17 out of 940 blood samples that had originally been collected in Hong
Kong in 2001 for a research project on hepatitis B carried antibodies either
to the human SARS coronavirus, to a closely related animal coronavirus,
or to both, indicating that the Hong Kong inhabitants were exposed to SARS
or to one of its animal cousins 18 months before the disease was known
or named. Such infections probably came from a market animal or an environment
contaminated by animal virusesref.
A 2003 study showed that 70% of civet cats were SARS-CoV carriers, but
about 40% of people trading in wild animals in the Chinese markets also
carried antibodies to SARS
an epidemic appeared in 7 municipalities of Guangdong province (China)
since 16 November 2002. The outbreak wasn't caused by a single species
jump : 11 people apparently were independently infected in the Pearl
River Delta area of Guangdong Province, where exotic animals are part
of the diet, beginning in November 2002. 7 of these cases had documented
contact with wild animals. 2 major genotypes predominated, whose sequences
were similar to those of coronaviruses found in some captive civetsref.
The first case of SARS was reported in Foshan and HeYuan city, an industrial
and fish-farming city, population 3.5 million, 20 km from Guangzhou city.
However the medical professor Xie JinKui in RenMin hospital of HeYuan county
said that the first case was detected on 17th of Dec 2002 in a 35 year
old man, a cook in ShenZhen, working in a restaurant where he has close
contact with wild animals, such as snakes : before he visited RenMin hospital
in HeYuan, he went to FuTian hospital in ShenZhen on 15th of Dec, 2002.
Prof. Xie emphasized that the patient's health was very bad when he was
first sent to RenMin hospital (high fever, dyspnea, and shadows in chest
X-ray test). On the 2nd day, the patient was sent to the GuangZhou Military
hospital, where he infected serveral medical staffs. Furthermore, his wife
and 2 sisters were also infected. Prof. Xie said that the first case of
HeYuan is from ShenZhen. From the medical record, several original patients
have close relationships with wild animals : some of them are cooks and
some of them are providers of wild animals to restaurants. Prof. Xie said
at last that HeYuan is the first county who reported SARS to Guangdong
local medical officials. But he emphasised that this does not mean that
SARS is originating from HeYuan. After the talk with Prof. Xie, reporters
of Ming Bao also visited the FuTian hospital in Shenzhen. And they did
find the record of the patient that Prof. Xie mentioned, but the date was
20th August, 2002, not 15th Dec, 2002. Finally they even found the patient
himself: he admitted that he got pneumonia last year, but refused to give
more details. In Guangdong, the habit to eat all kinds of wild food is
widely spread, and might have indeed an importance in the transfer of animal
viruses to humans. Rumors about the disease were rife, causing a run on
herbal medicines and price-gouging on white vinegar, heralded as deadly
to the infective agent, whatever it was. The evolution of the spike protein
from its animal to human attack mode began in mid-November 2002 and was
complete by the end of February 2003, a mere 15 weeks later : as the virus
perfected its human attack mechanism, its potency soared from being able
to infect only 3% of the people who came in contact with a patient to an
infectivity rate of 70% a few months later. Then came the outbreak's "middle
phase", started with the first "super-spreader event (SSE)", associated
with more than 130 primary and secondary infections in January 2003 in
the city of Guangzhou. The late phase involved an outbreak in Hong Kong,
traced to a physician who worked with patients in Guangzhou who visited
Hotel M. During the second phase, the SARS-CoV sequences contained a new
29-nucleotide deletion affecting the S protein (which is responsible for
virus-host interactions), that dominated the viral population for the rest
of the epidemic : the epidemic started and ended with deletion events together
with a progressive slowing of the non-synonymous mutation rates and a common
genotype that predominated during the latter part of the epidemic. In one
of its earliest reports about cases of atypical pneumonia to WHO, the Chinese
Ministry of Health reported 305 cases (105 of them medical workers and
200 household contacts of patients) and 5 deaths, from mid-November to
9 February, in 6 municipalities: Foshan, Guangzhou, Heyuan, Jiangmen, Shenzhen,
and Zhongshan. Guangzhou was the home of the 64-year old professor of nephrology
Liu Jianlun, at Zhongshan University, who is thought to be the index case
who sparked the outbreak in Hong Kong. During late February, he stayed
in room 911 on the ninth floor of the Metropole Hotel (nowadays it has
been assigned the number 913 and every subsequent odd-numbered room has
had its number changed too). 16 guests and visitors from Hong Kong, Toronto
and Singapore staying on the hotel’s 9th floor sparked outbreaks in other
countries when they returned to their homes. A 48-year-old American businessman,
who also stayed on the 9th floor, is believed to have originated the outbreaks
in Hanoi and in Hong Kong’s Princess Margaret Hotel, where he was transferred.
One local Hong Kong resident, who visited an acquaintance on the ninth
floor, subsequently sparked an outbreak in a second Hong Kong hospital.
Esther Mok went to Hong Kong to shop but came home carrying a deadly flu-like
virus that has since spread to more than 100 people in Singapore and killed
both of her parents and her pastor. Miraculously, she has survived. Mok,
a 26-year-old former flight attendant, was one of 3 original cases of severe
acute respiratory syndrome, or SARS, to emerge in Singapore early last
month. Mok was very sick — and very contagious — when admitted to a Singapore
hospital on March 1, but doctors had no idea that she was suffering from
the strange form of pneumonia that had already killed dozens in China.
She had regular visits from her family and members of her church — all
oblivious to the fact that they were exposing themselves to SARS. Her father,
mother and pastor have since died of SARS. Her uncle is in intensive care
battling the illness. Mok's grandmother and brother are also sick but in
stable condition. In fact, all but a handful of the 118 reported cases
in Singapore have been traced to Mok, and health officials have dubbed
her a SARS "super spreader". It remains unknown whether such “super-spreaders”
are persons secreting an exceptionally high amount of infectious material
or whether some other factor, perhaps in the environment, is working to
amplify transmission at some key phase of virus shedding. 2 other Singaporean
women also traveled to Hong Kong in February and developed SARS after exposure
to a Chinese doctor, Liu Jianjun, while staying at the Metropole Hotel.
