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Reports to:
TRUSTEES’ REPORT
EXTRACTS – YEAR TO 30 SEPTEMBER 2004
Significant events
The following is a report of the work of Dr Susan Hall who was funded by a grant from
the Foundation over the period under review. The grant holder is Professor David Hall of
the School of Health and Related Research, Sheffield University*. In the narration which
follows the * indicates grant-aided activity. The report also covers some other scientific
activities of the Foundation since these are related to Dr Hall’s (unremunerated) position
as Chair of its Medical and Scientific Advisory Board until January 2004.
- Epidemiological surveillance of Reye’s Syndrome (RS) and related scientific
matters*
Cases of RS reported
As noted in last year’s report, surveillance of RS via the British Paediatric Surveillance Unit ceased in April 2001. However, the arrangements with The Office of National Statistics and The General Register Offices of Northern Ireland and Scotland continued to be maintained throughout the year. Under these, the Offices sent Dr Hall copies of all death entries where RS was mentioned as a cause of death, whatever the age of the subject.
In the year 1 October 2003 to 30 September 2004, no death entries were reported from
Scotland or Northern Ireland; for England there were two deaths - a 21 year old woman
who had had an illness diagnosed as RS when she was 4 months old which left her with
severe brain damage, the complications of which were the cause of death; and a girl aged
2 years 9 months for whom the cause of death was recorded as “Reyes-like syndrome.
Professional education – Workshop on RS and Reye-like inherited metabolic
disorders *
The background, preliminary plans for, and report on this Workshop were outlined in all
the previous annual reports between 1999/2000 and 2002/2003. In summary, its purpose
was to bring together epidemiological, clinical, biochemical and pathologist experts in
the field of RS and RS-like illness to discuss issues of diagnosis and management which would lead to development of an educational package or format clinical guideline for
front line accident and emergency doctors, paediatricians and intensivists. This would
include a contribution to the Advanced Paediatric Life Support (APLS) course and
manual which is taken by all UK paediatricians in training.
The previous annual report to trustees referred to a grant application from the Division of Child Health at Queen’s Medical Centre, Nottingham, which had been stimulated by the
Workshop. Its purpose was to develop a formal evidence-based guideline for the diagnosis, investigation, and management of acute encephalopathy, including RS and metabolic disorders presenting as Reye-like illness in childhood. A Research Fellow (Dr
Richard Bowker) was appointed and the two year project began in November 2003.
Following the Workshop, Professor David Hall and Dr Susan Hall submitted a grant application to the National Reye’s Syndrome Foundation for an extension to their previous grant. This was to enable Dr Hall to:
prepare a report on the proceedings of the Workshop based on the edited transcript.
ii) prepare a report for publication, on 20 years of epidemiological surveillance of
RS in the UK and Ireland and maintain ongoing surveillance of RS via death
entries (v.s.).
implement permanent storage of the RS database.
After external refeering, the grant of £11,600 was awarded. It was intended to cover Dr Hall’s work (part-time – 1.1/2 sessions per week on average) on these projects between
1 June 2002 and 31 May 2003; this was subsequently found to be an over-optimistic estimate of the time required and, with the agreement of the trustees, was extended without alteration to the size of the grant to 31 May 2004.
In August 2004 Professor and Dr Hall submitted an application to the Foundation for an extension to the grant, of £750, specifically to cover the service and data handling charge which the Office for National Statistics had introduced for the first time in October 2002.
and which was therefore not budgeted for in the original grant application. This sum was estimated to cover the period up to December 2005. At the same time a further extension of the original timescale, to December 2005, was requested, again without any alteration to the original grant.
During the year under review, Dr Hall finalised the preparation of the Workshop Proceedings for publication on the Foundation’s website. This was a substantial exercise which involved editing nearly 300 pages of transcript of the recording of the meeting (oral presentations plus extensive discussion sessions). The Proceedings were in nine parts and as the draft of each was completed it was circulated to all participants for comment. A second draft incorporating all the comments was then undertaken. A copy of this second draft was sent to the Nottingham Research Fellow (se above) in October 2003 in order to provide an informative background to the guideline project. The full Proceedings were posted to the website in June 2004 and work began on an executive summary.
To publicise the Proceedings Dr Hall wrote an article for the Royal College of Paediatrics and Child Health (RCPCH) Newsletter which was published in September 2004.
During the year Dr Hall also initiated the process of implementing the Workshop participants’ recommendations for modification of the APLS course and manual. This was done in collaboration with the course organisers (the Advanced Life Support Group) and clinical colleagues. It was timely initiative as the manual was at the time scheduled for updating.
She also assisted with the guideline project by commenting on various papers and on a parent questionnaire.
Advisory scientific and medical support for the National Reye’s Syndrome
Foundation
Over the period under review Dr Hall advised Mr Gordon Denney, the Honorary
Administrator on a number of issues. However, she retired from the Chairmanship of the Medical and Scientific Advisory Board in January 2004. Support included help with responses to medical queries from members of the public and assistance with an update of the Foundation’s website. She also identified misinformation about aspirin use in children on a health site on the web and in the BUPA Newsletter and contacted the appropriate sources to correct this. In addition, regular literature searches for new articles on RS were undertaken and the Hon. Administrator informed about any of interest.
