ＷＨＯ記者会見：ＰｒｏＭＥＤ ＳＡＲＳ世界情報（５３）
04-16(0418-0020)#C#重症急性呼吸器症候群−世界各国(53)：病因。
[1] 情報源：WHO記者会見、4月16日
[モデレーター注：以下は、2003年4月16日水曜日にスイス、ジュネーブGeneva
で開催されたWHO記者会見からの要約で参加者は以下の通り。
WHOより；
執行長官Dr. David Heymann、
感染症プログラム 臨床管理コーディネーターDr. Mark Salter、
SARS病因コーディネーターDr. Klaus Stohr;
プロジェクトリーダー WHO世界インフルエンザプログラムDick Thompson報道官。
SARS研究所ネットワークから：
フランクフルト、ゲーテ大学
ヨハン・ウォルフガング臨床ウイルス医学研究所
（マールブルグ大学、ハンブルグ、熱帯医学研究所と共同）
Dr. Christian Drosten医師;
イギリス中央公衆衛生研究所Dr. Robin Gopal;
米国国立感染症センター、CDC, Dr. James Le Duc;
シンガポール、シンガポール総合病院(SGH) Dr. Aiee Ling;
オランダ、国立インフルエンザセンター、
エラスムス大学Dr.Albert Osterhaus;
日本、東京、国立感染症研究所 田代眞人博士;
フランス国立インフルエンザセンター、パスツール研究所 Dr.Sylvie van der Werf。]
フロアからの質問：
“第一はWHOがウェブサイトで提示しているPCR法に関しての質問。
この検査法は無症状のSARS患者も検出できるか？
第二は治療薬に関しての質問。
香港ではリバビリンとステロイドを治療に用いている。これらの薬剤が
乳幼児や妊婦に多大な副作用があることを経験しているが、あなた方の国
でこれらの薬剤を用いているか、あなた方の推奨する処方が何であるかお伺い
したい。漢方薬と西洋医学の薬剤を組み合わせる可能性についてもお伺いした
い。第3の質問はAmoy Gardensの状況に関してのものである。感染伝播様式の
特殊性だけでなく、Amoy Gardensの患者はリバビリンとステロイドに反応が悪
いようである。彼らは下痢などの他の症状がある。同様に、死亡したり重症化
したりする多くのSARS症例が40歳以上であるのに反して、香港では基礎疾患の
ない30歳代、40歳代の人が患者になり、SARSで死亡しており、多くはAmoy
Gardensからの患者である。これに関しする考えは？
”Stohr医師の返答：
“PCR法に関するフロアからの質問はDrosten医師に返答
をお願いしたいコロナウイルスが病原体として同定され、この病原体に対して
より特異的な診断法を開発可能となったことを強調したい。現在一つの病原体
に集中出来るようになったわけであるが、これは他の可能性のある病原体の検
査法開発を妨げるものではない。
”Drosten医師の返答：
“もちろん我々はこの検査を行なっているネットワー
クの唯一の研究室ではないから、いずれ時期が来れば同じような特異性、感度
を持つ複数の分子生物学的診断法が確立される。現在この検査法を評価中であ
る。我々が言えることは、呼吸器検体から1mLあたり500個のウイルスを検出で
きることが出来ることである。現在、臨床家にとってこの方法が臨床の場で実
用的であるか確認中である。患者が発病中の大部分の時期において、これらの
方法でウイルスを検出できるが、これが臨床的に本当に意味を持つかについて
は結論できない。これらの検査法の評価は、多くの症例と疫学的データが必要
である。”
（以下、Dr. Stohrのコメントとして、リバビリンは以前からある薬で副作用
は良く知られており、in vitroではコロナウイルスは感受性がないため効果の
臨床検討が必要であること。コッホ(Koch)の定義を満たすために病原体と断定
して良いこと。Heymann医師のコメントとして、下痢はこれまでにも報告があ
りAmoy Gardensの患者が特殊とはいえないこと。Osterhaus医師のコメントと
して、サルを用いた感染実験で新種コロナウイルスのみで臨床的・病理学的に
完全なSARS症状が起こり、ヒトメタニューモウイルス(HMPV)を重複感染させて
も症状が変化なく、HMPVでは軽症の感冒様症状しか起こらないことから、コッ
ホの定義上新種コロナウイルスが単独のSARS病原体と考えられること。Ling医
師とvan der Werf医師から、より特異的なプライマーや血清診断法、ワクチン
療法が研究開発中であるとのコメント。再びStohr医師より、ウイルス分泌と
感染経路の解明が進行中であること。Salter医師より、香港で死亡率が増加し
た事実がないことのコメント。詳細は原文を参照。）
[2]中国本土で得られたSARSウイルス4検体のゲノム解読完了。
情報源：Beijing Genomicsウェブサイト、4月16日。
本日午後、中国本土の共同研究施設、軍事医科学アカデミー微生物疫学研究所
と中国科学アカデミー北京ゲノム研究所の科学者らが、SARS患者から分離され
たSARS関連コロナウイルスを含む4検体のゲノム配列の生データを解読した。
（以下、中国北京と広東省のSARSコロナウイルス検体の遺伝子配列が、米国や
カナダのものと比較した場合に、幾つかの塩基変異が発見され、このウイルス
が短期間に容易に突然変異を起こすRNAウイルスであることが確認されたこと
の記載と、解読に貢献した著作者のリスト。）
[モデレーター注：中国本土のSARS関連コロナウイルスの塩基配列がカナダや
ハノイの患者から分離されたウイルスゲノム配列とわずか数個の核酸しか異な
らないことから、一部の遺伝子（ポリメラーゼ遺伝子フラグメント）から得ら
れたSARS流行の感染源は1カ所である可能性が高いとしたこれまでの結論が裏
付けられた。]
SARS - WORLDWIDE (53): ETIOLOGY
********************************
A ProMED-mail post
ProMED-mail is a program of the International Society for Infectious Diseases
[1]
Date: Wed 16 Apr 2003
