030515 Sars Associated Coronavirus
The new england journal of medicine
intravenous form, a clinician in the United States
Management of Suspected SARS.
must contact the CDC Emergency Operations Cen-
Isolate the patient
ter (770-488-7100). Health Canada recently stated,
however, that it will no longer provide access to ri-
Place patient in private room (with negative pres-
sure, if possible)
bavirin for the treatment of SARS, because of con-
cern about its side effects and lack of in vitro efficacy.
Wear gloves, gown, masks, eye protection
Some physicians have also prescribed cortico-
Wash hands carefully after removing gloves
steroids for patients with severe cases. A rationale
Limit number of health care workers caring for
for the use of corticosteroids derives from the patho-
patient
logical findings suggestive of cytokine dysregulation
Limit number of visitors
and hyperinduction of inflammatory mediators with
Perform diagnostic studies
diffuse alveolar damage. In the report by Lee et al.,
Obtain specimens to rule out causes of atypical
computed tomographic studies of the chest showed
pneumonia
bilateral peripheral changes with ground-glass con-
Obtain specimens for SARS testing (see CDC Web
solidation similar to that seen in bronchiolitis ob-
page, http://www.cdc.gov/ncidod/sars/
literans with organizing pneumonia. The latter is an
specimens.htm)
inflammatory disease involving both terminal bron-
Consider computed tomography of chest
chioles and alveoli that usually responds to cortico-
Provide treatment
steroids. In this time of uncertainty, we favor the
Supplementary oxygen for hypoxemia
use of corticosteroids only for the more ill patients.
Antibacterial agents for community-acquired
Because injectable methylprednisolone and hydro-
pneumonia
cortisone are currently in short supply in the United
Consider neuraminidase inhibitor for treatment of
States, the options are oral formulations or intrave-
influenza
nous dexamethasone.
Ribavirin (oral formulation: 1.2 g every 8 hr;
SARS has created international anxiety because
commercially available, intravenous form:
of its novelty, communicability, and rapid spread
8 mg/kg of body weight every 8 hr)
(available through the CDC)
through jet travel and because it has caused illness
Consider corticosteroids
in a large proportion of exposed medical and nurs-
ing personnel. We simply do not know where we
Notify public health department
are on the epidemic curve. Some fear is rational, but
the 4.9 percent mortality rate is in fact similar to that
antibacterial regimens for community-acquired seen generally with community-acquired pneu-
pneumonia, and some have added a neuraminidase monia in the United States. Furthermore, the total
inhibitor to cover both influenzavirus A and influ- number of deaths remains a small fraction of the
enzavirus B. Until we have a predictive test for the estimated 35,000 deaths from influenza each year
causative agent of SARS, this approach is reason- in the United States alone.
able. Supplementary oxygen should be adminis-
As the epidemic unfolds, praise is due to the hun-
tered if the patient has hypoxemia. The antiviral dreds of health care workers throughout the world
drug ribavirin has been used extensively to treat who come to work every day to assist patients with
SARS, but there are no data to show that it is effec- SARS despite some risks to their own health. Such
tive. Intravenous administration was used in the pa- dedication defines the best traditions of our pro-
tients who were most ill, and oral administration fession.
(resulting in bioavailability of approximately 50 per- From the Department of Internal Medicine, Virginia Common-
cent) was used in other patients. In order to use the wealth University, Richmond.
SARS-Associated Coronavirus
Kathryn V. Holmes, Ph.D.
The discovery that a novel coronavirus is the prob- piratory syndrome (SARS), reported by Ksiazek et
able cause of the newly recognized severe acute res- al. (pages 1953–1966), Drosten et al. (pages 1967–
n engl j med
1948
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p e r s p e c t i v e
1976), and Peiris et al.1 provides a dramatic exam- of the spike(S) glycoprotein, bind to receptors on
ple of an emerging coronavirus disease in humans, host cells and fuse the viral envelope with host cell
described by Poutanen et al. (pages 1995–2005), membranes. Coronaviruses in group 2 also have a
Tsang et al. (pages 1977–1985), and Lee et al. (pag- hemagglutinin–acetylesterase (HE) glycoprotein
es 1986–1994). Although human coronaviruses that binds to sugar moieties on cell membranes.
cause up to 30 percent of colds, they rarely cause Curiously, the gene for HE was apparently intro-
lower respiratory tract disease. In contrast, coro- duced into an ancestral coronavirus genome by re-
naviruses cause devastating epizootics of respira- combination with the messenger RNA encoding
tory or enteric disease in livestock and poultry.
