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Number20030405.0833Published Date05-APR-2003SubjectPRO/EDR> SARS - worldwide

(31): etiology

SARS - WORLDWIDE (31): ETIOLOGY*******************************A ProMED-mail

post<http://www.promedmail.org>ProMED-mail is a program of theInternational

Society for Infectious Diseases<http://www.isid.org>[1]4 Apr 2003

ProMED-mail <promedSource: OIE press release

[edited]<http://www.oie.int/eng/press/en_last.htm>Atypical pneumonia: Severe

acute respiratory syndrome (SARS)------------------------A human epidemic of

atypical pneumonia called severe acute respiratorysyndrome (SARS) is currently

raging across the globe and particularly inSouth-East Asia.The causative agent

has not yet been identified. It appears to be aParamyxovirus, a Coronavirus, or

a mixture. The World Health Organization(WHO) has hypothesised that the

causative virus(es) may be of animalorigin, from domestic or wild animals

located in Guangdong Province (inSouth China).This is why the World Organisation

for Animal Health (OIE) has contactedthe Chinese Veterinary Authorities to

obtain information on the animalhealth situation in China over the past 6 months

and, in particular, inGuangdong Province.The OIE has also approached its

Reference Laboratories and Expertsspecialising in Paramyxovirus and Coronavirus

diseases.As soon as it is available, the OIE, in close collaboration with the

WHO,will communicate the scientific information needed to confirm or

invalidatethe animal origin of SARS and to evaluate, if necessary, the risks

incurredby the international community.--ProMED-mail<promed[We

look forward to hearing the results of the OIE investigation. -

Mod.MPP]******[2]Fri 4 Apr 2003Steve Berger

<mbergerSARS - Deja vu ?----------------As SARS enters its fifth

month, a number of questions remain unanswered.Why Asia? Why now? Why young

adults? To these I would add a fourth question(Why the panic?) and an

hypothesis.Every 10 years or so, a pandemic spreads out from China and

surroundingcountries. The 'Asian flu' of 1957 claimed 98 000 lives worldwide,

and the'Hong Kong flu' of 1968 an additional 45 000 lives. Although the

worldcommunity was rightly concerned, I do not recall a collapse of air

travel,imposition of quarantine, or daily front-page headlines. To date, SARS

hasclaimed 79 lives, and the etiological agent appears to be far lesscontagious

than Influenza A virus.Current evidence suggests that new strains of Influenza A

virus evolve asrecombinants when they pass between swine and ducks, a process

favored byclose species proximity on Asian farms. Thus, I was surprised to learn

in arecent ProMed-mail posting that coronaviruses also exist in poultry

andswine, as well as cattle, cats, dogs, and rodents (see: Coronavirus,Chicken,

New - Brazil 20030403.0816). I do not know whether coronavirusesare capable of

recombination in the manner of influenza viruses, but such amechanism would

partially explain the origin of SARS.3 years ago, a 'new' human infection was

described in the Netherlands. Itsoon became evident that Human metapneumovirus

[HMP] was neither new norexotic, and seems to have affected most humans in every

countryinvestigated, going back decades. The clinical features of this

infectionmimic those of Human respiratory syncytial virus, and infant deaths are

notuncommon. Indeed, it may well be that more people die of HMP than from

SARSeach year. These facts only became evident when serological tests

weredeveloped. I suspect that use of serological and other tests for

SARSdeveloped over the next few weeks will reveal: (1) a high degree

ofsero-positivity in the 'healthy' community of Asia, if not other countries;and

(2) the existence of an animal (Porcine? Avian?) reservoir.During the H1N1

pandemic of 1977, there were suggestions that elderlypersons had a lower rate of

complications than would be expected. It wastheorized that persons who had

survived the prior H1N1 pandemic of 1918 hadretained partial immunity into old

age. If, as noted above, backgroundimmunity exists from a SARS outbreak several

decades ago, relatively lowdisease rates among the elderly during the current

epidemic would not besurprising. The fact that few children are affected is also

not surprising,when we recall that viral diseases (measles, varicella,

poliomyelitis,mumps) are often more overt and severe among adults.--Steve

BergerTel Aviv Medical Center, Israel<mberger[steve Berger has

posed some interesting questions and made some relevantcomments. My response is

limited to consideration of the geneticcharacteristics of coronaviruses. High

frequency recombination is acharacteristic property of coronaviruses, and is

probably restricted toclosely related coronaviruses. An example is Feline

infectious peritonitisvirus, a coronavirus that exists as 2 serotypes and causes

peritonitis,pneumonia, meningoencephalitis, and other immunopathologic

complications incats. Serotype 2 of feline infectious peritonitis virus appears

to be arecombinant virus incorporating genetic information from a

caninecoronavirus, which causes diarrhea in dogs. The serotype 2 virus,

inaddition to causing peritonitis, etc., in cats can -- unlike serotype 1

--infect pups (but does not cause acute disease).That said, it is not necessary

to hypothesize origin of the putativeSARS-associated coronavirus by

recombination with an animal or aviancoronavirus. There are many coronaviruses

in the natural environment thatcould become pathogenic in humans as a result of

progressive mutation, orperhaps have existed undetected.The origin of pandemic

influenza A viruses by " recombination " is anentirely different process and can

occur between dissimilar viruses. Thegenome of influenza viruses exists as a

complement of sub-units which canbe interchanged when genetically distinct

viruses replicate in a common (orintermediate) host, generating progeny with

non-parental combinations ofgenes (and potentially expressing novel combinations

of antigens andcausing an explosive pandemic). Consequently there could be

abundantopportunity for exchange of sub-units between human and avian viruses

wherehumans, domesticated mammals, and birds live in close proximity. This is

agross oversimplification, of course, but the origin of pandemic strains

ofinfluenza A virus in east Asia in the past should not be used as anargument

favouring the origin of the SARS agent by recombination between ahuman virus and

an animal virus.At this stage we simply do not know. Nor is it certain that the

coronavirus(and/or the human metapneumovirus) present in SARS patients is

thepathogenic agent. As Steve Berger points out, coronaviruses andpneumoviruses

are ubiquitous in the human population. Caution is requiredin advancing

hypotheses at this stage until more data become available. -Mod.CP]*****[3]Date:

5 Apr 2003ProMED-mail <promedSource: CDC press briefing 4

Apr 2003 [excerpted and

edited]<http://www.cdc.gov/od/oc/media/transcripts/t030404.htm>Update on the

ongoing laboratory investigation:-----CDC is

part of an international collaborating network of laboratories ledby WHO. There

are 12 laboratories and 10 companies participating in thisnetwork.Evidence for a

previously unrecognized Coronavirus has been found now inat least 10

laboratories, including the laboratories here at CDC. Thepreponderance of the

evidence continues to mount and continues to favor anetiologic role or this

previously unrecognized Coronavirus in the cause ofSARS.So far, in looking at

specimens from the suspect cases in the UnitedStates, we now have evidence of

infection with this agent in a total of 4people, and we are working with the

state health departments in the stateswhere these people reside, so that they

are provided with the informationand they, in turn, will provide the clinicians

and the patients with theinformation.We have cultured this Coronavirus from a

total of 4 patients. We haveelectron microscopic evidence from 2 patients of

this virus. We have PCR(Polymerase Chain Reaction) results -- , the

amplification technique --where we find evidence of Coronaviral nucleic acid in

11 patients.Looking at the antibody tests, of which we have 2 --an

IFA[immunofluorescent antibody] test and Allose test -- there is evidence

forinfection in a total of 5 patients. And from the standpoint ofhistopathology,

looking through the microscope at tissue from deceasedpatients, we have seen

evidence of an entity that the pathologist calldiffuse alveolar damage, which is

the pathologic correlate for the clinicalsyndrome of Acute Respiratory Distress

Syndrome, which has appeared inpatients with severe forms of SARS.We have seen

that evidence in a total of 4 specimens. Don't try to add thosenumbers up and

get a grand total because some patients, in some cases, havemore than one

positive result.[in response to a question on whether there were samples that

testednegative for coronavirus]:There are negative results. I don't have

numbers. For example though, whenyou think about antibody tests, what you really

need, [in order] to be ableto interpret those and to say that something's

negative, is 2 serumspecimens collected 2 or 3 weeks apart. So any negative that

we have now forthe most part represents a single serum that's negative. So we're

not in theposition to say that evaluation is complete. Part of our effort now,

workingwith the states, is to get paired serum specimens from patients so they

canbe tested.[in response to a question re: the information that some of the

earliercases had eaten wild game]:[Dr. Hughes had not heard the reports about

the wild game consumption.] But, we don't know the source, the original sourceof

this previously unrecognized virus. There are a number of Coronavirusesthat do

infect animals, though. So it may well be that there is an animalorigin for

this, and it's the sequencing of the full virus that will tell usthis. So I'm

interested actually to follow up and see what sort of wild gamethis is and what

the evidence might be.[in response to the question if they have run the tests on

controls] :In terms of PCR, yes, we have negative controls that we run, both for

thePCR and for the serologic tests that we have done, and it looks like

thesetests are performing quite well, but it is early in their use.There are

several diagnostic tests that look promising. There is the ELISAtest for

antibody, there's the Indirect Fluorescent Antibody -- or IFA --test, again, for

antibody, and then there's a PCR assay [for viruse] thatlook like they

havepotential to be useful.We will be collecting and testing as many specimens

as we can acquire fromsuspect cases, from health care workers exposed to them,

from householdcontacts, and from healthy controls over time to further validate