They have not infected others. 2 other so-called super spreaders, Canadian
Kwan Siu-Chiu and American Chinese businessman Johnny Chen, fell ill after
a stay at the Metropole hotel and have helped spread the illness around
the world. Unlike Mok, both died. Jiang Yanyong of the People's Liberation
Army General Hospital (known as Hospital 301) claimed that at one Beijing
hospital alone, more than 60 SARS patients had been admitted and at least
7 had died. The statement to Time magazine said that 2 People's Liberation
Army hospitals were now treating SARS patients--hospitals 309 and 302--and
Hospital 309 is already full to capacity. On 28 February 806 cases and
34 deaths, on 7 August, 5327 cases, 34 deaths (CFR
~ 7 %) and 4949 recovered (93.7%). Chinese mainland's last 2 SARS patients
were discharged from hospital on August 16 in Beijing after more than 100
days of medical treatment. Since 16 Dec 2003 there have been 4 other laboratory
confirmed cases in Guangdong Province : all 4 patients have recovered from
their illness and have been discharged from the hospital (none of their
contacts have developed SARS-like illness) :
on December 27, 2003 a 32-year-old man (a freelance TV station worker who
lived in Panyu District of Guangzhou, capital of Guangdong Province) who
has been receiving treatment in quarantine in south China's Guangdong Province
was confirmed to be a suspected case on the basis of unspecified rise in
neutralizing antibody titre in consecutive samples of the patent's blood,
usually a specific and unequivocal diagnostic test : however, as yet there
is no confirmation that an infectious SARS-coronavirus has been isolated
from this patient. This circumstance, in conjunction with the absence of
spread to contacts, suggests that the patient's virus load may have
been low, perhaps as a consequence of a low level of pre-existing immunity
from previous exposure in the spring of 2003 but, due to internally developing
antibodies, may not have shown any symptoms until now. He began to have
a fever and headache in the evening of 16 Dec and went to see a doctor
at No. 1 Hospital affiliated to Zhongshan University on 20 Dec. He was
diagnosed as pneumonia with the right lower lung and was quarantined for
treatment. The patient was transferred to the quarantine ward of Guangzhou
No. 8 People's Hospital on 24 Dec and was released on Jan 8. Earlier, he
had told the Chinese media that he had never eaten civet, and that his
only contact with wild game was with a mouse. He apparently threw a mouse
out a window at some point before he became ill. One Guangdong newspaper
quoted him as saying he had handled the mouse with chopsticks. Laboratory
tests have shown that some of the rats caught in his apartment also tested
positive for SARS. No further transmission.
a 20-years old waitress from Henan province who works at a seafood restaurant
that apparently serves civet in Guangzhou was indicated as a suspected
SARS case. State media said the waitress, a migrant worker from Henan Province,
came down with a fever on 25 Dec 2003, went to a hospital on 31 Dec, and
was discharged on Jan 2004. WHO found SARS-CoV in cages housing civet cats
at a restaurant where one of China's 2 present suspected cases worked.
No further transmission.
a 35-year-old patient from Shenzhen (a Hong Kong-China border city with
a large economic free zone) was admitted and isolated on 6 Jan 2004 after
developing symptoms (probable case) on 31 Dec 2003 and was discharged from
hospital on 21 Jan 2004. No further transmission
a 40-year-old director of a hospital and practicing physician from Guangzhou,
Guangdong Province who developed symptoms of SARS on 7 Jan 2004. He was
admitted to a hospital in Guangdong with pneumonia on 16 Jan and placed
in respiratory isolation on the suspicion of SARS. He has made a full recovery
and was discharged home on 30 Jan. No further transmission
Song Wei, a 26-year-old female medical student from Hefei, Anhui Province,
who travellled on 6 Mar 2004 on the Hefei - Beijing line 1410 train. She
studied from Mar 7 to Mar 22 in a viral morphology lab in the Beijing
Center for Disease Control and Prevention, China, and became ill on 22
March : on 23 Mar she took the Beijing - Hefei T63 "inferior" train [?second
class] to come back home. On 25 Mar she developed fever and on 27 Mar she
took the Hefei - Beijing T64 "inferior" train of 17 compartments [?second
class] back. What is not clear is whether the laboratory contamination
was from a specimen from another as yet unidentified patient with SARS-CoV
infection, or from research being conducted on the SARS-CoV during Feb
and Mar. The method used for decontamination of the laboratory (1% NP40
+ PBS + 1% SDS for 60 mins) had not been monitored. On 29 Mar she underwent
a medical examination, was found to have pneumonia and was admitted to
hospital at the Jiangong hospital. For reasons that are not clear, she
was discharged from Jiangong on 2 Apr and returned with her mother to a
hospital in Anhui Huai Nan by Beijing - Huai Nan 1409 train of 13 compartments.
There, on 4 Apr she was transferred to the Anhui Medical College for continued
treatment of viral pneumonia. She left the university hospital in the Anhui
provincial capital of Hefei on May 11, after 15 consecutive days without
fever: confirmation of SARS-CoV infection from an independent international
reference laboratory is still pending
beginning 31 Mar, her 53-years old mother, a medical doctor, continuously
cared for and accompanied her and provided nursing care. On 8 Apr she developed
a fever and was admitted to hospital in the Anjui Medical College Hospital
with viral pneumonia. On 19 Apr, her mother worsened and died : this appears
to be the 1st indication of classification as suspected case(s) of SARS.
Upon receipt of notification of this death by the local medical department,
the early warning mechanism was activated. On 21 Apr, the Anhui Province
Disease Control center had IgG positive blood tests for SARS-CoV, this
was reexamined by the Jiangsu Province Disease Control Center which also
had IgM and IgG seropositivity. On the evening of 21 Apr, the Anhui Province
Health Department reported the findings to the Medical Department. On the
morning of 22 Apr, the Medical Department expert group rushed to Anhui.
On 23 Apr the China Center for Disease Control senate compared the laboratory
tests (IgG and IgM findings). The medical department expert group reviewed
the 2 patients clinical courses/presentations, the laboratory examinations
and the epidemiologic investigation and confirmed the diagnosis of atypical
pneumonia in the index case from Anhui the graduate student and referred
autopsy specimens for confirmation on the index case's mother. Analysis
of a chest fluid sample identified a SARS-CoV (HT-SCoV-2) with a gene sequence
consistent with that studied in the laboratory
another 353 people in Anhui are under medical observation
: 3 of them had been isolated with fever symptoms but none have developed
signs of pneumonia, and 89 individuals have been released from observation
a 20 year old nurse who cared for the index case from Anhui during
the period 29 Mar to 2 Apr when the patient was in the Healthy Palace Hospital
in Beijing has also fallen ill with SARS-like symptoms (fever, cough and
shivering) in Beijing on 5 Apr and was admitted to Jiangong Hospital on
7 Apr. As her condition did not improve, she was transferred on 14 Apr
to ICU of the Ditan Renmin Hospital attached to the Beijing University.
A medical examination at the hospital showed that the patient was IgG positive
on Wed 21 Apr. In the morning of Thu 22 Apr, an examination by the Beijing
Center for Disease Prevention and Control (CDC) showed the patient was
IgG and IgM positive. She is stable, now with 18 consecutive days without
fever
among 640 contacts placed under observation, 5 have developed
symptoms of SARS and been isolated at Ditan Hospital : 3 are close
relatives of the Beijing case and 2 are from the hospital contacts at the
Earth Temple Hospital (one a patient and one a visitor caring for a patient).
99 individuals have been released from observation
both the nurse's 44 year old mother (fever and no signs of pneumonia)
and her 36 year old aunt (still in critical condition but appears
to be improving) have been confirmed to have been infected with SARS-CoV
based on IgM and IgG serologic findings :
the nurse's 45-years father has a fever without signs of pneumonia
2 patients hospitalized on the same ward as either the nurse or
the index patient have a fever and no signs of pneumonia
one of them was reported by Beijing on Apr 27, a 49 year old woman,
a retired doctor from Beijing Xuanwu district admitted to hospital because
of another illness. On 9 Apr, she had a chest infection with fluid in the
chest cavity and was admitted to the Xuanwu Hospital emergency medical
treatment ward. 3 days later she was transferred to another hospital in
Beijing when information became available that she had shared a hospital
ward with the nurse who had cared for the index case. On 22 Apr bilateral
pulmonary infiltrates were noted and she was transferred to Ditan Hospital
for isolation. On 27 Apr she was diagnosed as a suspected case of SARS
based on clinical and epidemiologic findings. At present the patient is
in a serious condition with bilateral infiltrates and respiratory failure.