From: ProMED-mail
Source: World Health Organisation (WHO), Press Briefing, Wed 16 Apr 2003
[edited]
[The following are extracts from the transcript of a WHO Press Briefing held
in Geneva on Wed 16 Apr 2003 and attended by the following. From:
World Health Organization; Dr David Heymann, Executive Director,
Communicable Diseases Dr Mark Salter, Clinical Management
Coordinator; Dr Klaus Stohr, SARS Etiology Coordinator; Project
Leader, WHO Global Influenza Programme; Mr Dick Thompson,
Communications Officer. From the SARS laboratory network: Dr
Christian Drosten, Institut fur Medizinische Virologie im Klinikum
der Johann Wolfgang, Goethe-Universitat, Frankfurt am Main (in
collaboration with the Institute for Tropical Medicine, Hamburg,
University of Marburg); Dr Robin Gopal, Central Public Health
Laboratory, United Kingdom; Dr James Le Duc, Centers for Disease
Control and Prevention, National Centers for Infectious Diseases,
United States; Dr Aiee Ling, Singapore General Hospital, Singapore;
Dr Albert Osterhaus, Erasmus Universiteit, National Influenza Centre,
the Netherlands; Dr Masato Tashiro, National Institute of Infectious
Diseases, Tokyo, Japan; Dr Sylvie van der Werf, Institut Pasteur,
National Influenza Centre, France]
..Three questions from the floor: "The first concerns the PCR test
that WHO put on the web site. Can this test detect asymptomatic
patients of SARS? The second concerns medication. In Hong Kong, they
use ribavirin and steroids. We have seen that they have a lot of
side-effects in babies and pregnant women. I wonder what are those
medications your countries use and what would be your recommendation.
Also, the possibility of a combination of Chinese medicine and
western medicine. The third question concerns the situation of Amoy
Gardens. Not only is atypical in terms of the means of transmission,
also it seems that patients in Amoy Gardens do not respond well to
ribavirin and steroids. They have other symptoms such as diarrhoea.
Also, unlike in most SARS cases where patients who die and became
seriously ill are aged over 40, in Hong Kong we have cases aged 30 or
40 with no chronic diseases in the past, but they also die of SARS
and they are all from Amoy Gardens. What are your views on this?
Thank you."
Reply by Dr Stohr: "Thank you for the question. I would like to give
the floor to Dr Drosten to talk about the PCR test. What I would like
to emphasize is that with the identification of the coronavirus as
the causative agent, now we can develop more specific diagnostic
tests for this pathogen. It is also now possible to fully focus on
one pathogen and not be forced perhaps to develop other diagnostic
tests for other possible agents."
