 907-19.
SIR,-You cite a study by Tracey et al on recombinant human cachectin. This was published in Science, not Nature, and the work was done in rats, not baboons. Interested readers will find it difficult to locate the reference in Nature. Furthermore, although the article is important in emphasising the significance of monoclonal antibodies to tumour necrosis factor, stating that the study was done in baboons when it was in a non-primate species, may imply a greater relevance to man. There is, however, a study demonstrating efficacy of anti-cachectin antibodies in baboons by Tracey et al, published in Nature in 1987.2This reference, if included, would have rendered the editorial not so wide of the mark, and enhanced its relevance to man. Division of Infectious Diseases, Maimonides Medical Center, Brooklyn, NY 11219, USA
EDWARD K. CHAPNICK LARRY I. LUTWICK
et al Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234: 470-74. 2. Tracey KJ, Fong Y, Hesse DG, et al Anti-cachectin TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 1987, 330: 662-64
1. Tracey KJ, Berther B, Lowry SF,
SiR,—Your leading article misrepresents the result of the HA- 1A antibody triaJ.1 In the intention-to-treat population of 543 cases with sepsis, there was no significant benefit from HA-1A anubodB. The "benefit" was seen only in a subset analysis of cases shown or. blood culture to have sepsis caused by gram-negative rods. This group accounted for only one-third of the total study population. and cannot be identified until long after the treatment has beer given. Since the subset who may benefit cannot be identified the only valid analysis is that based on the intention-to-treat data from all cases enrolled; this showed no difference. From both this result and the findings of the subse: analysis, one may ask what harm the HA-1 A treatment did in 0.: subset who did not have organisms that HA-1 A recognises ?%
prospectively,