Onset of symptoms for all 4 occurred between 16 and 19 Apr
the retired doctor's 23 year old daughter-in-law, who accompanied
her at the time of hospital admission, is the 5th case
2 doctors who treated the postgraduate student during her hospitalization
in Hefai, Anhui, have developed fever. A person in close contact with one
of the doctors has also developed fever
a 31 year old male post-doctoral student in Beijing who worked alongside
the 26 year old patient from Anhui in the lab was also suspected of having
the disease : he fell ill on 17 Apr (the dates of symptom onset in the
2 cases were separated by 23 days, suggesting that more than one opportunity
for exposure may have occurred in the laboratory from mid-March through
early April), on 22 Apr he was admitted in isolation to the Ditan Earth
Temple Hospital and on 23 Apr he was diagnosed as a suspected case of SARS.
On 30 Apr, the Beijing Disease Control Center reported positive IgG and
IgM serology on specimens from this patient and accordingly has reclassified
this case as confirmed based on clinical, epidemiologic, and laboratory
examinations.
Close contacts of this case have not demonstrated any signs of illness.
that lab was closed on 23 Apr and the 200 staff were put in isolation
in a hotel near another lab in Cham Ping, about 20 km North of Bei
2 laboratory workers in Beijing had suffered SARS-like illnesses
in Feb 2004, recovered and went back to work : they weren't detected until
they tested positive for SARS IgG when hundreds of lab workers were screened
following the April outbreak traced to the same facility 2 months later
killed one person. ne of the ill workers oversaw the inactivation of the
virus, which should have made her a prime suspect for SARS
Hence, it appears that in the period 25 Mar through 19 Apr, the index case
and her mother were clinically ill with probable SARS CoV infection, and
were potentially infectious to others in their contact environment, including
during 2 travels on trains between Beijing and Anhui province, and during
hospitalization in general clinical care wards without isolation. No cases
were further reported. This is now the 3rd incident of SARS transmission
within a laboratory working on SARS research. The first 2 occurred in Singapore
in September 2003 and Taiwan, China in December 2003. In addition, 4 cases
(3 confirmed and 1 probable) were reported in Guangdong Province in December
2003 and January 2004, presumably acquired from an environmental source.
Unlike the present outbreak, these cases were associated with mild illness
only and did not result in secondary transmission to others. Since the
2003 outbreak, it seems as though laboratory exposure is a higher risk
factor than the possible zoonotic exposure. During and after the SARS outbreak
of 2003, a large number of specimens were collected from possible human
cases, animals and the environment. These specimens, which may contain
live SARS coronavirus, are still kept in various laboratories around the
world. Some of them are stored in laboratories at an inappropriate containment
level. SARS coronavirus has also been propagated in reference and research
laboratories, and distributed to other laboratories for research purposes.
Research using live and inactivated SARS coronavirus - and other pathogens
capable of causing serious illness -- is being conducted in many laboratories.
WHO strongly recommends BSL
3
as the minimum containment level to work with live SARS coronavirus. WHO
also urges member states to maintain a thorough inventory of laboratories
working with and/or storing live SARS coronavirus and to ensure that necessary
biosafety standards are in place. The Chinese doctor who exposed China
SARS cover-up last year has disappeared in what is believed to be part
of a government crackdown on potential dissidents before the 15th anniversary
of the Tiananmen Square massacre : Jiang Yanyong, who is also a leading
democracy campaigner, was reported missing along with his wife by their
daughter on June 4 2004. He is likely to be among dozens of people -- including
elderly mothers, young dissidents and ailing reformers -- put under house
arrest or taken out of Beijing by security agents.
Web resources :
The decision to kill up to 10,000 civet cats and other speciality-food
creatures (including raccoon dogs, ferret badgers, hog badgers and Eurasian
badgers) in the wildlife markets of the southern province of Guangdong
came on 5 Jan 2004 : Guangdong’s wildlife markets were ordered closed,
and the provincial Forestry Department put 2,030 presumably doomed civet
cats in quarantine.
Hong Kong Special Administrative
Region (SAR) of ChinaRef1,
Ref2
: 1755 cases, 300 deaths (CFR ~ 17 %) and
1448 recovered (81.4%). The Prince of Wales Hospital was the initial epicentre
of the outbreak : hospitals are becoming overwhelmed and a decision to
suspend all primary, secondary, special schools and kindergartens until
6 April has been extended up to 21 April. In Hong Kong, a large and sudden
cluster of almost simultaneous cases (321) seen in residents of the Amoy
Gardens housing estate has raised the possibility of transmission from
an environmental source. The epidemic curve and spatial distribution of
the cases are consistent with virus-laden aerosols spread from a single
sourceref.
The vast majority of Amoy Gardens cases have been traced to vertically
linked apartments in a single building, Block E. In addition, reports from
Hong Kong health authorities indicate that patients in this cluster depart
in some ways from the previously established clinical picture. The disease
appears to be more severe both in Amoy residents and in related cases among
hospital staff. Around 20% of Amoy-related cases require intensive care,
compared with 10% seen in non-Amoy cases. Some deaths are now occurring
in younger, previously healthy persons as well as in the elderly and persons
with underlying disease. Around 66% of Amoy Gardens patients present with
diarrhea
as a symptom, compared with 2% to 7% of cases in other outbreaks. Speculation
centres on whether these cases represent infection with high virus loads,
as might occur following exposure to a concentrated environmental source,
or whether the virus may have mutated into a more virulent form (viruses
in the Coronavirus family are known to mutate frequently) : alterations
in the SARS coronavirus genome are unlikely to have caused the distinctive
clinical features of the Amoy Gardens patientsref
a single case of infection with SARS coronavirus in a 44 year old Taiwanese
senior male SARS research scientist at a Taipei military hospital (National
Defence University, the only level P4 lab in Taiwan) was reported on December
17, 2003. 6 Dec 2003 was the last day he worked in the laboratory. He recalled
an incident during the final cleaning after an experiment on SARS before
his exit from the laboratory. In the negative-pressure transporting chamber
-- a part of the biosafety containment facility for transporting experimental
reagents in the laboratory -- he noted some spillage of waste medium in
an area he could not reach with the attached chamber gloves. Before opening
a Class III biological Safety Cabinet (a special transport cabinet), the
principal investigator "inactivated" a spill using 70% ethanol instead
of the time-consuming procedure recommended (H2O2)
: he disinfected the area with alcohol spray and opened the chamber door
to clean up the spilled medium -- an unusual process for him to carry out.
In this case, the principal investigator was working alone at BSL-4. He
worked excessive hours, and methods were not approved. There is also a
major problem with a lack of understanding of chemical disinfection. Many
scientific staff think that 70% ethanol is a good disinfectant (its use
is not recommended except for bench decontamination in a relatively clean
laboratory, and, certainly, not in a biological safety cabinet). The researcher
had earlier travelled to Singapore from 7 to 10, but started to run a fever
only hours after returning to taiwan : anyway Singapore ordered 70 people
into quarantine. He began to feel unwell late on December 10 and placed
himself in home quarantine. On December 16, he called an ambulance and
was admitted to the hospital with a fever.