Reply by Dr Christian Drosten: "We were of course not the only
laboratory within the network that did this, so for the time being
there are some molecular diagnostic tests which in principle all work
the same and should in principle all have the same performance
characteristics. We have done some evaluation of this. What I can
tell is that we can analytically find about 500 viruses per
millilitre of respiratory material. But what epidemiology has now to
confirm is how useful this will be in clinical terms, for clinicians.
There are of course some hints from beforehand that I can tell from
now. This is that, most probably, through most of the symptomatic
period that the patients show, we can see the virus in these tests,
but we cannot for the time being say this will have any consequence
to real clinical acting. For this we need more patients and more
epidemiology and more evaluating of these tests."
Comment by Dr Stohr: "We would like to better understand what the
performance criteria are of these tests. With PCR you can only detect
genetic material. You cannot detect, you are not sure whether what
you are seeing is a live virus or is only an immature virus that
cannot cause disease. So from that perspective, even finding of
coronavirus traces, in possibly non-clinically ill patients, is not
very indicative. I would briefly like to go with the ribavirin
questions. Ribavirin has been tested in Hong Kong for a relatively
long period of time. It is no more than two weeks that the Department
of Health has been recommending ribavirin treatment in combination
with high doses of corticosteroids. They are
reporting a significant improvement of the clinical course of the disease.
Ribavirin is known for very many years. It has side-effects. They are
not unusual, they are not unexpected. On the other hand, in vitro
testing, the testing outside the human body, of ribavirin with
coronavirus has shown that coronaviruses are resistant. So all this
has to be verified. These tests are
ongoing. There is a battery of other antiviral drugs that are currently
being tested. This is the reason why we believe the finding of this
coronavirus as the causative agent after we have now fulfilled the
Koch postulates is so important. Now the research can be focusing on
this virus. This virus will help us, or let us say that the research
will help us to develop new drugs. Now we can focus on one pathogen,
which has now been sequenced, which provides additional information
for the development of
tests. Now one can also think perhaps about vaccine, if there is a need be.
We are still I think optimistic that we can control the disease with
the measures that have been implemented and the understanding of the
genetic composition of the virus will certainly also help to implement
global surveillance."
Comment by Dr Heymann: "Re Amoy Gardens, as Klaus just said, they
have found that the virus particles at least are in faeces and in
urine. It is normal that if it is in faeces that it may be causing
diarrhoea, and actually 10% of patients do have diarrhoea worldwide.
So diarrhoea is a symptom. In fact, I went through Paris airport and
on their alert for SARS they do list diarrhoea as one of the
symptoms. It is a common symptom. That is some of the intrigue of
knowing why people in Amoy Gardnes might be different than other
places. It may be the way in which they are getting infected. There
are all kinds of theories that you could use in saying why they get
diarrhoea. Maybe that they are getting infected by the mouth, that it
is only to be determined as time goes on and as the studies are
done."...
..Question from Fuji from Kyoto News Japan. "Previously there was
some speculation that paramyxovirus and/or chlamydia could have been
playing a role in causing SARS. Now today that you have identified
the causative agent as coronavirus, can we now safely say that it is
caused solely by coronavirus and that paramyxovirus and chlamydia
does not play any role in this? Secondly, there has also been some
speculation and concern that the SARS virus may still be evolving,
could change its composition or shape. Can you comment on this issue
as well?"
