- Email: [email protected]
The filovirus enigma
,
,
The importance of treatment plans is highlighted by Stiller’s3 review of cancer treatment in the UK; he found that not only centralised treatment but also entrance into trials improved survival. Davis and colleagues,4 in their study of Hodgkin’s disease in the USA (a condition where there have been real advances in treatment in recent years) emphasise that the challenge is the "diffusion of knowledge and technology to the surrounding communities" from
comprehensive The
cancer centres.
report to the Chief Medical Officers of England and Wales entitled A Policy Framework for Commissioning Cancer Services5 makes the helpful distinction between the cancer unit, which may well be in a district general hospital, and the centralised cancer centre with radiotherapy and other facilities. The report points out that the changes needed are mainly matters of organisation, agreed treatment plans, communications, and appropriate referral patterns. This approach can only work for the common surgical cancers if there are sufficient surgeons in a district general hospital to allow effective subspecialisation with at least two surgeons in each subspecialty-eg, breast disease and colorectal cancer. Schipper6 has described how outreach programmes for cancer care in Manitoba, Canada, make effective use of community physicians for this purpose. In Britain, the existing funding recent
’v,
, ,
,
,
>, ",
’ z .
-
’ , .-;:;’°;’=‘’;°,,,,";, d;I;
arrangements for the internal market can obstruct the transfer of patients. In any country the contracting and financing arrangements must enhance team-work and easy referral to the
appropriate facilities. No one supports "dabblers" in any branch of medicine but dedicated clinicians who treat relatively few patients in their community, provided they are appropriately trained and supported and are linked to a major centre by agreed treatment plans, not are necessarily dabblers. The immediate challenge is to achieve cooperation and coordination rather than confrontation in planning services for the benefit of the patients. The Lancet Matthews HR, Powell DJ, McConkey CC. Effect of surgical experience on the results of resection for oesophageal carcinoma. Br J Surg 1986, 73: 621-23. 2 McArdle CS, Hole D. Impact of variability among surgeons on postoperative morbidity and mortality and ultimate survival. BMJ 1991; 302: 1501-05. 3 Stiller CA. Centralised treatment, entry to trials and survival. Br J Cancer 1994; 70: 352-62. 4 Davis S, Dahlberg S, Myers M, et al. Hodgkin’s disease in the United States: a comparison of patient characteristics and survival in the centralized cancer patient data system and the surveillance, epidemiology and end results program. J Natl Cancer Inst 1987; 78: 471-78. 5 Expert Advisory Group on Cancer to CMOs of England and Wales. A policy framework for commissioning cancer services. London: Department of Health, 1995. 6 Schipper H. Whither cancer centres? Lancet 1994; 344: 281-82. 1
COM ENTARY
The filovirus
and
enigma
See page 1271
and Ebola are the prototypes, are so named because of their long filamentous appearance when viewed by electron microscopy. Both Marburg and Ebola viruses have caused brief but catastrophic self-limiting outbreaks, and Ebola virus is at present causing numerous deaths in Zaire. Since the first descriptions of filovirus disease in the 1960s we have learnt a lot about the clinical features but the natural reservoir remains a mystery. Marburg virus disease is a severe haemorrhagic febrile illness first described in 1967 when 31 cases with 7 deaths in Germany and Yugoslavia were traced to direct contact with blood, organs, or cell culture from a batch of African green monkeys that had been trapped in Uganda. The first recognised outbreak of Marburg disease in Africa occurred in South Africa in 1975 and sporadic cases have been reported from Kenya. In 1976, outbreaks of severe and frequently fatal viral haemorrhagic fever caused by Ebola virus occurred in the equatorial provinces of Sudan and Zaire, giving rise to widespread international concern;l small self-limiting outbreaks recurred in southern Sudan in 1979. There is no evidence that primates were involved in Sudan and Zaire. The illnesses caused by Marburg and Ebola viruses are virtually indistinguishable: an abrupt onset with severe frontal and temporal headache is followed by high fever
Filoviruses,
1252
of
which
Marburg
generalised pains, particularly in the back. The patient rapidly becomes prostrated and develops severe watery diarrhoea with rapid dehydration. In the Sudanese outbreak, knife-like chest and pleuritic pain was an early symptom and many patients complained of a dry throat and cough. On white skins, a characteristic maculopapular rash appears between days 5 and 7 and lasts 3-4 days before desquamation. On black skins the rash is not so obvious. Conjunctivitis has been a regular feature. Many patients in the original outbreaks developed severe bleeding between days 5 and 7. The gut and lungs were most frequently involved, with haematemesis, passage of fresh blood in the stools. There was also bleeding from the nose, gums, and vagina, and subconjunctival haemorrhages were common, as were petechiae and bleeding from needle puncture sites. The patients usually died between days 7 and 16, after severe blood loss and shock. Although monkeys were the source of the 1967 outbreak in Germany and Yugoslavia, primates are not believed to be natural reservoirs of the virus. Studies in the Lake Kyoga region of Uganda, where the Marburg vervet monkeys had been collected, revealed no evidence of an epizootic, nor was any illness detected among monkey trappers. Claims of naturally occurring antibodies to Marburg virus in some African primates have not been generally accepted. Experimental laboratory infection of several primate species produces a uniformly fatal
melaena, and sometimes the
.