Dr Hall is also asked from time to time to referee articles on RS submitted in scientific journals. She also kept the Hon. Administrator informed about progress with a chapter on Aspirin and Reye’s Syndrome written by her and Dr John Glasgow for a book entitled “Aspirin and Related Drugs” under the editorship of K.D. Rainsford. This was published in September 2004.
Development of a national guideline for the management of children with a reduced conscious level
The following is a statement by Dr Richard Bowker, Clinical Research Fellow, University of Nottingham
As a direct result of the workshop on Reye’s syndrome and Reye-like illnesses held at Doncaster in March 2002, a new project was funded by the National Reye’s Syndrome Foundation commencing November 2003. The project will produce a national clinical guideline for the management of children with a reduced conscious level.
Many children with Reye’s syndrome or Reye-like illness present to hospital with reduced consciousness or coma. Unfortunately, as several other more common
conditions present in childhood with reduced consciousness, the diagnosis of rare metabolic conditions is often overlooked. This inevitably leads to delay in diagnosis and
treatment which can increase the risk of death or long term disability. Developing a guideline based on an easily recognisable problem (i.e. reduced consciousness) should allow junior staff to manage both the common and rare conditions without the need for initial diagnostic skills.
In November 2003, Dr Richard Bowker, a paediatrician in training, was appointed to develop the guideline over two years along with Professor Terence Stephenson, who has produced several national guidelines for children. During the first 18 months, Dr Bowker has brought together a national panel of experts – the guideline development group – to help produce the guideline. He has completed a thorough search of the scientific literature to ensure that the recommendations are evidence-based. The formal consensus process to fill in the gaps where the evidence is lacking, has now been completed The recommendations are nearing their final draft stage and several simple algorithms for use by doctors and nurses have been developed and are about to be piloted.
Many parents have also been invoved in the project, helping the panel of experts to understand what parents and patients expect of the health service when they bring a child to hospital with a reduced conscious level. Dr Bowker and the guideline development group would like to take this opportunity to thank all those who have been involved. Before the final guideline has been published, a parent information leaflet will be drafted. This will be piloted on parents and patients before being published, so your help with this will be greatly appreciated also.
The guideline will be published towards the end of 2005. An external appraisal process by the RCPCH will take place, after which time the guideline will be available for all paediatricians and emergency department staff to use when children present to them with a reduced level of consciousness. This should improve the rapid access to the best treatments available.
For further details on the production of the guideline, there is a website which can be accessed. viz www.nottingham.ac.uk/paediatric-guideline
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TRUSTEES’ REPORT
EXTRACTS – YEAR TO 30 SEPTEMBER 2003
Significant events
The following details set out in paragraphs 1,2 and 3 below is a report of the work of Dr Susan Hall who was awarded a grant from the Foundation over the period under review. The grant holder is Professor David Hall of the School of Health and Related Research, Sheffield University. The items indicated with a * indicate grant-aided activity. The report also covers other scientific activities of the Foundation since these are related to Dr Hall’s (unremunerated) position as Chair of its Medical and Scientific Advisory Board (MSAB).
1. Epidemiological surveillance of Reye’s Syndrome (RS) and related scientific
matters*
Cases of RS Reported
As noted in last year’s report, surveillance of RS via the British Paediatric Surveillance Unit ceased in April 2001. However, the arrangements with the Office of National Statistics and The General Register Offices of Northern Ireland and Scotland continued to be maintained throughout the year. Under these, the Offices sent Dr Hall copies of all death entries where RS was mentioned as a cause of death, whatever the age of the subject.
In the financial year 2002/2003, no RS deaths were reported from Scotland and Northern Ireland; for England there were two deaths – a 23 year old male and a 17 year old female. In both of these it was apparent from the information on the death entry that RS was not the primary cause of death which was probably caused by complications of RS, or a Reye-like illness, acquired some time previously.
Work with the Medicines Control Agency (MCA – now the Medicines and
Healthcare Products Regulatory Agency (MHRA) and the Committee on
Safety of Medicines (CSM),
Background
It was noted in an earlier report that, towards the end of 2001, the CSM had considered reversing its earlier decision not to increase the upper age limit (12 years) on the warning on all aspirin-containing medications. This was at least in part because representations
made by Dr Hall and the Foundation, based on results from the Reye’s Syndrome Surveillance Scheme. A new warning was subsequently announced in April 2002 which stated ‘do not give to children under 12 unless medically indicated and avoid in children aged up to and including 15 if feverish’. There was modest media coverage but no major public information campaign or indication as to when product labelling would change.
In May 2002 Dr Hall was asked by the MCA to comment on the proposed new warning after she had written to ask when there was to be a publicity campaign and changes to labelling. She pointed out that the plan to delay the campaign until the start of the following influenza season could result in the occurrence of preventable cases of RS in teenagers in the ensuing 6 months or so. Unfortunately the MCA’s response was that there was concern that an ‘immediate’ public campaign would cause alarm and have a negative impact on the use of aspirin for important therapeutic indications such as cardiovascular prophylaxis. The MCA considered that alerting medical professionals was sufficient at that time. Dr Hall registered her concern at this approach.