Reply by Dr Albert Osterhaus: "As to the cause of the disease, I think that
if you look, what happens is that first of all this paramyxovirus _Human
metapnuemovirus_ (HPV)" was found. HMPV is a virus that we discovered about
two years ago as the cause of serious respiratory infections in children,
the elderly and also immuno-compromised individuals. But we were quite
astonished that this virus as such should be the cause of this new disease;
now that would not make sense. Then we were very happy to learn that
originally in Malik Pierce's work in Hong Kong, identified the virus
that we have all followed up. So we ended up with two different
viruses: the coronavirus and HMPV. There is also discussion about
this chlamydia agent. This led us to postulate that it would not be
impossible that we would perhaps have a double etiology, so one virus
coming first and the other one coming later and then aggravating the
situation. This is the reason why in discussions with the network, we
discussed that in our telephone conferences. Then we decided to do an
experiment in monkeys. This experiment was set up in such a way that
we infected monkeys either with the coronavirus that was cultured or
with HMPV. A third group we infected first with coronavirus and then
with HMPV. The interesting thing we found, and that goes back to the
Koch's postulates that were formulated more than 100 years ago, that
the animals infected with the coronavirus alone developed full-blown
disease. They developed SARS, they developed clinical symptoms, and
they also developed the pathological lesions that are identical to
what we have seen in people who have died from SARS. The animals with
HMPV, the first virus that was found, developed only a very mild
rhinitis, they had very mild symptoms, and definitely not the typical
SARS pattern. The third group of animals, first infected with the
coronavirus and then super-infected with HMPV, did not develop more
serious disease.
***Koch's postulates are firstly that the agent should be present in basically
all the individuals that are suffering from the disease. That holds true
predominantly for the coronavirus and not for HMPV because it is less than
50% of the people infected or having SARS that were infected with HMPV me.
The second postulate is that you should be able to cultivate the virus. That
holds true for the two viruses. The third postulate is that you should be
able to reproduce the disease in the host or a related host. That is what we
have done for the coronavirus, and coronavirus only. The last postulate then
is that you should reisolate the virus back from the animals that you have
infected with that virus. Those four things have been fulfilled for
coronavirus and only three of those for HMPV.***
The conclusion today, the people in the network agreed, that the coronavirus
alone is capable of causing the typical symptoms. We cannot formally exclude
that other agents, such as HMPV, and the chlamydia that has been found in
China, or a number of other viruses after you have this primary infection
with the coronavirus, would eventually aggravate the situation. We cannot
exclude this, but the data especially from Hong Kong, suggest that where we
have coronavirus alone, also in humans, those data together with the monkey
data I think quite strongly show that the coronavirus is the primary cause
of this disease the new coronavirus that was identified a couple of weeks
ago."...
..Question from Stefan Tile, Newsweek: "I have two questions. One
is, can you give us an update on countries where first cases were
recently reported, like Brazil or South Africa, how they are dealing
with the situation, what measures governments there are undertaking?
And the second question is, now that the virus has been pin-pointed
and the genome has been sequenced, can you tell us what that means
for a) the diagnostics, b) the development of antiviral therapy and
c) the search for a vaccine? And to what extent any of this research
is either under way or specifically planned. Thank you."
Reply by Dr Aiee Ling: "With regard to the sequencing of the virus,
it of course gives us tremendous ability to develop more specific
primers. Because, as has been stated before, this virus is quite
distinct in its grouping. Which means that the previous primers that
we were using were not as specific and therefore not as sensitive. So
that, of course, the specific primers that we should be able now to
develop will go a long way to improving the sensitivity of test.
That's with regard to diagnostics. With regard to vaccines, again of
course the sequencing will have a direct ability for us to form
clones, to produce the necessary requirements for vaccine.
Comment by Dr Sylvie van der Werf: "So, about other developments that
one can expect from the availability of the sequence. Apart from
developing other primer sets for molecular diagnostics, also this
should prove extremely useful for serological diagnostics, producing
antigens by molecular techniques that can be made readily available.
And there are a number of laboratories in the network working on
this. Different vaccine strategies can also be explored using
recombinant vaccine approaches. Again, based on the possibility to
express various proteins through molecular cloning techniques from
using the genes from this virus. And finally, this will also allow to
set up, probably, maybe some [in vitro] tests for testing of
antivirals that might be of use against this virus. So, really using
molecular techniques based on the sequence information, it will be
possible to develop methodologies that will not have to rely anymore
on infectious virus, which will also allow to work at a different
containment level and make things easier...
..Two questions from the floor: "One is, do you have any new
findings on the way of transmission? And the second is, how many
people do you have right now in China and are you planning to send
more people? Thank you."
Reply by Dr Stohr: "This morning the network members presented overviews on
the excretion patterns of this coronavirus and the people you are
seeing here, and those you unfortunately cannot see because they are
linked by video conference, are those who know most about how this
virus is being excreted, for how long, by which means. But still the
matrix of excretion which we have drawn is still incomplete. We are
still not fully aware how much virus is being excreted, by which
[route] and for how long. Is virus excreted before the clinical signs
would occur? Would virus continue to be excreted when persons are
already discharged? All this has to be looked into. And its ongoing...