Vietnam outbreak began on 26/2 when an American businessman was
admitted to hospital shortly after arriving in Hanoi from China. 63 cases,
5 deaths (CFR ~ 8 %) and 58 recovered. It
was declared SARS-free by WHO on 28/4, 20 consecutive days (the duration
of two incubation periods) since the last new case was detected.
a doctor believed to be infected was taken off a New York-to-Singapore
flight in Frankfurt, Germany on 15/3 and quarantined at Wolfgang Goethe
University Clinic as well as 2 accompanying family members (his wife and
another doctor) when they developed fever and respiratory symptoms several
days later. As a result of this prompt action, Germany experienced no further
spread linked to the 3 imported cases. Another 155 passengers who deplaned
in Frankfurt were quarantined at the airport : German nationals were released
while passengers in transit to other cities in Europe were awaiting travel
permission from those countries. 85 people bound for Singapore and the
plane's 20-member crew continued their journey but were to be quarantined
upon arrival
a super-spreader Chinese man in his 60s was treated at Singapore General
Hospital from 5 to 20 March for chronic kidney disease and diabetes
a 27-years old National University of Singapore virologist caught SARS
at one of 2 Singapore BSL-3 laboratories where he worked and where SARS
research is done due to inappropriate laboratory procedures and a cross-contamination
of West Nile virus samples with SARS coronavirus : he tested positive on
September 9 (the world's first reported case since the WHO declared a global
outbreak of the disease over on July 5) and left hospital on September
16, diagnosed as healthy after a week without fever, sent home by ambulance
to begin a 14-day quarantine. The Singapore incident is clearly documented
on the Singapore Ministry of Health web-site.
The main causes were, firstly, that the laboratory did not handle West
Nile virus in the same way as SARS-CoV in the same BSL-3 laboratory. Secondly,
there was little training of staff, and, finally, the laboratory procedures
were not consistent with BSL-3 procedures, and significant breaches occurred
when the accident took place. A major problem in all of these incidents
has been the poor training of staff, and, improper operating procedures,
rather than with accidents associated with containment. There would appear
to be no justification for moving SARS-CoV to BSL-4, but, rather, a need
for laboratory accreditation and proper training of staff. In virtually
all of the laboratories there was little understanding of infection control
and how to handle laboratory spills. This becomes of greater concern as
molecular biologists move into these laboratories with little microbiology
training.
8422 people has sickened in 29 countries, with 918 deaths (CFR
~ 10.9 %) and 7442 recovered. The last known case of the February 2003
outbreak was detected and isolated in Taiwan on June 15 : successively
2 laboratoy-related infections have been reported on September in Singapore
and December in Taiwan (see above) and some cases in China. In the outbreak
in Guangdong reported in February 2003, the proportion of SARS cases in
health care workers was approximately 30% : in the final analysis of the
global outbreak, approximately 21% of SARS cases reported in 2003 were
in health care workers, with a high of 43% reported in Canada. Most patients
have been previously healthy adults aged 25-70 years. Very few and milder
suspected cases of SARS have been reported among children (< 15 years)
: the immaturity of kids' immune systems could protect them from the virus
and make immune-mediated damage milder, as occurs for HAV
and HHV-3 / VZV.
The CFR, among those admitted to hospital, in patients > 60 years of age
is estimated to be far higher (43.3%) than in those < 60 (13.2%) : additional
infections in the community that do not lead to hospitalisation or death
would lower this CFR estimateref.
According to the final analyses, the age-specific CFRs reported in China
were 0.9% for those 20-29 years of age, 3.0% for 30-39 years, and 5.0%
for 40-49 years. Some outbreaks have reassuring features. A high awareness
of SARS symptoms among travellers and the medical and nursing professions
has often resulted in good management of imported cases – prompt isolation
of patients and management according to strict procedures of infection
control. As a result, many countries having only a single or a few imported
cases have experienced no further spread to hospital staff, families of
patients and hospital visitors, or the community at large
Genomics :
The virus, 29,727-29,751 bpref,
11 ORFs, diverges by 50–60% from the 3 known groups of coronavirusref,
but that is typical of the variation between coronavirus groups : the origin
is completely unclear because no other coronavirus is closely relatedref.
Scientists in the Netherlands were able to switch the host of a coronavirus
just by swapping one of their genesref.
A few nucleotide differences among individual genomes were detected as
the virus is expected to mutate very fast. Here is the list of shared mutations
:
orf1ab [putative polymerase gene]:
3047 V to A [Val to Ala] in BJ01, BJ02, BJ03, CUHK-W1
3072 V to A [Val to Ala] in CUHK-W1
3196 A to V [Ala to Val} in BJ01, BJ02, BJ03
5768 D to E [Asp to Glu] in BJ01, BJ02, BJ03, BJ04, GZ01, CUHK-W1
E2 [putative glycoprotein gene]:
77 G to D [Gly to Asp] in BJ03, CUHK-W1
244 T to I [Thr to Ile] in BJ01, BJ02, BJ03, BJ04, GZ01, CUHK-W1
577 A to S [Ala to Ser] in KYK, BJ01, GZ01
N [putative nucleoprotein gene] : 387 N to P [Asn to Pro] in GZ01, BJ02
When the S-gene sequences of 4 animal viruses [3 Himalayan palm civet and
one raccoon dog] were compared with 11 human SCoV viruses [HKU65806, Urbani,
Tor 2, HKU 39849, HKU 66078, CUHK-W1, HKU 36871, GZ50, GZ01, GZ60 and GZ43],
38 nucleotide polymorphisms were noted, with 26 of them being non-synonymous
changes. The S genes among the 4 animal viruses had 8 nucleotide differences,
whereas there were 20 nucleotide differences among 11 human viruses. Thus
the animal viruses, though isolated from the same market, are no less divergent
than the human viruses isolated from Hong Kong, Guangdong, Canada, and
Vietnam. However, whereas 14 (70%) of the 20 polymorphisms among the human
viruses were non-synonymous mutations, only 2 (25%) of the 8 nucleotide
substitutions within the animal viruses were. An amino acid deletion (nucleotide
positions: 21690-21692) was observed in 2 of the human viruses (GZ43 and
GZ60). Of the 38 polymorphisms, there were 11 consistent nucleotide signatures
that appeared to distinguish animal and human viruses. Phylogenetic analysis
showed that the human and animal viruses form distinct clusters, which
makes it highly unlikely that the isolation of SCoV-like viruses in these
wild animals is due to the transmission of SCoV from human to animalsref.
Despite the recent onset of the SARS epidemic, genetic signatures are emerging
that partition the worldwide SARS viral isolates into groups on the basis
of contact source history and geography. 2 isolates (BJ01 and BJ03) come
from the same individual : they share 4 mutations but each isolate has
3 additional unshared mutations (all 3 in orf1ab for BJ01; 2 in E2 and
1 in orf1ab for BJ03). In addition, a common variant associated with a
non-conservative amino acid change in the S1 region of the spike protein
suggests that immunological pressures might be starting to influence the
evolution of the SARS virus in human populationsref.