Events in the year under review:-
In October 2002, the CSM decided that the April warning was too complex and modified it to ‘do not give to children under 16 years unless on the advice of a doctor’. This was announced in a press release (which resulted in considerable press and TV coverage of RS and the Foundation) and in the MCA’s journal – Current Problems in Pharmacovigilance. The MCA also announced its launch of an 8 week public consultation on a proposal to amend the Medicines for Human Use Regulations 1994, in order to introduce a legal requirement for a harmonised warning (the October one above) on all aspirin products about the risk of RS associated with aspirin use. Dr Hall prepared and submitted a response to this consultation in her capacity as consultant epidemiologist responsible for RS surveillance, in collaboration with Mr Richard Lynn, Scientific Officer of the British Paediatric Surveillance Unit; she also assisted in the preparation of the Foundation’s response by the Honorary Administrator, Mr Gordon Denney.
The results of this consultation exercise were made public in April 2003. Of 39 replies, 25 supported the proposals, 12 made no comment and only 2 objected – one individual and one pharmaceutical company.
In June 2003 the Amendment Regulations were laid before Parliament, they came into force on 1st October 2003. This now concludes the efforts of Dr Hall, the Foundation and many others to introduce this important public health measure to prevent childhood deaths and disability from RS.
Advisory Scientific and Medical Support for the National Reye’s Syndrome
Foundation
Over the period under review, Dr Hall has advised the Honorary Administrator on a number of items.
Grant applications:-
The previous annual report referred to a grant application from the School of
Biomedical Sciences, Queen’s Medical College (QMC), Nottingham; to undertake laboratory studies into the causation of RS. In October 2002, following a review of the responses of external referees, Dr Hall wrote to the Hon Administrator to recommend to the trustees that the Foundation should support the project by awarding the £50,000 requested. However, she also advised that the release of the funds should be conditional on the applicant’s response to a number of points, for example evidence of local research ethics committee approval. The trustees agreed to make the award under these conditions and the investigators were informed of their decision later that month. One of the investigators wrote to Dr Hall in May 2003 to say that ethics approval confirmation was due within a month and that the project would probably begin in January 2004. However, there was no further communication from the investigators in the period under review*
ii) The previous annual report also referred to a grant application from the Division of
Child Health at QMC, Nottingham, submitted in July 2002. It had been stimulated by the
Workshop (see below) and its purpose was to develop a guideline for the diagnosis,
investigation and management of acute encephalopathy, including RS and metabolic
disorders presenting as Reye-like illness in childhood. The application was referred by 8
reviewers including Dr Hall and the Foundation’s Medical and Scientific Advisory
Board.
In October 2002 Dr Hall wrote to the lead investigator – Professor Terence Stephenson – to ask him to respond to the referees’ comments. A response was received in January 2003 and on the basis of this Dr Hall wrote to the Honorary Administrator to recommend to the trustees that the Foundation should support the project by awarding £96,000 requested. Following a visit to Nottingham by the Hon. Administrator, the trustees agreed to make this award. A Research Fellow – Dr Richard Bowker – was appointed in September and the two year project began in November 2003.
Other support:-
This included help with responses to medical queries from members of the public and assistance with an update to the Foundation’s leaflets and the website and a contribution to the Foundation’s 2003 Newsletter on the history of Dr Hall’s association with epidemiological studies of RS and with the Foundation. In addition, regular literature searches for new articles on RS were undertaken, and the Hon Administrator informed about any of interest. Dr Hall is also asked from time to time to referee articles on RS submitted to scientific journals. She also kept Mr Denney informed about progress with a chapter on Aspirin and Reye’s Syndrome written by her and Dr John Glasgow for a book entitled “Aspirin and Related Drugs” to be published in 2004.
Professional education – Workshop on RS and Reye-like inherited metabolic
disorders*
The background, preliminary plans for, and report on this Workshop were outlined in previous Annual Reports, 1999/2000 through to 2001/2002. In summary, its purpose was to bring together epidemiological, clinical, biochemical and pathologist experts in the field of RS and RS-like illness to discuss issues of diagnosis and management which would lead to development of an educational package or formal clinical guideline for front line accident and emergency doctors, paediatricians and intensivists. This would include a contribution to the Advanced Paediatric Life Support course and manual which is taken by all UK paediatricians in training.
Following the Workshop, Professor David Hall and Dr Susan Hall submitted a grant application to the National Reye’s Syndrome Foundation for an extension to their previous grant. This was to enable Dr Hall to:
Prepare a report on the proceedings of the Workshop based on the edited transcript..
Prepare a report for publication, on the 20 years of epidemiological surveillance of RS in the UK and Ireland and maintain ongoing surveillance of RS via death entries (v.s.).
3 Implement permanent storage of the RS database.
After external refereeing, the grant of £11,600 was awarded. It was intended to cover Dr Hall’s work (part-time – 1 ½ sessions per week on average) on these projects between 1 June 2002 and 31 May 2003; this was subsequently found to be an overoptimistic estimate of the time required and, with the agreement of the Hon. Administrator, was extended without alteration to the size of the grant, to 31 May 2004.
During the year under review, Dr Hall worked on the preparation of the Workshop Proceedings for publication on the Foundation’s website. This was a substantial exercise which involved editing nearly 300 pages of transcript of the recording of the meeting (oral presentations plus extensive discussion sessions). Because the subject matter was so complex, the typists had had difficulties at times and much of the editing had to be done in conjunction with the original recordings. In addition, there were written contributions in a variety of formats from 23 participants – ranging in length from 1 to 27 pages – and two PowerPoint presentations, to be incorporated in the text and co-ordinated with each participant’s oral presentation. The Proceedings are in seven parts and as the draft of each was completed it was circulated to all participants for comment. A second draft incorporating all the comments was then undertaken. A copy of this second draft was sent to the Nottingham Research Fellow (see above) in October 2003 in order to provide an informative background to the guideline project.