’.’
,
. .’","
illness similar to that seen in Ebola human beings. virus, once established, can be transmitted person-to-person, but close and prolonged contact, and particularly blood contact, is necessary for successful transmission.’ Quarantining of known cases is an effective way to contain the spread of infection, but arbitrary quarantining of unproven cases is ridiculous. What happens to primates infected in the wild? Strains of Ebola virus were introduced into the USA in 1989 and 1990 by non-human primates orginating in the Philippines. Although seroconversion occurred in 4 handlers there was no evidence of clinical illness. The monkeys, however, were severely ill and several died. In this issue Le Guenno et al report deaths in wild chimpanzees in a forest area of the Ivory Coast. Ebola virus is the cause of the outbreak and a young zoologist who carried out post-mortem examinations on dead chimpanzees herself became infected but recovered. The latest report is the first clear documentation of a filovirus infection in wild primates. Even so, there is no indication as to where the infection originated, just as there is no indication of the source of infection in the current human outbreak in Zaire. The chimpanzee outbreak reemphasises the susceptibility of primates to filovirus infection-chimpanzees are naturally inquisitive animals with catholic and cannibalistic feeding habits, so infection within the troop is readily understandable-but this susceptibility makes them unlikely candidates as natural reservoirs. Monkeys, rodents, or bats may be stronger candidates. Amid the human tragedy in Zaire, the international research teams have been presented with a golden opportunity to trace Ebola to its origins.
infection and
causes an
D I H Simpson Department of Microbiology and Immunobiology, Queen’s University of Belfast, UK 1 Simpson DIS. Viral hemorrhagic fevers. In: Gillies HM, ed. Epidemiology and control of tropical diseases, vol 1, no 3. Philadelphia: W B Saunders, 1986.
Cardiopulmonary resuscitation and neurological complications in the elderly is that, in a study of cerebral function in The good 774 patients who were comatose after successful cardiopulmonary resuscitation (CPR), Rogove et all found that age alone bore no relation to neurological recovery up to 6 months post arrest. The bad news is that news
6-monthly mortality was considerably higher among elderly individuals. The death rate was 68% in those aged less but 94% in those over 80 years. Good neurological outcome, defined as functional independence outside of institutional care, was achieved in 27%, with no significant difference across age groups. Of the total sample, 86% of the 6-month survivors had a good neurological outcome; this finding was not stratified by age. One could question whether neuropsychological testing would reveal deficits not detected by measurements of functional independence alone. Poor neurological status before the arrest was associated with a high mortality. Earlier studies accord with these general observations. In patients who arrested in hospital, age alone did not influence the chance of survival, but of those who were functionally dependent before arrest, only 4% survived to 45 years
or
discharge and those with severe medical problems did poorly.2 In a report of CPR in patients aged above 70, only 3-8% survived, but with little or no mental impairmentwhereas in another study of in-hospital ex-servicemen none of the patients over age 70 years survived to discharge.4 In a sample of patients with out-ofhospital cardiac arrest, Tresch et a15 reported that those over 70 years had higher mortality than younger patients (71 vs 53%) but no greater neurological impairment on discharge. Other studies in elderly people with a high burden of medical and cognitive dysfunction have shown survival.6 Thus, although mortality from poor arrest is considerably greater in the cardiopulmonary elderly, those who do survive do not seem to have a substantially greater risk of neurological impairment. The