Phylogenetic analysis of SARS-CoV spike protein :
Molecular characterization of the SARS coronavirus has revealed genetic
diversity among isolates. The spike (S) glycoprotein, the major target
for vaccine and immune therapy, shows up to 17 substitutions in its 1,255-aa
sequence. The functional effects of S mutations have been determined by
analyzing their affinity for a viral receptor, human angiotensin-converting
enzyme 2 (ACE2),
and their sensitivity to Ab neutralization with viral pseudotypes. Although
minor differences among 8 strains transmitted during human outbreaks in
early 2003 were found, substantial functional changes were detected in
S derived from a case in late 2003 from Guangdong province [S(GD03T0013)]
and from 2 palm civets, S(SZ3) and S(SZ16). S(GD03T0013) depended less
on the hACE-2 receptor and was markedly resistant to Ab inhibition. Antibodies
collected from mice injected with S protein from a SARS virus taken from
a human patient infected in early 2003 were unable to attack S protein
from a different strain of SARS, isolated from a patient infected in late
2003. Unexpectedly, Abs that neutralized most human S glycoproteins enhanced
entry mediated by the civet virus S glycoproteins. The mechanism of antibody-dependent
enhancement (ADE)
involved the interaction of Abs with conformational epitopes in the hACE-2-binding
domain. Finally, improved immunogens and mAbs that minimize this complication
have been defined. The virus changes over time, so that a strain that crops
up in one outbreak might be quite different from that in a later outbreak.
This raises the prospect that a vaccine against one strain of SARS virus
could prove ineffective against others. Worse, a jab against one strain
might even aggravate an infection with SARS virus from civets or another
speciesref.
Some (opportunistic ?) co-infections have been associated with the
disease :
mammalian orthoreovirus
(63% of patients; 0.03% of controls) : preliminary animal experiments showed
that inoculation of the orthoreovirus into mice caused death with
atypical pneumonia
HMPV
has been identified in 12% of SARS patientsRef,
but, on the contrary of the coronavirus, it doesn't satisfy first Koch's
postulate
SARS E2-spike protein has a superantigen
(SAg)
in the region of 690 to about 1050 residues. Using carbohydrate microarrays,
the carbohydrate binding activity of SARS-CoV neutralizing antibodies elicited
by an inactivated SARS-CoV vaccine has been characterized. In these antibodies,
undesired autoantibody reactivity specific for the carbohydrate moieties
of an abundant human serum glycoprotein asialo-orosomucoid (ASOR) has been
detected. This observation provides important clues for the selection of
specific immunologic probes to examine whether SARS-CoV expresses antigenic
structures that mimic the host glycan. Lectin PHA-L (Phaseolus vulgaris
L.), which is specific for a defined complex carbohydrate of ASOR, stained
the SARS-CoV-infected cells specifically and intensively. A carbohydrate
structure of SARS-CoV shares antigenic similarity with host glycan complex
carbohydratesref
membrane (M) protein is predicted to contain a triple-spanning transmembrane
(TM) region, a single N-glycosylation site near its N-terminus
that is in the exterior of the virion, and a long C-terminal region in
the interior. The M protein harbors a higher substitution rate (0.6% correlated
to its size) among viral open reading frames (ORFs) from published data.
The 4 substitutions detected in the M protein, which cause non-synonymous
changes, can be classified into 3 types
changes of pI (isoelectric point) and charge, affecting antigenicity
changes hydrophobicity of the TM region
relates to hydrophilicity of the interior structure.
Phylogenetic tree building based on the variations of the M protein appears
to support the non-human origin of SARS-CoV. To investigate its immunogenicity,
8 oligopeptides covering 69.2% of the entire ORF were synthesized and screened
by using ELISA with sera from SARS patients : the results confirmed predictions
on antigenic sitesref.
a section of '3C-like protease', the protein that causes SARS virus to
multiply in humans, must be 'switched on' before replication can occur.
A possible mechanism for the extensive damage seen in the major target
organs for this disease involves cell entry mechanisms :
endosomal pathway
proteases such as trypsin and thermolysin enabled SARS-CoV adsorbed onto
the cell surface to enter cells directly from that site. The protease-mediated
entry facilitated a 100- to 1,000-fold higher efficient infection than
did the endosomal pathway used in the absence of proteases. These results
suggest that the proteases produced in the lungs by inflammatory cells
are responsible for high multiplication of SARS-CoV, which results in severe
lung tissue damage. Likewise, elastase, a major protease produced in the
lungs during inflammation, also enhanced SARS-CoV infection in cultured
cellsref.
Transmission :
the presence of the virus has been demonstrated in some mammals ...
Chinese horseshoe bats (Rhinolophus
sinicus)
a CoV closely related to SARS-CoV (bat-SARS-CoV) was isolated from
23 (39%) of 59 anal swabs by using RT-PCR. Sequencing and analysis of three
bat-SARS-CoV genomes from samples collected at different dates showed that
bat-SARS-CoV is closely related to SARS-CoV from humans and civets. Phylogenetic
analysis showed that bat-SARS-CoV formed a distinct cluster with SARS-CoV
as group 2b CoV, distantly related to known group 2 CoV. Most differences
between the bat-SARS-CoV and SARS-CoV genomes were observed in the spike
genes, ORF 3 and ORF 8, which are the regions where most variations also
were observed between human and civet SARS-CoV genomes. In addition, the
presence of a 29-bp insertion in ORF 8 of bat-SARS-CoV genome, not in most
human SARS-CoV genomes, suggests that it has a common ancestor with civet
SARS-CoV. Antibody against recombinant bat-SARS-CoV nucleocapsid protein
was detected in 84% of Chinese horseshoe bats by using an enzyme immunoassay.
Neutralizing antibody to human SARS-CoV also was detected in bats with
lower viral loads. Precautions should be exercised in the handling of these
animalsref.
The researchers could not determine how the bats were originally infected
or whether bats were responsible for transmitting the SARS coronavirus
to other mammals including the civets. But because bat feces are used in
Chinese traditional medicine, and bat meat is considered a delicacy in
parts of Asia, the researchers suggest caution in handling them. 3 species
of horseshoe bat of the genus Rhinolophus are a natural host of
coronaviruses closely related (92% similarity) to those responsible for
the SARS outbreak. These viruses, termed SARS-like coronaviruses (SL-CoV),
display greater genetic variation than SARS-CoV isolated from humans or
civets. The human and civet isolates of SARS-CoV nestle phylogenetically
within the spectrum of SL-CoVs, indicating that the virus responsible for
the SARS outbreak was a member of this coronavirus groupref.