HE of influenza C. The unique RNA-dependent RNA
Most coronaviruses cause disease in only one polymerase of coronaviruses often switches tem-
host species. All known coronaviruses are found in plate strands during replication, causing RNA re-
three serologically unrelated groups. The Figure combination when a cell is infected with several
shows the structure of the virion. The message- coronaviruses. This error-prone polymerase also
sense RNA genome and the viral nucleocapsid generates point mutations and large deletions or
phosphoprotein form a helical nucleocapsid. A co- insertions of foreign RNA into the viral genome.
rona of large, distinctive spikes in the envelope
The SARS-associated coronavirus could have
makes possible the identification of coronavirus- arisen as a mutant of a human coronavirus that ac-
es by electron microscopy. The spikes, oligomers quired new virulence factors, as a mutant of an an-
Spike glycoprotein
Hemagglutinin–acetylesterase
glycoprotein
Membrane
glycoprotein
Small envelope
glycoprotein
Nucleocapsid
phosphoprotein
RNA
Structure of the Coronavirus Virion.
n engl j med 348;20
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may 15, 2003
1949
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The new england journal of medicine
imal coronavirus that can infect human cells, or as in immunosuppressed animals may differ from
a recombinant of two human coronaviruses or a hu- those in immunocompetent animals; immunosup-
man coronavirus and an animal coronavirus. Anti- pressed animals may also shed virus for prolonged
bodies to the SARS-associated coronavirus were periods and accumulate and possibly spread mutant
found in serum samples obtained from patients viruses. The detection of SARS-associated corona-
with SARS during convalescence but not in human virus in fecal and serum samples from patients, as
serum samples banked before the SARS outbreak, well as in respiratory specimens, suggests that
suggesting that the SARS-associated coronavirus is this virus, like many animal coronaviruses, may be
new to the human population. The nucleotide se- spread both by fecal contamination and by respira-
quence of the SARS-associated coronavirus genome tory droplets. Host genes that affect the viral recep-
(http://www.bcgsc.ca/bioinfo/SARS; http://www. tor, viral production, and immune responses to in-
cdc.gov/ncidod/sars/sequence.htm) differs sub- fection can determine the outcome of coronavirus
stantially from sequences of all known coronavi- infections, making certain species or strains of an-
ruses.
imals highly susceptible to lethal infection. For ex-
Thus, the SARS-associated coronavirus is neither ample, coronaviruses from domestic cats almost
a mutant of any known coronavirus nor a recombi- always cause death in cheetahs. Coinfection with
nant of known coronaviruses. It is a previously un- other viruses, parasites, or bacteria exacerbates
known coronavirus, probably from a nonhuman some animal coronavirus diseases. The deaths of
host, that somehow acquired the ability to infect 3 to 4 percent of patients with SARS may result
humans. Serologic tests of wild and domestic ani- from host factors that exacerbate the disease.
mals and birds in the region where the outbreak first
Although there are no approved drugs with prov-
appeared may identify the usual host. Comparison en efficacy against coronaviruses, there are poten-
of isolates of the SARS-associated coronavirus from tial targets for the development of new drugs. Pro-
infected patients and from the natural host may re- tease inhibitors could prevent processing of the
veal how the virus jumped to humans. In jumping RNA polymerase or cleavage of the viral S glycopro-
to humans, did the SARS-associated coronavirus tein. Inhibitors of coronavirus acetylesterase activity
lose the ability to infect its original host? If there is might limit viral replication, as neuraminidase in-
no animal reservoir, there will be a better chance of hibitors inhibit the replication of influenzaviruses
eliminating the virus from humans.
A and B. Inhibitors of membrane fusion might
The host range, tissue tropism, and virulence of block viral entry, as do several new drugs against
animal coronaviruses can be changed by mutations the human immunodeficiency virus. Antibodies
in the S gene. The sequence of the S gene in the against the viral S glycoprotein or the unidentified
SARS-associated coronavirus may suggest how receptor for the SARS-associated coronavirus might
S glycoprotein affects the pathogenesis of SARS. also block entry of the virus.
The SARS-associated coronavirus genome sequence
Vaccines are available for some animal corona-
shows that it does not contain a gene encoding HE viruses. Vaccination with live, attenuated virus is ef-
or large genes derived from another virus or host fective against porcine epidemic diarrhea virus and
cell. It is an amazing feat that the SARS-associated avian infectious bronchitis virus. However, recom-
coronavirus genome has been completely se- bination of genomes of vaccine strains with wild-
quenced so quickly. The surprising discovery that type coronaviruses is a potential risk associated with
the virus can be readily isolated in a monkey-kidney using live, attenuated coronavirus vaccines in hu-
cell line was the key to the rapid molecular charac- mans. Killed or subunit vaccines containing the
terization of this novel coronavirus and the devel- spike glycoprotein, perhaps with other viral pro-
opment of diagnostic tests for SARS. SARS-associ- teins, might prevent lower respiratory tract disease
ated coronavirus has recently been proved to be the in humans. However, some vaccines against feline
cause of SARS. Inoculation of monkeys with SARS- coronaviruses actually enhanced disease when vac-
associated coronavirus from cell cultures caused cinated animals were exposed to wild-type virus, and
lower respiratory tract disease, fulfilling Koch’s antibody enhancement of disease is a potential risk
postulate.