..Question from Warren Giles, Bloomberg News: "A couple of things. I
wonder, is there any evidence that the mortality rate of this virus
is increasing just because of the evolution we see in cases and
deaths in Hong Kong? And secondly, I wonder at what point a virus
that's not contained becomes an epidemic? Is there any kind of model
that suggests theres a critical point of infections at which point
infections become exponential in some way? Thanks."
Reply by Dr Salter: "The first question was: has the case mortality
rate increased? No, it hasn't but what we have seen across the globe
is that there are variable case fatalities rates with the different
countries. And that probably reflects to some degree the level of
facilities available in those countries and the rapidity with which
those individual countries have
been able to implement their infection control measures........
--
ProMED-mail
[A article published in the New York Times on Wed 16 Apr 2003
forwarded by Rashid Chotani
the WHO Press Briefing.]
[The most significant information communicated during this press briefing
was the account by Dr. Osterhaus of the primate experiments undertaken in
Rotterdam, and the conclusion that Koch's postulates have been confirmed
experimentally in the case of the SARS-associated coronavirus, and not in
the case of the human metapneumovirus isolated from SARS patients. - Mod.CP]
[There's an excellent description of the discussion of the
fulfillment of Koch's postulates in the body of the press release
highlighted by ***. - Mod.MPP]
******
[2]
Date: Wed 16 Apr 2003
From: David Cowhig
Source: Beijing Genomics web-site, Wed 16 Apr 2003 [edited]
Genomes of Four Mainland China SARS Viral Samples Sequenced
-----------------------------------------------------------
This afternoon scientists at collaborating research institutes in
mainland China, the Institute of Microbiology and Epidemiology of the
Academy of Military Medical Sciences and the Beijing Genomics
Institute of Chinese Academy of Sciences, obtained draft genome
sequences from four samples containing the SARS-associated
coronavirus from SARS patients.
All four samples of the SARS-associated coronavirus were isolated
from patients in Beijing and Guangdong Province, where the first case
of SARS was treated. Two of the isolates were from autopsies of the
lung tissue of deceased patients, one from Beijing and the other from
Guangdong. The third one was from a mixed autopsy sample of the liver
and lymph nodes isolated from the same Beijing patient from whom the
lung tissue was taken. The fourth sample was from nasal/throat swabs
of several patients with SARS in Beijing.
The DNA sequences reverse-transcribed from the RNA virus isolated
from the mainland Chinese samples were compared to genome sequences
previously reported by Canadian and US scientists. A few nucleotide
differences among individual genomes were detected as the virus is
expected to mutate very fast and easily.
The SARS-associated coronavirus is believed to be a member of the
_Coronaviridae_ family. RNA viruses, such as the human
immunodeficiency
virus (HIV) and Influenza virus, are known to change their genetic
makeup readily in different tissues during their rapid propagation
(genome replication and viron assembly) in living cells over a short
period of time. For effective diagnosis and treatment of these viral
infections, it is essential to study the mutation spectra of the
virus. The detailed comparative analyses from different viral
isolates both at the genome sequence and protein levels will be an
important contribution to SARS research efforts currently underway in
the international biomedical research community and help scientists
worldwide to develop accurate diagnostic tests, effective disease
treatments and vaccines to prevent further spread of the virus.
Complete genome sequences will be updated and released to public
databases as soon as they become available. Efforts to identify viral
proteins with proteomic tools are underway, and findings are expected
tomorrow.
Background Information [from the web-site]:
A coronavirus is believed to be the causative agent of severe acute
respiratory syndrome (SARS). Coronaviruses belong to a viral family,
_Coronaviridae_ (from Latin, corona or 'crown-like'), infect
vertebrates especially the warm-blooded vertebrates, including
several mammalian species (e.g. human, cattle, cat, pig, and rat),
and a few avian species (e.g. turkey and chicken). Virions of
coronavirus contain a single stranded RNA molecule in a linear
positive-sense form, ranging between 29,000 and 31,000 nucleotides in
length.