This virus cannot infect humans : one of the big questions is, then, how
the virus jumped from bats to humans -- and whether in the body of an intermediary,
such as the civet, it can adapt in such a way that it can then infect a
human
caged masked palm civets or civet cats (Paguma
larvata)
: the civet may have served only as an amplification host for SARS-CoV
and provided the environment for major genetic variations permitting efficient
animal-to human and human-to-human transmissions
rats (Rattus rattus)
: however, this does not necessarily mean that the rats are the definitive
source. The result may have been caused by some other strain of coronavirus
carried by the rats, since there is a slight difference from the kind that
caused the SARS outbreak in human beings in the spring of 2003. In fact,
other strains have been found in rats, as well as in other animals long
before the new case emerged
ferrets (Mustela
putorius furo)
and cats (Felis
catus)
are susceptible to infection by SARS coronavirus and they can efficiently
transmit the virus to previously uninfected animals that are housed with
themref
: anyway both are unlikely to be the reservoir (ferrets densities are likely
too low to support an enzootic cycle of SCV transmission and the ferret
species examined does not naturally occur in China; cats would have caused
human cases of SARS over a broad geographic area long before had it been
the host). In April 2004 a Chinese team tested thousands of people for
SARS antibodies in 16 cities in Guangdong and found that among 994 people
working in animal markets, 10.6% carried positive antibodies, and among
123 civet cat husbandry staff, only 3.25% tested positive.
all the 6 index cases in 4 cities in Guandong had either eaten wildlife,
or had dealt with wildlife, particularly snakes, 10 days before they fell
ill
17 of the 18 complete sequences of isolates of the human SARS coronavirus
exhibit the same 29-nucleotide deletion (5'-CCTACTGGTTACCAACCTGAATGGAATAT
-3', residue 27869 to 27897, at 246 nucleotides upstream of the start codon
of the N gene) relative to the genome sequences of at least 2 Prionailurus
viverrinus
(a.k.a. Felis viverrinus, fishing cat) coronavirus -- and 1 of the
18 human isolates (the GZ01 sequence). The additional 29 nucleotides in
the GZ01 and the civet cat sequences bring ORF10 (coding for N-protein,
which is attached to the interior of the virus envelope) in frame with
ORF 11 and may generate a protein with 122 amino acids and a transmembrane
domain. A deletion of sequence in the same region occurred during a few
passages of the Frankfurt 1 strain of SARS coronavirus in cultured cells.
In addition to that, there were 43 to 57 nucleotide differences observed
over the rest of the genome. Most of these differences were found in the
S gene coding region. The analyses support a mammalian-like origin for
the replicase protein, an avian-like origin for the matrix and nucleocapsid
proteins, and a mammalian-avian mosaic origin for the host-determining
spike protein. A bootscan recombination analysis of the S gene reveals
high nucleotide identity between the SARS virus and a feline
infectious peritonitis virus (FIPV) throughout the gene, except for
a 200- base-pair region of high identity to an avian sequence. These data
support the phylogenetic analyses and suggest a possible past recombination
event between mammalian-like and avian-like parent viruses. This event
occurred near a region that has been implicated to be the human receptor
binding site and may have been directly responsible for the switch of host
of the SARS coronavirus from animals to humansref.
It seems that this first mutation has been followed by 2 mutations (A19838G
and C27243T) in CUHK-W1 and then by 2 mutations (C9404T and A21721G) in
BJ04
SARS-CoV has been found in ...
lung, trachea/bronchus => exposure to large respiratory droplets reaching
the mucous membranes of nose and lungs during close face-to-face contact,
such as among hospital health care workers and striking family members;
additional protective measures should be taken, such as requiring patients
to wear gloves and gowns. But healthcare workers are currently advised
to wear masks and carry out frequent handwashing.
as droplets are generated when patients cough and, to a lesser extent,
when they talk during the early stages of disease, some believe that the
efficiency of transmission of SARS by talking might be affected by the
language spoken. As of mid June, 2003, the number of probable cases of
SARS in Japan remained 0, whereas there were > 70 cases diagnosed in the
USA.1 There were about 3.1 million Japanese travellers to mainland China,
Hong Kong, and Taiwan in 2000, and about 2.3 million US citizens visited
these areas in 2001. The Chinese language has an aspiration/non-aspiration
pronunciation system: the consonants p, t, k, q, ch, and c, when placed
in front of vowels, are pronounced with a strong breath, by contrast with
b, d, g, j, zh, and z. In English, but not in Japanese, p, t, and k are
pronounced with a similar accompanying exhalation of breath. Furthermore,
the p sound is not used as frequently in Japanese as in English. Aspiration
could produce droplets. A Chinese attendant in a souvenir shop probably
speaks to American tourists in English, and to Japanese tourists in Japanese.
If the shop assistant is in the early stages of SARS and has no cough,
American tourists would, hence, be exposed to the infectious droplets to
a greater extent than would Japanese tourists
stomach, pancreas, liver and small intestine => excreted in faeces : Amoy
Gardens, where feces and urine from SARS patients with diarrhea
were aerosolized through inadequate plumbing and a faulty sewage system
and emerged into apartments, shows that you can aerosolize other sorts
of infectious materials, like feces or urine that can be inhaled and have
contact with mucous membranes, but this is not what is normally understood
as the "oral–fecal" transmission route. At RT the virus survives in faeces
for > 2 dd (in diarrhoic faeces, with a higher pH, for > 4 days)
distal convoluted renal tubule => excreted in urine. At RT the virus survives
in urine for > 24 hrs
brain tissue specimen obtained from a patient with SARS with significant
central nervous symptoms : pathologic examination of the brain tissue revealed
necrosis of neuron cells and broad hyperplasia of gliocytes. Immunostaining
demonstrated that CXCL9 / MIG
was expressed in gliocytes with the infiltration of CD68+ monocytes/macrophages
and CD3+ T lymphocytes in the brain mesenchyme. Cytokine/chemokine
assay revealed that levels of IP10 and Mig in the blood were highly elevated,
although the levels of other cytokines and chemokines were close to normalref
SARS-CoV GVU6109 can survive for 4 days in diarrheal stool samples with
an alkaline pH, and it can remain infectious in respiratory specimens for
>7 days at room temperature. Even at a relatively high concentration (104
tissue culture infective doses/mL), the virus could not be recovered after
drying of a paper request form, and its infectivity was shown to last longer
on the disposable gown than on the cotton gown. All disinfectants tested
were shown to be able to reduce the virus load by >3 log within 5 minref.
Susceptibility : HLA-B*4601 (in about
10-15% of Taiwan's and other southern Asians populations, including people
from China's Guangdong and Fujian provinces, and people from Hong Kong,
Singapore and parts of Vietnam, where people have maintained close genetic
connections over the past 400 years. Taiwan's Aborigines, as well as Caucasians
and African people, do not have the SARS-prone HLA-B46 gene)
Resistance : HLA-B13. 1.2-2.9% of healthy
individuals tested in Guangdong are seropositive for SARS-associated coronavirus
Pathogenesis
: the largest series of fatal cases of SARS with autopsy material to date
was collected by merging the pathological material from two regions involved
in the 2003 worldwide SARS outbreak in Hong Kong, China, and Toronto, Canada.
A mAb against the SARS-CoV nucleoprotein was used together with in situ
hybridization
(ISH) to analyze the autopsy lung tissues of 32 patients with SARS from
Hong Kong and Toronto. The results of these assays were compared with the
pulmonary pathologies and the clinical course of illness for each patient.
SARS-CoV nucleoprotein and RNA were detected by immunohistochemistry and
ISH, respectively, primarily in alveolar pneumocytes and, less frequently,
in macrophages. Such localization was detected in 4 of the 7 patients who
died within 2 weeks of illness onset, and in 0 of the 25 patients who died
> 2 weeks after symptom onset. The pulmonary alveolar epithelium is the
chief target of SARS-CoV, with macrophages infected subsequently. Viral
replication appears to be limited to the first 2 weeks after symptom onset,
with little evidence of continued widespread replication after this period.
If antiviral therapy is considered for future treatment, it should be focused
on this 2-week period of acute clinical diseaseref.