them.We are going to be trying very soon to transfer some of these tests tostate

public health laboratories through the Laboratory Response Network sowe can get

the diagnostics, such as they are at the moment, closer to wherethe illnesses

are occurring. So that's a high priority[in response to the question on reports

ot the isolation of Chlamydia]:The outbreak in Guangdong Province initially was

reported based on some labevidence that I don't know the details of, to be

caused by _Chlamydia and[sic] pneumoniae_. My impression is that they had

relatively few positiveresults for that. We certainly put _Chlamydia and [sic]

pneumoniae_ on ourlong list of differential diagnostic possibilities when we

first heard aboutthe situation in Vietnam, Hong Kong and Canada. We, in our

laboratories,looked for evidence of _Chlamydia and [sic] pneumoniae_ infection

in suspectcases, and so far have not found

it.--ProMED-mail<promed[The new information provided in this

briefing from CDC is consistent withthe hypothesis that a novel (or perhaps

previously unrecognized) humancoronavirus is the etiologic agent of SARS, either

alone or in combinationwith another agent still to be identified. The supporting

evidence is farfrom conclusive, however. If at the CDC only specimens from

suspected casesin the United States have been examined so far, an undetermined

proportionof whom may not be SARS patients, this would be a limitation. The

RT-PCR amplification of coronavirus sequences produced 11 positiveresults and

was the most sensitive diagnostic procedure employed, but evenwith this

technique an unspecified number of negative results was obtained.The most

encouraging result is successful propagation of virus from 2 of thesuspected

SARS cases. This will allow the entire genome of the virus to besequenced and

its phylogenetic position in the family _Coronaviridae_ to beestablished. It

will be possible then to deduce whether this virus is a newhuman pathogen

derived by recombination with an animal coronavirus, orwhether it has evolved by

progressive mutation from either of the 2 knownhuman coronaviruses, which are

associated with upper respiratory tractinfections, or from one of the known

animal coronaviruses. It is curiousthat a virus, which has such devastating

pathological potential in somepeople, is present in these specimens in such low

abundance.Specific antibodies were detected in five patients by ELISA and/or

IFAtests, but samples suitable for demonstrating seroconversion appear to

havebeen lacking. The response to the question on controls is confusing.

Itshould be a priority to extend these diagnostic procedures to a matchedseries

of non-SARS patients to exclude the possibility that this novelhuman coronavirus

is no more than a ubiquitous resident in the humanrespiratory tract. Several

respiratory viruses, suchas the common cold-associated coronaviruses and human

respiratory syncytialvirus, are distributed world-wide and affect individuals of

all ages. Atthe moment the single fact that best identifies this virus as the

etiologicagent of SARS is its apparent low nucleotide sequence homology with

othercoronaviruses. - Mod.CP][see also:SARS - worldwide (04): etiology

20030325.0737SARS - worldwide (10): infectious disease perspectives

20030326.0752SARS - worldwide (13): etiology 20030327.0758SARS - worldwide

(14): overview 20030327.0769SARS - worldwide (16): etiology 20030328.0774SARS

- worldwide (19): etiology 20030330.0786SARS - worldwide (26): etiology

20030403.0819SARS - worldwide (28): overview 20030403.0822Severe acute

respiratory syndrome - Worldwide (02)... 20030315.0649Severe acute respiratory

syndrome - worldwide (17) 20030322.0713Severe Acute Respiratory Syndrome -

Worldwide:alert

20030315.0637]...........................jw/mpp/cp/pg/jw*#######################\

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