results of the Brain Resuscitation Clinical Trial reported by Rogove et al seem counter-intuitive, since most clinicians believe that the brain, like other organs, becomes more vulnerable to hypoxic-ischaemic insults with age. Head injury and stroke (focal ischaemia) data suggest that advanced age is a risk factor for poor neurological outcome.7,1 These two insults probably reflect different pathophysiological processes than those after cardiac arrest, which is usually associated with global ischaemia. Aged brain differs in many respects from the younger-mature brain. There is increasing atrophy9 and neurological loss’° with ageing. There are many theories to explain brain ageing-eg, defects in mitochondrial metabolism," free radicals,12 glucocorticoid sensitivity, 13 calcium neurotoxicity, 14 and excitatory neurotransmitter (glutamate and aspartate) toxicity. 15 Some researchers have extrapolated from changes in excitatory aminoacid metabolism measured in immature brain to propose a mechanism of neural death with ageing.l6 Because it is difficult to culture aged brain tissue, virtually all studies use culture systems from immature brain. However, the assumption that we can understand neurotoxicity in aged brain from such studies is probably erroneous, and there have been no studies on cardiopulmonary arrest or cerebrovascular occlusion in aged animals. Patients who have severe premorbid cerebral impairment or multiple medical disorders, or who are
already substantially functionally dependent, are unlikely survive CPR2-6 The ethical issue, if there is one, is whether we should offer such therapy to individuals whose premorbid state clearly makes functional recovery unlikely. For those elderly people who do survive CPR, the neurological complications do not seem to be substantially worse than those of younger survivors. The next step is to find ways of selecting, for CPR, elderly patients with a reasonable chance of physical survival and to
intact cerebral function. Peter L Carlen, Michael Gordon Playfair Neuroscience Unit, Toronto Hospital Research Institute, Baycrest Centre for Geriatric Care, University of Toronto,
and
Toronto, Ontario, Canada 1
2
Rogove HJ, Safar P, Sutton-Tyrrell K, Abramson NS, Brain Resuscitation Clinical Trial and 11 Study Groups. Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analysis from the Brain Resuscitation Clinical Trials. Crit Care Med 1995; 23: 18-25. Bedell SE, Delbanco TL, Cook EF, Epstein FH. Survival after cardiopulmonary resuscitation in the hospital. N Engl J Med 1983; 309: 570-76.
3
Murphy DJ, Murray AM, Robinson BE, Campion EW. Outcomes of
1253
,
The importance of treatment plans is highlighted by Stiller’s3 review of cancer treatment in the UK; he found that not only centralised treatment but also entrance into trials improved survival. Davis and colleagues,4 in their study of Hodgkin’s disease in the USA (a condition where there have been real advances in treatment in recent years) emphasise that the challenge is the "diffusion of knowledge and technology to the surrounding communities" from
comprehensive The
cancer centres.
report to the Chief Medical Officers of England and Wales entitled A Policy Framework for Commissioning Cancer Services5 makes the helpful distinction between the cancer unit, which may well be in a district general hospital, and the centralised cancer centre with radiotherapy and other facilities. The report points out that the changes needed are mainly matters of organisation, agreed treatment plans, communications, and appropriate referral patterns. This approach can only work for the common surgical cancers if there are sufficient surgeons in a district general hospital to allow effective subspecialisation with at least two surgeons in each subspecialty-eg, breast disease and colorectal cancer. Schipper6 has described how outreach programmes for cancer care in Manitoba, Canada, make effective use of community physicians for this purpose. In Britain, the existing funding recent
’v,
, ,
,
,
>, ",
’ z .