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TRUSTEES’ REPORT
EXTRACTS – YEAR TO 30 SEPTEMBER 2002
Significant events
- The following detail set out in paragraphs 1 and 2 below is a report of the work of Dr Susan Hall
who was awarded grants from the Foundation over the period under review. The grant holder is
Professor David Hall of the School of Health and Related Research, Sheffield University.
- Epidemiological surveillance of Reye's Syndrome (RS) and related scientific matters
(a) Cases of RS Reported
As noted in last year's report, surveillance of RS via the British Paediatric Surveillance Unit
ceased in April 2001. However, the arrangements with The Office of National Statistics and
The General Register Offices of Northern Ireland and Scotland continued to be maintained
throughout the year. Under these, the Offices sent Dr Hall copies of all death entries where
RS was mentioned as a cause of death, whatever the age of the subject.
In the year ended 30 September 2002, no RS deaths were reported from Scotland; there were no RS deaths in Northern Ireland in 2001 but data for 2002 are still awaited; for England there were three deaths - a 35 year old man in December 2001, a 13 year old girl in April 2002 and a one year old boy in May 2002. Only the second case had classical RS and she had been given aspirin. One further death was notified during the year, although the child; a 13 year old boy, had died in 2000.
This was an atypical case, being a sudden unexpected death, and there was no report of
aspirin having been given.
There are three other possible mechanisms by which RS continues to be monitored:
the most important, because it is permanent, is the 'yellow card' adverse drug reaction (ADR)
voluntary reporting scheme run by The Medicines Control Agency (MCA - now called The
Medicines & Health Care Products Regulatory Agency - MHPRA). As RS is an adverse
reaction to aspirin, all aspirin associated cases should be reported. Dr Hall informed the
MCA about the 13 year old girl mentioned above. The case had not been notified at the time,
but the report was subsequently validated by the MCA via the clinician and the pathologists
involved and was officially entered into the ADR system.
There are two studies conducted via the British Paediatric Surveillance Unit which might
ascertain cases of RS. Dr Hall is not directly involved with them, but has asked to be informed if this occurs. They are surveillance schemes for Suspected Fatal Adverse Drug reactions in Children, which runs between June 2002 and June 2003, lead investigator Professor Terence Stephenson, Queens Medical Centre, Nottingham; and Severe Complications of Varicella, which runs for one year from Autumn 2002, lead investigator Dr Claire Bramley, Scottish Centre for Infection and Environmental Health, Glasgow.
(b) Work with the MCA/MHPRA and Associated Work arising from Representations made by
the European Aspirin Foundation (EAF)
It was noted in the previous report that, towards the end of 2001, the Committee on Safety of
Medicines had considered reversing its earlier decision not to increase the age limit on the
aspirin warning. This was at least in part because of representations made by Dr Hall based
on results from the Reye's Syndrome Surveillance Scheme. A new warning was subsequently announced in April 2002 which stated 'do not give to children under 12 unless medically indicated and avoid in children aged up to and including 15 if feverish'. There was modest media coverage but no major public information campaign or indication as to when product labelling would change.
In October 2001, presumably at a time when the CSM/MCA was discussing its proposed new labelling with industry, Dr Hall was approached by the chairman of the Liver Steering Group (LSG) of the British Society for Paediatric Gastroenterology, Hepatology and Nutrition, for advice on how to respond to representations recently made to its members by the EAF. The EAF was seeking help to 'resist pressure from the MCA to agree to a voluntary ban on aspirin use in teenagers'. Dr Hall prepared a briefing paper to assist the LSG chairman in his discussions with his members as to how to respond to the EAF. In the end, the Society decided not to assist the EAF with an opinion on this issue.
In May 2002 Dr Hall was asked by the MCA to comment on the proposed new warning after
she had written to ask when there was to be a publicity campaign and changes to labelling.
She pointed out that the plan to delay the campaign until the start of the following influenza
season could result in the occurrence of preventable cases of RS in teenagers in the ensuing 6 months or so. Unfortunately the response was that there was concern that an ‘immediate’ public campaign would cause alarm and have a negative impact on the use of aspirin for important therapeutic indications such as cardiovascular prophylaxis. The MCA considered that alerting medical professionals was sufficient at that time. Dr Hall registered her concern at this approach. {In October 2002, the CSM decided that the April warning was too complex and modified it to 'do not give to children under 16 years unless on the advice of a doctor'}.
(c) Advisory Scientific and Medical Support for the National Reye's Syndrome Foundation
Over the period under review, Dr Hall has advised the Honorary Administrator - Mr G Denney - on a number of issues arising from correspondence received by him. These included a further review, following referees' responses, of a grant application from the School of Biomedical Sciences, Queens Medical College (QMC) Nottingham, to undertake laboratory studies into the causation of RS. There was also a new grant application from the Division of Child Health at QMC, Nottingham, submitted in July 2002. It had been stimulated by the Workshop (see below) and its purpose was to develop a guideline for the diagnosis, investigation, and management of acute encephalopathy, including RS and metabolic disorders presenting as Reye-like illness in childhood. The application was refereed by 8 reviewers including Dr Hall and the Foundation's Medical and Scientific Advisory Board.