of SARS vaccines in humans. It is possible that the
Both viral and host factors affect the virulence of current outbreak may be controlled and the virus
coronavirus diseases in animals. The disease is usu- eliminated by quarantine alone. Nevertheless, it is
ally most severe in neonates. The signs of infection prudent to develop safe, effective drugs and vaccines
n engl j med
1950
348;20
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p e r s p e c t i v e
against the Urbani SARS-associated coronavirus
From the University of Colorado Health Sciences Center, Denver.
as quickly as possible, in case the outbreak cannot
1.
Peiris JSM, Lai ST, Poon LLM, et al. Coronavirus as a possible
be contained. The development of drugs and vac-
cause of severe acute respiratory syndrome. Lancet 2003;361:
cines for SARS will also provide new strategies for
1319-25.
the prevention and treatment of other coronavirus
diseases of animals and humans.
SARS and Carlo Urbani
Brigg Reilley, M.P.H., Michel Van Herp, M.D., M.P.H., Dan Sermand, Ph.D.,
and Nicoletta Dentico, M.P.H.
On February 28, the Vietnam French Hospital of emergency meeting on Sunday, March 9, with the
Hanoi, a private hospital of about 60 beds, con- Vice Minister of Health of Vietnam. Dr. Urbani’s
tacted the Hanoi office of the World Health Or- temperament and intuition and the strong trust he
ganization (WHO). A patient had presented with an had built with Vietnamese authorities were critical
unusual influenza-like virus. Hospital officials sus- at this juncture. The four-hour discussion led the
pected an avian influenzavirus and asked whether government to take the extraordinary steps of quar-
someone from the WHO could take a look. Dr. Car- antining the Vietnam French Hospital, introducing
lo Urbani, a specialist in infectious diseases, an- new infection-control procedures in other hospi-
swered that call. In a matter of weeks, he and five tals, and issuing an international appeal for expert
other health care professionals would be dead from assistance. Additional specialists from the WHO
a previously unknown pathogen.
and the Centers for Disease Control and Prevention
We now know that Hanoi was experiencing (CDC) arrived on the scene, and Médecins sans
an outbreak of severe acute respiratory syndrome Frontières (MSF, or Doctors without Borders) re-
(SARS). Dr. Urbani swiftly determined that the sponded with staff members as well as infection-
small private hospital was facing something unusu- control suits and kits that were previously stocked
al. For the next several days, he chose to work at the for outbreaks of Ebola virus. The Vietnam French
hospital, documenting findings, arranging for sam- Hospital has been closed temporarily, and patients
ples to be sent for testing, and reinforcing infection with SARS are cared for in two wards of the public
control. The hospital established an isolation ward Bach Mai Hospital, with the assistance of a team
that was kept under guard. Dr. Urbani worked di- from MSF. No new cases in health care workers have
rectly with the medical staff of the hospital to been reported, and the outbreak in Vietnam appears
strengthen morale and to keep fear in check as to be contained. By dealing with the outbreak open-
SARS revealed itself to be highly contagious and ly and decisively, Vietnam risked damage to its im-
virulent. Of the first 60 patients with SARS, more age and economy. If it had decided to take refuge in
than half were health care workers. At a certain mo- secrecy, however, the results might have been cata-
ment, many of the staff members made the difficult strophic.
decision to quarantine themselves. To protect their
Dr. Urbani would not survive to see the success-
families and community, some health care workers es resulting from his early detection of SARS. On
put themselves at great personal risk, deciding to March 11, he began to have symptoms during a
sleep in the hospital and effectively sealing them- flight to Bangkok. On his arrival, he told a colleague
selves off from the outside world.
from the CDC who greeted him at the airport not to
In some ways, the SARS outbreak in Hanoi is a approach him. They sat down at a distance from
story of what can go right, of public health’s com- each other, in silence, waiting for an ambulance to
ing before politics. First-line health care providers assemble protective gear. He fought SARS for the
quickly alerted the WHO of an atypical pneumonia. next 18 days in a makeshift isolation room in a
Dr. Urbani recognized the severity of the public Bangkok hospital. Dr. Carlo Urbani died on March
health threat. Immediately, the WHO requested an 29, 2003.
n engl j med 348;20
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may 15, 2003
1951
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Copyright © 2003 Massachusetts Medical Society. All rights reserved.