-
’ , .-;:;’°;’=‘’;°,,,,";, d;I;
arrangements for the internal market can obstruct the transfer of patients. In any country the contracting and financing arrangements must enhance team-work and easy referral to the
appropriate facilities. No one supports "dabblers" in any branch of medicine but dedicated clinicians who treat relatively few patients in their community, provided they are appropriately trained and supported and are linked to a major centre by agreed treatment plans, not are necessarily dabblers. The immediate challenge is to achieve cooperation and coordination rather than confrontation in planning services for the benefit of the patients. The Lancet Matthews HR, Powell DJ, McConkey CC. Effect of surgical experience on the results of resection for oesophageal carcinoma. Br J Surg 1986, 73: 621-23. 2 McArdle CS, Hole D. Impact of variability among surgeons on postoperative morbidity and mortality and ultimate survival. BMJ 1991; 302: 1501-05. 3 Stiller CA. Centralised treatment, entry to trials and survival. Br J Cancer 1994; 70: 352-62. 4 Davis S, Dahlberg S, Myers M, et al. Hodgkin’s disease in the United States: a comparison of patient characteristics and survival in the centralized cancer patient data system and the surveillance, epidemiology and end results program. J Natl Cancer Inst 1987; 78: 471-78. 5 Expert Advisory Group on Cancer to CMOs of England and Wales. A policy framework for commissioning cancer services. London: Department of Health, 1995. 6 Schipper H. Whither cancer centres? Lancet 1994; 344: 281-82. 1
COM ENTARY
The filovirus
and
enigma
See page 1271
and Ebola are the prototypes, are so named because of their long filamentous appearance when viewed by electron microscopy. Both Marburg and Ebola viruses have caused brief but catastrophic self-limiting outbreaks, and Ebola virus is at present causing numerous deaths in Zaire. Since the first descriptions of filovirus disease in the 1960s we have learnt a lot about the clinical features but the natural reservoir remains a mystery. Marburg virus disease is a severe haemorrhagic febrile illness first described in 1967 when 31 cases with 7 deaths in Germany and Yugoslavia were traced to direct contact with blood, organs, or cell culture from a batch of African green monkeys that had been trapped in Uganda. The first recognised outbreak of Marburg disease in Africa occurred in South Africa in 1975 and sporadic cases have been reported from Kenya. In 1976, outbreaks of severe and frequently fatal viral haemorrhagic fever caused by Ebola virus occurred in the equatorial provinces of Sudan and Zaire, giving rise to widespread international concern;l small self-limiting outbreaks recurred in southern Sudan in 1979. There is no evidence that primates were involved in Sudan and Zaire. The illnesses caused by Marburg and Ebola viruses are virtually indistinguishable: an abrupt onset with severe frontal and temporal headache is followed by high fever
Filoviruses,
1252
of
which
Marburg
generalised pains, particularly in the back. The patient rapidly becomes prostrated and develops severe watery diarrhoea with rapid dehydration. In the Sudanese outbreak, knife-like chest and pleuritic pain was an early symptom and many patients complained of a dry throat and cough. On white skins, a characteristic maculopapular rash appears between days 5 and 7 and lasts 3-4 days before desquamation. On black skins the rash is not so obvious. Conjunctivitis has been a regular feature. Many patients in the original outbreaks developed severe bleeding between days 5 and 7. The gut and lungs were most frequently involved, with haematemesis, passage of fresh blood in the stools. There was also bleeding from the nose, gums, and vagina, and subconjunctival haemorrhages were common, as were petechiae and bleeding from needle puncture sites. The patients usually died between days 7 and 16, after severe blood loss and shock. Although monkeys were the source of the 1967 outbreak in Germany and Yugoslavia, primates are not believed to be natural reservoirs of the virus. Studies in the Lake Kyoga region of Uganda, where the Marburg vervet monkeys had been collected, revealed no evidence of an epizootic, nor was any illness detected among monkey trappers. Claims of naturally occurring antibodies to Marburg virus in some African primates have not been generally accepted. Experimental laboratory infection of several primate species produces a uniformly fatal
melaena, and sometimes the
.
’.’
,
. .’","
illness similar to that seen in Ebola human beings. virus, once established, can be transmitted person-to-person, but close and prolonged contact, and particularly blood contact, is necessary for successful transmission.’ Quarantining of known cases is an effective way to contain the spread of infection, but arbitrary quarantining of unproven cases is ridiculous. What happens to primates infected in the wild? Strains of Ebola virus were introduced into the USA in 1989 and 1990 by non-human primates orginating in the Philippines. Although seroconversion occurred in 4 handlers there was no evidence of clinical illness. The monkeys, however, were severely ill and several died. In this issue Le Guenno et al report deaths in wild chimpanzees in a forest area of the Ivory Coast. Ebola virus is the cause of the outbreak and a young zoologist who carried out post-mortem examinations on dead chimpanzees herself became infected but recovered. The latest report is the first clear documentation of a filovirus infection in wild primates. Even so, there is no indication as to where the infection originated, just as there is no indication of the source of infection in the current human outbreak in Zaire. The chimpanzee outbreak reemphasises the susceptibility of primates to filovirus infection-chimpanzees are naturally inquisitive animals with catholic and cannibalistic feeding habits, so infection within the troop is readily understandable-but this susceptibility makes them unlikely candidates as natural reservoirs. Monkeys, rodents, or bats may be stronger candidates. Amid the human tragedy in Zaire, the international research teams have been presented with a golden opportunity to trace Ebola to its origins.
infection and
causes an
D I H Simpson Department of Microbiology and Immunobiology, Queen’s University of Belfast, UK 1 Simpson DIS. Viral hemorrhagic fevers. In: Gillies HM, ed. Epidemiology and control of tropical diseases, vol 1, no 3. Philadelphia: W B Saunders, 1986.