In September 2002 the Foundation was approached by the EAF with a further request for a meeting to revisit the evidence linking aspirin and RS (they had earlier made such a request in April 2000 - see annual report 1999/2000). The EAF considered that some recent publications justified this and also enclosed material devised by them for a public information campaign about the new age limit on the warning (see 1b above). Dr Hall reviewed all the evidence as well as the original request and advised the NRSF that there was no case for such a meeting. She advised the NRSF to express concern about some of the content of the EAF material. The correspondence was copied to the MCA, who also expressed concern about this material.
Other support includes responses to medical queries from members of the public and assistance with an update of the Foundation's leaflets.
- Professional education - Workshop on RS and Reye-like inherited metabolic disorders
The background and preliminary plans for this Workshop are outlined in previous Annual Reports, 1999/2000 and 2000/2001. In summary, its purpose was to bring together epidemiological, clinical, biochemical and pathologist experts in the field of RS and RS-like illness to discuss issues of diagnosis and management which would lead to development of an educational package or formal clinical guideline for front line accident and emergency doctors, paediatricians and intensivists.
The Workshop was residential and was held over one and a half days in March 2002 at a College of Further Education near Doncaster. There were 28 participants including 2 moderators (Dr Roddy McFaul and Professor David Hall, the then President of the Royal College of Paediatrics and Child Health). Among the participants were - paediatricians specialising in inherited metabolic disorders (IMDs), IMD specialist nurses, paediatric neurologists, paediatric hepatologists, paediatric A & E specialists, a paediatric intensivist, clinical chemists, paediatric pathologists, general paediatricians and a guideline methodologist. There were two parent representatives - one from the National Reye's Syndrome Foundation (Mr G Denney), the other from CLIMB (Mrs L Greene).
In November 2001, a briefing document was sent to Workshop participants which included a
framework of detailed questions which broke down the main issues into a series of small steps in question form. Twenty six participants were invited to address specific questions related to their area of expertise. They were asked to submit a short paper with their responses supported by published evidence wherever possible. These papers were submitted in advance and circulated prior to the Workshop so that, on the day, only a brief oral presentation was required and most of the time could be spent in round table discussion.
The main subject headings of the sessions were - "what is the evidence that we have a problem?; clinical diagnosis; laboratory diagnosis; autopsy diagnosis; management; obstacles to achieving best practice; dissemination and implementation of educational packages/guidelines".
The entire meeting was professionally recorded and the transcript typed. The organisation of the meeting was undertaken by Dr Hall supported by a small Steering Group. The Workshop was fully funded by the National Reye's Syndrome Foundation. Participants considered that it had been most successful. One of the most important outcomes was the stimulation of a highly respected and experienced group at Nottingham University to submit a grant application to the Foundation for development of a formal guideline (see above). This was unlikely to have happened in the absence of the Workshop.
Shortly after the Workshop, Professor David Hall and Dr Susan Hall submitted a grant application to the National Reye's Syndrome Foundation for a 1 year extension to their previous grant. This was to enable Dr Hall to:
i) Prepare a report on the proceedings of the Workshop based on the edited transcript. It was proposed that this should be made available eventually on a CD and on the Reye's Syndrome Foundation website. The CD would be publicised via the website and the Royal College of Paediatrics and Child Health and was hoped to be subject of an annotation to be submitted to the Archives of Disease in Childhood by the Workshop Steering Group. It would also be made available to the Nottingham researchers preparing the guideline (see above).
ii) Prepare a report for publication, on 20 years of epidemiological surveillance of RS in the UK and Ireland.
iii) Implement permanent storage of the RS database.
After external refereeing, the grant was awarded in August 2002 and work on the proceedings is currently (May 2003) in progress.
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TRUSTEES’ REPORT
EXTRACTS – YEAR TO 30 SEPTEMBER 2001
Significant events
- The significant events in the year ended 30 September 2001 were as follows:
(i) Epidemiological surveillance of Reye's Syndrome
- The objectives of this project are to describe the epidemiological and clinical features of Reye's Syndrome (RS) in children in the British Isles, to monitor long term trends, and to
provide a database for detailed clinical, laboratory, and aetiological studies. The work is
undertaken by Dr Susan Hall, consultant epidemiologist and honorary lecturer in the Department of Paediatrics, Sheffield University; and by Mr Richard Lynn, research officer at
the Royal College of Paediatrics and Child Health (RCPCH).
Surveillance of RS began in August 1981 as a venture shared between the (then) British
Paediatric Association and the Public Health Laboratory Service Communicable Disease
Surveillance Unit (CDSC). Responsibility for case ascertainment was transferred to the
British Paediatric Surveillance Unit (BPSU) of the RCPCH in June 1986 and from CDSC to
the Department of Paediatrics at Sheffield in 1995. From this point onwards the surveillance
scheme has been supported entirely by the National Reye's Syndrome Foundation of the UK. The grant holder is Professor David Hall, Sheffield Centre for Health and Related Research, Sheffield University.
- In addition to BPSU reporting, cases are also ascertained via death entries provided by the Office for National Statistics, the General Registry Office for Scotland, the Northern Ireland Statistics and Research Agency, and via laboratory reports to CDSC.
There is increasing recognition that a number of inherited metabolic disorders - most notably those affecting fat oxidation and ureagenesis, may present as a 'Reye-like' illness, clinically and pathologically indistinguishable from classic RS. The surveillance questionnaire therefore seeks information on whether patients have been investigated for these disorders.
- The surveillance scheme ended in April 2001 because so few cases of classic RS were occurring and because of competition for space on the BPSU report card from other projects.