Severe SARS is associated with a more robust IgG responseref.
Analyses of T cell repertoires in health care workers who survived SARS-CoV
infection during the 2003 outbreak revealed that their effector memory
Vg9Vd2 T cell populations
were selectively expanded ~3 months after the onset of disease. No such
expansion of their alpha beta T cell pools was detected. The expansion
of the Vg9Vd2 T cell
population was associated with higher anti-SARS-CoV IgG titers. In addition,
in vitro experiments demonstrated that stimulated Vg9Vd2
T cells display an IFN-g-dependent anti-SARS-CoV
activity and are able to directly kill SARS-CoV-infected target cells.
These findings are compatible with the possibility that Vg9Vd2
T cells play a protective role during SARSref.
Deletion allele (D allele) of ACE
gene is associated with hypoxemia in SARS patients. Moreover, the ACE D
allele has been shown to be more prevalent in patients suffering from adult
respiratory distress syndrome (ARDS) in a previous study. Anyway the ACE
I/D polymorphism is not directly related to increased susceptibility to
SARS-coronavirus infection and is not associated with poor outcomes after
SARS-coronavirus infectionref.
Analyses of T cell repertoires in health care workers who survived
SARS-CoV infection during the 2003 outbreak revealed that their effector
memory Vg9Vd2 T cell
populations were selectively expanded ~3 months after the onset of disease.
No such expansion of their abT cell pools was
detected. The expansion of the Vg9Vd2
T cell population was associated with higher anti-SARS-CoV IgG titers.
In addition, in vitro experiments demonstrated that stimulated Vg9Vd2
T cells display an IFN-g-dependent anti-SARS-CoV
activity and are able to directly kill SARS-CoV-infected target cells.
These findings are compatible with the possibility that Vg9Vd2
T cells play a protective role during SARSref Incubation period
: 2-10 days, allowing the infectious agent to be transported, unsuspected
and undetected, in a symptomless air traveller from one city in the world
to any other city having an international airport
=> severe acute respiratory
syndrome (SARS) : it was initially believed to be due to influenzavirus
A H5N1 subtype
as Guangdong lies between Hong Kong and Fujian province. SARS-CoV infection
was diagnosed in 75% (329 of 436) of postmortem samples from patients fitting
the case definition of SARSRef,
compared with 0% for a control group of healthy individuals or those with
unrelated illnesses. SARS-CoV-infected macaques excreted SARS-CoV from
nose, mouth, and pharynx from 2 days after infection : 3 of 4 macaques
developed diffuse alveolar damage, similar to that in SARS patients, and
characterised by epithelial necrosis, serosanguineous exudate, formation
of hyaline membranes, type 2 pneumocyte hyperplasia, and the presence of
syncytia. SARS-CoV was detected in pneumonic areas by virus isolation and
RT-PCR, and was localised to alveolar epithelial cells and syncytia by
immunohistochemistry and transmission electron microscopy.
Symptoms & signs : prodrome of fever
> 38°C sometimes associated with chills, rigors, headache,
malaise, myalgias, and sometimes mild respiratory symptoms and diarrhea
(2-7%; 60% in residents in Amoy Gardens => possible transmission via the
sewage system). Myocarditis
has also been described. After 3-7 days, a lower respiratory phase begins
with the onset of a dry, non-productive cough or dyspnea that may be accompanied
by or progress to hypoxemia via ARDS.
Hematological changes are common and include lymphopenia,
thrombocytopenia
and occasionally leukopenia.
A significant decrease was also observed in peripheral CD4+ and
CD8+ T lymphocyte subsets and it was related to onset
of SARS. A number of potential mechanisms may be involved. The development
of auto-immune antibodies or immune complexes triggered by viral infection
may play a major role in inducing lymphopenia and thrombocytopenia. Moreover,
SARS-CoV may also directly infect hematopoietic stem/progenitor cells via
CD13 or CD66a inducing their growth inhibition and apoptosis. The receptor
for group I and III CoV is CD13
/ aminopeptidase N.
CD13 has been identified in human bone marrow CD34+ cells, platelets,
megakaryocytes, myeloid cells, and erythroid cells, but not in lymphocytes.
The common receptor for group II CoV is CEACAM1a
/ CD66a. CD66a is an adhesion molecule expressed on bone marrow CD34+
cells, platelets, granulocytes and activated lymphocytes. In addition,
glucocorticoids could induce lymphopenia and the use of steroids may account
for the decrease of lymphocytes in some SARS patients. The increased consumption
of platelets and/or the decreased production of platelets in the damaged
lungs are a potential alternative but often overlooked mechanism that can
contribute to thrombocytopenia in severe critical pulmonary conditionsref Laboratory
examinations :
direct (early) diagnosis (at 3 to 5 days after onset of clinical
signs, when they come to the hospital) requires viral isolation from patients
: patients don't produce sputum because it's a nonproductive cough and,
although you can get virus by doing a BAL, you'd be exposing yourself to
high amounts of infectious agent. The URT specimens and swabs are unfortunately
not very good in the early stages
nested primers RNA PCR with generic
coronavirus primers is useful in the early stages of infection but
can analytically find about 500 viruses per mL of respiratory material
(sensitivity = 20-25%). Further you are not sure whether what you are seeing
is a live virus or is only an immature virus that cannot cause disease
cytopathogenic effect (CPE) in VERO cells, FRhk-4 cells, or human
Caco-2 cells, which can be inhibited with serum from SARS convalescent
patients
IFA with serum from convalescent patients after day 10 of infection
detects viral antigens in cells from the nasopharyngeal samples
genotypying with allelic discrimination assays based on the use
of fluorogenic oligonucleotide probes (TaqMan). Genotyping of the SARS-coronavirus
isolates obtained from these patients were carried out by the allelic discrimination
assays and confirmed by direct sequencing. Genotyping based on the allelic
discrimination assays were fully concordant with direct sequencing. All
of the 30 SARS-coronavirus genotypes studied were characteristic of genotypes
previously documented to be associated with the latter part of the epidemic.
7 of the isolates contained a previously reported major deletion but in
patients not epidemiologically related to the previously studied cohortref.
indirect diagnosis
IFA with serum from convalescent patients after day 10 of infection
detects cells infected with the virus in cell-culture. Reactivity with
SARS-virus could not be detected in serum from several hundreds of non-SARS
individuals in the U.S.A., Canada and Hong Kong !