Cardiopulmonary resuscitation and neurological complications in the elderly is that, in a study of cerebral function in The good 774 patients who were comatose after successful cardiopulmonary resuscitation (CPR), Rogove et all found that age alone bore no relation to neurological recovery up to 6 months post arrest. The bad news is that news
6-monthly mortality was considerably higher among elderly individuals. The death rate was 68% in those aged less but 94% in those over 80 years. Good neurological outcome, defined as functional independence outside of institutional care, was achieved in 27%, with no significant difference across age groups. Of the total sample, 86% of the 6-month survivors had a good neurological outcome; this finding was not stratified by age. One could question whether neuropsychological testing would reveal deficits not detected by measurements of functional independence alone. Poor neurological status before the arrest was associated with a high mortality. Earlier studies accord with these general observations. In patients who arrested in hospital, age alone did not influence the chance of survival, but of those who were functionally dependent before arrest, only 4% survived to 45 years
or
discharge and those with severe medical problems did poorly.2 In a report of CPR in patients aged above 70, only 3-8% survived, but with little or no mental impairmentwhereas in another study of in-hospital ex-servicemen none of the patients over age 70 years survived to discharge.4 In a sample of patients with out-ofhospital cardiac arrest, Tresch et a15 reported that those over 70 years had higher mortality than younger patients (71 vs 53%) but no greater neurological impairment on discharge. Other studies in elderly people with a high burden of medical and cognitive dysfunction have shown survival.6 Thus, although mortality from poor arrest is considerably greater in the cardiopulmonary elderly, those who do survive do not seem to have a substantially greater risk of neurological impairment. The results of the Brain Resuscitation Clinical Trial reported by Rogove et al seem counter-intuitive, since most clinicians believe that the brain, like other organs, becomes more vulnerable to hypoxic-ischaemic insults with age. Head injury and stroke (focal ischaemia) data suggest that advanced age is a risk factor for poor neurological outcome.7,1 These two insults probably reflect different pathophysiological processes than those after cardiac arrest, which is usually associated with global ischaemia. Aged brain differs in many respects from the younger-mature brain. There is increasing atrophy9 and neurological loss’° with ageing. There are many theories to explain brain ageing-eg, defects in mitochondrial metabolism," free radicals,12 glucocorticoid sensitivity, 13 calcium neurotoxicity, 14 and excitatory neurotransmitter (glutamate and aspartate) toxicity. 15 Some researchers have extrapolated from changes in excitatory aminoacid metabolism measured in immature brain to propose a mechanism of neural death with ageing.l6 Because it is difficult to culture aged brain tissue, virtually all studies use culture systems from immature brain. However, the assumption that we can understand neurotoxicity in aged brain from such studies is probably erroneous, and there have been no studies on cardiopulmonary arrest or cerebrovascular occlusion in aged animals. Patients who have severe premorbid cerebral impairment or multiple medical disorders, or who are
already substantially functionally dependent, are unlikely survive CPR2-6 The ethical issue, if there is one, is whether we should offer such therapy to individuals whose premorbid state clearly makes functional recovery unlikely. For those elderly people who do survive CPR, the neurological complications do not seem to be substantially worse than those of younger survivors. The next step is to find ways of selecting, for CPR, elderly patients with a reasonable chance of physical survival and to
intact cerebral function. Peter L Carlen, Michael Gordon Playfair Neuroscience Unit, Toronto Hospital Research Institute, Baycrest Centre for Geriatric Care, University of Toronto,
and
Toronto, Ontario, Canada 1
2
Rogove HJ, Safar P, Sutton-Tyrrell K, Abramson NS, Brain Resuscitation Clinical Trial and 11 Study Groups. Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analysis from the Brain Resuscitation Clinical Trials. Crit Care Med 1995; 23: 18-25. Bedell SE, Delbanco TL, Cook EF, Epstein FH. Survival after cardiopulmonary resuscitation in the hospital. N Engl J Med 1983; 309: 570-76.
3
Murphy DJ, Murray AM, Robinson BE, Campion EW. Outcomes of
1253