Annual Report
- The report for the period 1 August 1999 - 30 April 2001 was published in the BPSU Annual Report in September 2001. Key findings were as follows:
Between August 1981 and April 2001 a total of 632 suspected cases of RS were reported but the diagnosis was subsequently revised in 164 (26%). Eighty one (49%) of the revisions were to one of the 'Reye-like' inherited metabolic disorders. Two hundred and thirty nine (53%) of the total 450 cases compatible with a diagnosis of RS died.
In the year to 31 July 2000, four reports of new cases were received and further information was provided on all of them. One of the four diagnoses was later revised, leaving three patients whose clinical and pathological features were compatible with the case definition of RS. Three of the cases were first reported via the BPSU, one was ascertained only via a death entry.
In the period 1 August 2000 to 30 April 2001, three reports were received; further information was provided on two. One of the diagnoses was later revised; in the other case a specific alternative diagnosis was not reached, but an inherited metabolic disorder was so strongly suspected that RS was not recorded as a cause of death.
This Annual Report was the last in the series which started in 1981/82, when surveillance of RS began. As the first clinical reporting scheme involving paediatricians in the UK and Ireland in the epidemiological surveillance of rare disorders of public health importance, the RS surveillance scheme was a forerunner of the BPSU. It is fitting that the total cases in the last complete surveillance year, three (none of whom had classic, aspirin associated RS) equalled the lowest total recorded in 19 years and that, up to the end of surveillance in April 2001, there were no cases at all. It is fitting because the trends vindicate the public health action taken on the use of aspirin in children in 1986 which, as also reported in the United States, represents a triumph for primary prevention of a devastating childhood illness.
National surveillance of RS through paediatrician reporting has now ceased, but two important issues remain:
First - classic, aspirin-associated Reye's syndrome has now become so rare that some clinicians have dismissed it as being no longer of any clinical importance. However, this is a dangerously complacent view of a disease capable of re-emergence during a major influenza epidemic or pandemic (it is now 10 years since the annual influenza incidence rose to epidemic levels and even these were not as high as in the last major epidemic in the 1970's) if aspirin warnings are disregarded or ignored because the child is over 12. The decline of RS means that a new generation of paediatricians in training and young consultants will certainly never have seen or heard about a case and are unlikely to have read about it or had it included in educational materials.
Furthermore, it is likely to be under-recognised by physicians caring for teenagers and older adults with acute encephalopathy. Thus if there is a resurgence, the "old days" of late diagnosis, late or inappropriate treatment and poor outcome in terms of mortality and brain damaged survivors may be seen again.
It is, therefore, most important that RS is not forgotten or removed from the differential diagnosis of a child presenting with encephalopathy following a viral prodrome. The incidence should continue to be monitored, if less intensively that via the BPSU. Methods of achieving this are currently under consideration, but in the meantime it is essential that such cases are considered as an adverse drug reaction to aspirin and reported to the Committee on Safety of Medicines via the "yellow card". This will reveal any upsurge in the event of an influenza epidemic which might require action in the form of public education, and will inform any re-evaluation by the regulatory authorities of the upper age limit on the warning.
Second - because the classic form of the illness has become so rare, it is now more likely that a patient presenting with a Reye's syndrome-like illness has an inherited metabolic disorder especially if the child is aged under three years (although these disorders can present in later childhood or even in adult life). All of the six cases reported in 1999/2000 and 2000/2001 for whom further information was provided were atypical for classic RS and five were under two years of age. Three of them subsequently did have a revised diagnosis - to an inherited metabolic disorder in two.
The observation that all reported cases in these last one and a half surveillance years had at least some investigations for inherited metabolic disorders and that numbers of reports of atypical cases have also declined in recent years, suggests that diagnostic awareness of these conditions has increased.
(ii) Work with the Medicines Control Agency
- During 1999, anonymised data from the surveillance scheme were requested by the Medicines Control Agency for a paper to be put before the Committee on Safety of Medicines. This paper reviewed the case for increasing the age limit on the UK aspirin warning to include teenagers (as it does in the USA) and was partly prompted by the observation that, of 17 aspirin-associated cases reported since June 1986,10 were aged over 12. The Committee on Safety of Medicines reached its decision in November 2000: it concluded that extension of the existing advice to include children aged 12 years and above "could not presently be justified".
This disappointing decision was challenged by Dr Hall in 2001. The outcome was that the Committee on Safety of Medicines reversed its decision. It sought further input from the Surveillance Scheme into the preparation of new cautionary advice on the use of aspirin in children under 16, which was recently published (April 2002).
(iii) Advisory support for the National Reye's Syndrome Foundation
Over the period under review, Dr Hall has advised the Honorary Administrator of the Foundation on a number of issues arising from correspondence received by him. These include a review of a grant application from the School of Biomedical Sciences, Queens Medical Centre, Nottingham to undertake laboratory studies into the causation of RS and an approach from an animal rights organisation. She also advised on the content of the Foundation's new website which was set up in 2001.
(iv) Professional Education
- In the report for the year ending September 2000, mention was made of a proposal to organise a Workshop, to be fully funded by the Foundation. The principal goal of this workshop would be to set up an educational initiative to optimise the diagnosis and management of Reye-like childhood encephalopathies and of classic RS in the UK.