ELISA (15' test sold at < $10 each only to hospitals and maybe
family doctors) detects antibodies in convalescent sera reliably (99% accurate)
but only from about day 16-20 after the onset of clinical symptoms
immunochromatography (ICT) detects antibodies in 16% of those who
had disease for 7-8 days and in 50-60% of those who had disease for 14
days
antibodies against the hypothetical (SARS 3a, 3b, 6, 7a and 9b) and structural
proteins (envelope, membrane, nucleocapsid and spike) of the coronavirus
were generated from predicted antigenic epitopes of each protein. The presence
of these proteins were first verified in coronavirus-infected Vero E6 tissue
culture model. IHC studies on different human tissues, including a cohort
of 9 autopsies, 2 liver biopsies and intestinal biopsies of SARS patients,
further confirmed the existence of coronaviral hypothetical and structural
proteins in the cytoplasm of pneumocytes and small intestinal surface enterocytes
in SARS patients. With this vast array of antibodies, no signal was observed
in other cell types including those organs in which RT-PCRs were reported
to be positive. Structural proteins and the functionally undefined hypothetical
proteins were expressed in coronavirus-infected cells with distinct expression
pattern in different organs in SARS patients. These antipeptide antibodies
can be useful for the diagnosis of SARS at the tissue levelref
a peptide chip platform was created and the profiles of antibodies
to these epitopes were investigated in 59 different SARS patients' sera
that were obtained at 6-103 days after the onset of the illness. Serial
sera of 5 additional patients were also studied. Epitopes at the N-terminus
of the membrane protein and the C-terminus of nucleocapsid protein elicited
strong antibody responses. Epitopes on the Spike protein were only moderately
immunogenic but the effects were persistent. Antibodies were also detected
for some putative proteins, noticeably, the C-termini of SARS3a and SARS6ref
chest radiographs
may be normal during the febrile prodrome and throughout the course of
illness. However, in a substantial proportion of patients, the respiratory
phase is characterized by early focal infiltrates progressing to
more generalized, patchy, interstitial infiltrates. Some chest radiographs
from patients in the late stages of SARS have also shown areas of consolidation.
thrombocytopenia
or low-normal platelet counts (50,000 – 150,000 / mL).
CPK levels up to 3000 IU / L
hepatic transaminases 2- to 6-times the upper limits of normal
diffuse alveolar damage (DAD) : haemophagocytosis, epithelial cell proliferation,
rise in number of macrophages, bronchial epithelial denudation
Therapy :
glycyrrhizin / glycyrrhizic
acid
> IFN-b
> PEG-IFN-a
(macaques given 3 doses and then infected have their throats almost free
of viral particles 2 days later, meaning they exhaled fewer infectious
particles. Treated monkeys also have 10,000 times fewer infectious viral
particles in their type 1 pneumocytes than non-treated animals. And macaques
on interferon had fewer fluid-filled cells in their lungs' lining, allowing
them to breathe more easily. When IFN-a is given
after infection with the virus, the effects were similar but less pronouncedref)
> ribavirinref
short interfering RNA (siRNA) inhibitors exemplifies a powerful
new means to combat emerging infectious diseases. Potent siRNA inhibitors
of SARS-CoV in vitro were further evaluated for efficacy and safety
in a rhesus macaque (Macaca mulatta) SARS model using clinically
viable delivery while comparing 3 dosing regimens. Observations of SARS-like
symptoms, measurements of SCV RNA presence and lung histopathology and
IHC consistently showed siRNA-mediated anti-SARS efficacy by either prophylactic
or therapeutic regimens. The siRNAs used provided relief from SCV infection-induced
fever, diminished SCV viral levels and reduced acute diffuse alveoli damage.
The 10-40 mg/kg accumulated dosages of siRNA did not show any sign of siRNA-induced
toxicity. These results suggest that a clinical investigation is warranted
and illustrate the prospects for siRNA to enable a massive reduction in
development time for new targeted therapeutic agentsref.
10% decline, usually around day 7, and need mechanical assistance
to breathe. The care of these people is often complicated by the presence
of other diseases. In this group, mortality is high. Age over 40 years
also appears to be associated with a more severe form of disease.
10 food handlers from Guandong province have been tested for antibodies
to the human SARS virus, and 5 had seroconverted : the food-handlers' antibodies
could inhibit both the human and the civet cat virus
convalescent plasma (500 mL) was obtained from each of 3 SARS patients
and transfused into 3 infected HCW. Donors were blood type O and seronegative
for hepatitis B and C, HIV, syphilis and human T-cell lymphotropic virus
types I and II (HTLV-I and -II). Serum antibody (IgG) titre was >640. Apharesis
was performed with a CS 3000 plus cell separator followed by the forming
of the convalescent phase plasma. As part of the routine check with donated
plasma, the convalescent plasma was confirmed free of residual SARS-CoV
by RT-PCR. Serial serum samples obtained from the recipients of the convalescent
plasma were collected to undertake real-time quantitative RT-PCR for SARS-CoV
for direct measurement of viral concentration. Specific immunoglobulin
IgM and IgG concentrations were titrated using an antigen microarray developed
in-house. Viral load dropped from 495 x 103, 76 x 103
or 650 x 103 copies/mL to zero or 1 copy/mL 1 day after transfusion.
Anti-SARS-CoV IgM and IgG also increased in a time-dependent manner following
transfusion. All three patients survived. One HCW became pregnant subsequently,
delivering 13 months after discharge. Positive anti-SARS-CoV IgG was detected
in the newborn. Passive transfer of anti-SARS-CoV antibody from the mother
was considered as a possibility. All infected HCW whose condition had progressed
severely and who had failed to respond to the available treatment, survived
after transfusion with convalescent plasmaref
The following criteria are considered prior to making a decision regarding
discharge
from hospital regarding a convalescent case who is medically fit
for discharge :
clinical symptoms/findings:
afebrile for 48 hours
no cough
laboratory tests: if previously abnormal
white cell (lymphocyte) count returning to normal
platelet count returning to normal
creatinine phosphokinase returning to normal
liver function tests returning to normal
radiological findings:
improving chest x-ray changes
follow-up for convalescent cases:
Discharged convalescent patients should be asked to monitor and record
their temperature twice daily. If they have an elevated temperature > 38°C
on 2 consecutive occasions they should report to the health care facility
from which they were discharged. Follow up is recommended at 1 week at
which time they should have a repeat chest x-ray, full blood count and
any other blood tests that were previously abnormal. The patient should
be followed up by the health care facility from which they were discharged.
In addition, the clinician may decide that the patient needs to be followed
up before 1 week. Subsequent follow-ups are recommended until the chest
x-ray and patient’s health returns to normal. As part of the follow-up
we ask that convalescent serology is taken at 3 weeks after the date of
the presenting symptoms and provided to the health care facility from which
they were discharged. Until more is known about the aetiological agent,
and the potential for continued carriage (and hence the risk of continuing
transmission) a cautious approach is warranted. Therefore, we advise that
following discharge from hospital convalescent cases should be advised
to wait for a minimum of 14 days (twice the known maximum incubation period),
before considering returning to work/school/college. During this period
they should stay indoors, keeping contact with others to a minimum. Clear
instructions should be given to convalescent cases to return to the health
care facility from which they were discharged if their condition deteriorates
and any further symptoms develop.
Prognosis : plasma
CXCL10
/ IP-10
concentration (but not CXCL9 / MIG,
CCL2
/ MCP-1,
CCL5
/ RANTES,
and CXCL8 / IL-8)
at the first week is an independent prognostic factor, with an odds ratio
for adverse outcome of 1.52 (95% confidence interval, 1.05-2.55) per fold
increase in plasma IP-10 concentration above the median. During the second
week, chemokines provided little independent prognostic information. IP-10
was increased in lung tissue from patients who died of SARSref Prevention :
it is killed at 10,000 U / 15' with heat at 56° C
subunit
vaccine
: epitopes at the N-terminus of the membrane protein and the C-terminus
of nucleocapsid protein elicited strong antibody responses. Epitopes on
the spike protein were only moderately immunogenic but the effects were
persistent. Antibodies were also detected for some putative proteins, noticeably
the C-termini of SARS3a and SARS6ref