Scientists from several countries, Canada, United States and China
including Hong Kong, have carried out heroic sequencing efforts,
attempting to decipher the genetic code of the unknown human
coronavirus believed to be responsible for the global epidemic of SARS.
The sequencing result first came on 12 Apr 2003 from the Canadian group at
Canada's Michael Smith Genome Sciences Center of the British Columbia Cancer
Agency, in collaboration with the British Columbia Center for Disease
Control and the National Microbiology Laboratory, Winnipeg. A draft assembly
of the SARS-associated Coronavirus (TOR2) genome (Release 1) is 29 736
nucleotides in length. It was deposited in the NCBI Genbank database under
accession AY274119. On 14 Apr 2003, the Centers for Disease Control and
Prevention (CDC) announced that it has sequenced the genome of the
coronavirus. The CDC sequence is nearly identical to that determined
by a Canadian group. The significant difference is that the
CDC-determined sequence has 15 additional nucleotides, which provides
the important beginning of the sequence. The virus from a throat
culture taken from one of the SARS patients was grown in Vero cells
(African green monkey kidney cells) to reproduce enough RNA for
sequencing experiments. The new sequence has 29 727 nucleotides,
which places it well within the typical RNA boundaries for
coronaviruses. Both the CDC group and the UBC group have published
their sequences, which differ by about 10 bases.
Author List:
At the Institute of Microbiology and Epidemiology, Academy of Military
Medical Sciences: E'de Qin, Qingyu Zhu, Man Yu, Baochang Fan, Guohui Chang,
Bingyin Si, Bao'an Yang, Wenming Peng, Tao Jiang, Bohua Liu, Yongqiang Deng,
Hong Liu, Yu Zhang, Cui'e Wang, Yuquan Li, Yonghua Gan, Xiaoyu Li, Fushuang
Lv, Gang Tan, Ruifu Yang, Wuchun Cao
At the Beijing Genomics Institute, Chinese Academy of Sciences: Jian Wang,
Wei Dong, Wei Lin, Wei Li, Jun Wang, Ting Cao, Weijun Chen, Lijuan Cong,
Yajun Deng, Yujun Han, Wei Hu, Meng Lei, Changfeng Li, Guoqing Li, Shengting
Li, Shuangli Li, Wenjie Li, Juan Liu, Zhen Liu, Hong Lv, Peixiang Ni, Qiuhui
Qi, Yongqiao Sun, Ling Tang, Zongzhong Tong, Xiaoling Wang, Qingfa Wu, Yan
Xi, Zuyuan Xu, Lihong Yang, Chen Ye, Bo Zhang, Feng Zhang, Jianguo Zhang,
Xiaowei Zhang, Jun Zhou, Huanming Yang
--
David Cowhig
[The finding that the sequences of the genomes of four SARS-associated
coronaviruses isolated in mainland China differ only by a few nucleotides
from the sequences determined for the Canadian and Hanoi (sequenced at CDC)
isolates reinforces an earlier conclusion from partial genome sequencing
(polymerase gene fragments) that there may be a point source for the SARS
epidemic. - Mod.CP]
[see also:
SARS - worldwide (04): etiology 20030325.0737
SARS - worldwide (06): WHO press briefing 20030325.0744
SARS - worldwide (13): etiology 20030327.0758
SARS - worldwide (14): overview 20030327.0769
SARS - worldwide (16): etiology 20030328.0774
SARS - worldwide (19): etiology 20030330.0786
SARS - worldwide (26): etiology 20030403.0819
SARS - worldwide (28): overview 20030403.0822
SARS - worldwide (31): etiology 20030405.0833
SARS - worldwide (34): etiology 20030408.0857
SARS - worldwide (38): etiology 20030410.0869
SARS - worldwide (41):overview 20030411.0876
SARS - worldwide (42): WHO historical overview 20030411.0878
SARS - worldwide (46): diagnostic test 20030413.0901
SARS - worldwide (48): etiology 20030414.0909
SARS - worldwide (51): etiology 20030416.0925
SARS - worldwide: cases 20030323.0722
Severe acute respiratory syndrome - Worldwide (02) 20030315.0649
Severe acute respiratory syndrome - worldwide (17) 20030322.0713
Severe Acute Respiratory Syndrome - Worldwide:alert 20030315.0637]