During the remainder of 2000 and in 2001, support for the Workshop was gained from the Executive Committee of the RCPCH and from the British Inherited Metabolic Disease Group (BIMDG - a professional association to which doctors and others in allied disciplines who specialise in these disorders belong). A Workshop Steering Group was convened. This consisted of Dr Hall, the Chair of the RCPCH Quality of Practice Committee and a consultant paediatrician specialising in inherited metabolic disorders and representing the BIMDG.
Preliminary plans were drawn up at a meeting of the Group in April.
At this time, Dr Hall obtained permission from the Foundation's Trustees to use part of the balance of her grant for running the surveillance scheme to support her in planning and organising the Workshop. This work included selecting and inviting participants, organising a suitable date and venue and preparing a briefing document. The latter consisted of a framework of questions about the diagnosis and management of RS and Reye-like disorders, which were to be allocated to individual participants according to their expertise. By the end of September 2001, a date (March 2002) and venue for the Workshop had been set, participants invited and the briefing document drafted.
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The significant events in the year ended 30 September 2000 were as follows:
(I) Epidemiological surveillance of Reye's Syndrome
The objectives of this project are: to describe the epidemiological and clinical features of Reye's syndrome in children in the British Isles, to monitor long term trends, and to provide a database for detailed clinical, laboratory, and aetiological studies. The work is undertaken by Dr Susan Hall, consultant epidemiologist and honorary lecturer in the Department of Paediatrics, Sheffield University; and by Mr. Richard Lynn, research officer of the Royal College of Paediatrics and Child Health (RCPCH).
Surveillance of Reye's syndrome began in August 1981 as a venture shared between the (then) British Paediatric Association and the Public Health Laboratory Service Communicable Disease Surveillance Centre (CDSC). Responsibility for case ascertainment was transferred to the British Paediatric Surveillance Unit (BPSU) of the RCPCH in June 1986 and from the CDSC to the Department of Paediatrics at Sheffield in 1995. From this point onwards the surveillance scheme has been supported entirely by the National Reye's Syndrome Foundation of the UK. The grant holder is Professor David Hall, Sheffield Centre of Health and Related Research, Sheffield University.
In addition to BPSU reporting, cases are also ascertained via death entries provided by the Office for National Statistics, the General Registry Office for Scotland, the Northern Ireland Statistics and Research Agency, and via laboratory reports to CDSC.
There is increasing recognition that a number of inherited metabolic disorders - most notably those affecting fat oxidation and ureagenesis, may present as a 'Reye-like' illness, clinically and pathologically indistinguishable from Reye's syndrome. The surveillance questionnaire, although currently in its simplest and shortest format since 1981, therefore seeks information on whether patients have been investigated for these disorders.
Annual Report
The report for the year 1 August 1998 - 31 July 1999 was published in the BPSU Annual Report in September 2000.
(http://bpsu.rcpch.ac.uk)
(ii) Work with the Medicines Control Agency
During 1999 anonymised data from surveillance scheme were requested by the Medicines Control Agency for a paper to be put before the Committee on Safety of Medicines. This paper reviewed the case for increasing the age limit on the UK aspirin warning to include teenagers (as it does in the USA) and was partly prompted by the observation that, of 17 aspirin-associated cases reported since June 1986, 10 have been aged over 12. The Committee on Safety of Medicines reached its decision in November 2000; it "was of the opinion that there is currently insufficient evidence of a causal association in these children, and therefore advised that extension of the existing advice to include children aged 12 years and above could not presently be justified."
This was a disappointing decision, especially in view of the two aspirin associated cases over 12 in the year under review and the decision has been challenged by Dr. Hall. However, the Committee went on to advise that: "monitoring of the incidence of Reye's syndrome should continue, as clearer trends may emerge in the future". They further noted that "a review of this issue might well be appropriate when additional information is available". (See also www.bmj.com June 30th 2001, MC McGovern et al: Reye's syndrome and aspirin: "lest we forget" for further information on Reye's syndrome in children over 12).
(iii) Advisory Support for the National Reye's Syndrome Foundation (NRSF/UK)
Over the period under review, Dr Hall has advised the Honorary Administrator of the Foundation on a number of issues arising from correspondence received by him. These included a grant application from the Department of Clinical Chemistry at Sheffield Children's Hospital, which was awarded after minor modifications to the protocol. She has also maintained literature searches, provided the Foundation with copies and has obtained copies of relevant original papers.
European Aspirin Foundation (EAF)
Towards the end of 1999, the Honorary Administrator was invited to meet the Executive Director of the EAF in order to discuss issues raised at a scientific meeting hosted by the EAF in Edinburgh in September 1999. There had been two presentations by statisticians who sought to demonstrate that the evidence linking aspirin and Reye's syndrome was seriously flawed. There were also unpublished data from France, made available to the EAF but not presented at Edinburgh, which allegedly threw further doubt on the link. The EAF was now proposing a further meeting involving both the MCA and scientists nominated by both it and the NRSF/UK, to attempt to establish "the scientific truth". There was also a suggestion of possible collaborative research.
This approach clearly required a considerable response by the NRSF/UK and Dr Hall undertook to prepare this by both formally consulting members of its Medical and Scientific Advisory Board and seeking independent statistical advice. She also contacted the author of the French work. The responses were collated into a report which was forwarded to the EAF.
This report concluded that, while the approach from the EAF had raised some most interesting issues and provided the stimulus to revisit the evidence linking aspirin and Reye's syndrome, it was the EAF who had a case to make, not the NRSF/UK. How they would do this was up to them, but one would expect to see both the statistical critiques, presented at Edinburgh, and the French data, published in peer review journals. Once these had undergone scrutiny and acceptance by the scientific community, for example in journal correspondence or in accompanying commentary, then there might be a case for the EAF to commission someone to design a protocol to answer whatever research questions they thought appropriate. This might then be submitted as a grant application to the NRSF/UK and it would have to undergo the same peer review process expected of other applications.
If that research (whether funded by the NRSF/UK or elsewhere) demonstrates that there is substantial cause to doubt the Reye's syndrome-aspirin association, then clearly it would be important for the two organisations to meet, with Medicines Control Agency involvement, to try to establish agreement on the scientific truth. Until that time comes, such a meeting would not serve any useful purpose. By September 2000 no response to the Foundation's report had been received from the EAF.
(iv) Register of Inherited Metabolic Disorders
In 1998 a grant, the application for which was prepared by Dr S Hall and Professor D Hall, was awarded to the Research Unit of the Royal College of Paediatrics and Child Health (RCPCH) jointly by the Research Trust for Metabolic Diseases in Childhood (now called "Climb") and the NRSF/UK. This was for a feasibility study of a surveillance scheme to monitor the effectiveness of tandem mass spectrometry (TMS) screening for inherited metabolic disorders (IMDs) when this is initiated as a national programme. The study was to be conducted by a senior researcher who was in part advised and supervised by Dr Hall. The work was relevant to Reye's syndrome surveillance because of the potential importance of ascertaining all unexplained childhood encephalopathies, including those which are Reye-like, in order to detect cases missed by screening.
The study was completed and the report was published by the RCPCH in August 2000. It was also submitted to the National Screening Committee of the Department of Health, who wished to consider the implications of implementing its recommendations.
(v) Professional Education
Concerns about "Classic" RS
Some clinicians have dismissed classic Reye's syndrome as being no longer of any clinical importance because of the action on aspirin which has reduced the incidence of this condition. However, for a disease with the capability of re-emergence during a major influenza epidemic or pandemic, especially if aspirin warnings are disregarded or else ignored because the child is aged over 12 years, this is a dangerously complacent view. The decline of Reye's syndrome means that a new generation of paediatricians in training and young consultants will certainly never have seen or heard about a case and are unlikely to have read about it or had it included in educational materials. Furthermore, it is very likely to be unknown to/under-recognised by, physicians caring for teenagers and older adults. Thus, if there is a resurgence, we shall return to the "old days" of late diagnosis, late or inappropriate treatment and poor outcome in terms of mortality and brain damaged survivors.
Concerns about Reye-like disorders
The findings of the British Reye's syndrome surveillance scheme (BRSSS) have recently prompted concern that some infants and children are sub-optimally investigated for IMDs when they present with a Reye-like encephalopathy or when they die suddenly and unexpectedly. In the latter situation the diagnosis of "Reye's syndrome" is made at autopsy, usually on the basis of fatty change in the liver and (but not always) cerebral oedema. Of 54 cases reported between 1992/93 and 1999/00 in whom the diagnosis of Reye's syndrome was not revised, 24 fell in this second category. It is depressing that this state of affairs continues in 1999/2000 in spite of publications in 1992 and 1996, based on the BRSSS, which emphasised the importance of investigating such cases for IMDs.
Although numbers of cases are relatively small, patients and parents still deserve accurate diagnoses, not least because of the implications for specific treatment, pre-natal diagnosis of future siblings and investigation of existing siblings. In these days of heightened public expectations and of availability of information about medical conditions on the Internet, clinicians and pathologists will be under increasing pressure from parents to provide specific diagnostic labels to account for a child's unexplained illness or death. The frustration, grief and anger of unfulfilled expectations may eventually result in litigation in some cases.
In recent years, the children of parents who approach the NRSF/UK for support have increasingly been likely to have had a Reye-like illness rather than classic Reye's syndrome. Some of these children have been reported to the BRSSS as having had Reye's syndrome, but have been inadequately investigated for IMDs or not at all, and therefore the Foundation has become interested in widening its educational initiatives to address methods of improving the diagnosis of these disorders.
In August 2000 a meeting between the Foundation's Honorary Administrator and Professor and Dr Hall was held at which, inter alia, possible educational strategies were discussed. It was agreed that Professor and Dr Hall should approach the chairman of the British Inherited Metabolic Disease Group with a view to organising a workshop in 2001. The principal goal of this workshop would be to set up an educational initiative to optimise the diagnosis and management of Reye-like childhood encephalopathies and of classic Reye's syndrome in the UK. There would be three specific objectives to achieve:
a) Determining the content of the educational package
b) Determining the optimum methods of its dissemination
c) Implementation
The content of the package would consist of consensus evidence-based guidelines devised by experts in the field. Methods of dissemination might include publication in a journal; publication on the RCPCH and RCPath websites; a dedicated website; a CD; a poster, a proforma for insertion in medical records; other media recommended by experts in medical education. It would also be important to include the guidelines in paediatric and pathologist training curricula and to include them in Membership examination questions.
It was further agreed that, in principle, the Foundation would be willing to consider a grant application from the steering group which would be convened to organise the workshop. (About the National Reye's Syndrome Foundation).
Submitted by
Dr Susan Hall, MSc, FRCP, FFPHM, FRCPCH
9.2.01
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