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Jian-Zhong
Zhang, Department of Pathology, 306 Hospital of PLA, Beijing 100101,
China
Correspondence to: Professor Jian-Zhong Zhang, Director of
Department of Pathology, Beijing 306 Hospital, 9 North Anxiang Road,
P.O.Box 9720, Chaoyang District, Beijing 100101, China.
zhangjz55@sina.com
Telephone: +86-10-66356237
Fax: +86-10-64871261
Received: 2003-05-20
Accepted: 2003-05-27
Abstract
Severe acute respiratory syndrome (SARS) is an infectious
atypical pneumonia that has recently been recognized in the patients
in 32 countries and regions. This brief review summarizes some of
the initial etiologic findings, pathological description, and its
lesions of digestive system caused by SARS virus. It is an attempt
to draw gastroenterologists and hepatologists' attention to this
fatal illness, especially when it manifests itself initially as
digestive symptoms.
Zhang JZ. Severe acute respiratory syndrome and its lesions in
digestive system. World J Gastroenterol
2003; 9(6): 1135-1138
http://www.wjgnet.com/1007-9327/9/1135.asp
INTRODUCTION
In November 2002, a so-called atypical pneumonia with unknown
etiology appeared in Guangdong Province, China, followed by reports
from Hong Kong, Vietnam, Singapore, Canada and Beijing of severe
febrile respiratory illness that spread to household members and
health care workers[1-6,23-26]. This disease was
designated "severe acute respiratory syndrome (SARS)"
later by the World Health Organization (WHO) and global efforts to
understand the cause of this illness and prevent its spread were
instituted in March 2003. Many cases could be linked through chains
of transmission to a health care worker from Guangdong Province,
China, who visited Hong Kong, where he was hospitalized with SARS
and died. Till May 19, 2003, a cumulative total of 7 864 SARS cases
were reported to WHO from 29 countries; 643 deaths (case-fatality
proportion: 8.2 %) have been reported, in which most cases occurred
in China (7291 cases)[7]. The incubation period for the
disease is usually 2 to 7 days. Infection is characterized by fever,
non-productive cough, and shortness of breath, and the presence of
minimal auscultatory findings with consolidation on chest
radiographs. Lymphopenia, leucopenia, thrombocytopenia, and elevated
liver enzymes and creatinine kinase may also present in
most cases.
In
response to this outbreak, WHO coordinated an international
collaboration that included clinical, epidemiologic, and laboratory
investigation, and initiated efforts to control the spread of SARS.
Rapid research progress has been made in last three months. This
brief review is to focus on the etiologic and pathologic findings
with an emphasis on the known lesions in the liver and intestine.
ETIOLOGICAL
FINDINGS
The isolation of a novel coronavirus was obtained from the
respiratory secretions of patients with SARS and subsequently
demonstrating this virus or a serologic response to this virus,
points to a possible etiologic association with SARS[5,6,17,20,22,27].
The discovery of this new virus occurred through a broad-based and
multidisciplinary effort by clinical, epidemiologic, and laboratory
investigators.
Researchers
around the world have sequenced the genetic codes of SARS virus, and
are searching for clues to the virus's origins, behavior, and
future. Science is set to publish online a paper analyzing the
genome from the BCCA Genome Sciences Center in Vancouver, as well as
one from the Centers for Disease Control and Prevention (CDC) in
Atlanta (www.sciencemag.org/feature/data/sars). Now that sequencing
technology has become cheap and widely available, almost every
country or area affected by SARS is sequencing its own version,
including Hong Kong, Singapore and China[8-10]. The
viruses themselves are something of an oddity. With a genome of the
complete -29 700 nucleotides, coronaviruses are relative giants, and
they have a complex two-step replication mechanism. Many RNA virus
genomes contain a single, large gene that is translated by the
host's cellular machinery to produce all viral proteins.
Coronaviruses, instead, can have up to 10 separate genes. Most
ribosomes translate the biggest one of these, called replicase,
which by itself is twice the size of many other RNA viral genomes.
The replicase gene produces a series of enzymes that use the rest of
the genome as a template to produce a set of smaller, overlapping
messenger RNA molecules, which are then translated into the
so-called structural proteins - the building blocks of new viral
particles. Most coronaviruses cause either a respiratory or an
enteric disease, and some do both. But the differences among these
types can be small. In 1999, for instance, a team led by Luís
Enjuanes of the Autonomous University of Madrid, Spain, showed that
just two point mutations can change a mostly enteric virus that can
kill piglets into a nondeadly one that excels at the respiratory
route but replicates poorly in the gut[11].
Researchers
have grouped coronaviruses into three categories based on
cross-reactivity of antibodies backed up by genetic data; the two
previously known human viruses fell into different groups.
Investigators have hoped that the genome sequence of the new virus
would help pinpoint its origins. But a first glance at the data has
yielded few clues. The new coronavirus does not fit into any of the
clusters but is a new one by itself. Phylogenetic analysis of the
predicted viral proteins indicates that the virus does not closely
resemble any of the three previously known groups of coronaviruses.
The genome sequence will aid in the diagnosis of SARS virus
infection in humans and potential animal hosts (using PCR and
immunological tests), in the development of antivirals (including
neutralizing antibodies), and in the identification of putative
epitopes for vaccine development.
PATHOLOGICAL
CHANGES IN THE LUNG
Pathological studies of patients who died of SARS from Guangdong,
Hongkong, Beijing and Singapore showed diffuse alveolar damage (DAD)
in the lung as the most notable feature[5,6,12,15,21]. In
those individuals with severe disease resulting in death, scattered
type II pneumocytes showed marked cytologic changes including
multinucleation, cytomegaly, nucleomegaly, clearing of nuclear
chromatin, and prominent nucleoli. Although these changes were
severe, they were within the spectrum of epithelial changes seen in
other cases of DAD. Definite viral inclusions were not always found
in the cytoplasm of epithelial cells. Nicholis et al[12]
found that DAD was common but not universal. Morphologic changes
identified were bronchial epithelial denudation, loss of cilia, and
squamous metaplasia. Other findings included focal intraalveolar
hemorrhage, hemophagocytosis, necrotic inflammatory debris in small
airways, organizing pneumonia or secondary bacterial pneumonia.
DAD
is a pattern of acute lung injury characterized, in the acute phase,
by hyaline membranes, interstitial and intraalveolar edema, patchy
type II pneumocyte hyperplasia, microthrombi, and scant interstitial
infiltrates of mononuclear cells. The acute phase forms a continuum
with the proliferative or organizing phase in which proliferation of
interstitial fibroblasts and prominent type II pneumocyte
hyperplasia are the histologic hallmarks. In addition to DAD, the
autopsy cases showed acute bronchopneumonia and variable
intravascular thrombosis, all of which are common as terminal
events. Biopsy material from milder cases or earlier in the course
of illness may better define the initial lesion in SARS.
Multinucleated
syncytial cells were identified in the alveolar spaces in a few
patients. These cells contained abundant vacuolated cytoplasm with
cleaved and convoluted nuclei, which show either CD68 or cytokeratin
positive. No obvious intranuclear or intracytoplasmic viral
inclusions were identified, and electron-microscopical examination
of a limited number of these syncytial cells revealed no coronavirus
particles. No definitive immunostaining was identified in tissues
from a patient with SARS, with the use of a battery of
immunohistochemical stains reactive with coronavirus from antigenic
groups I, II, and III. In addition, no staining of patient tissues
was identified with the use of immunohistochemical stains for
influenza viruses A and B, adenoviruses, Hendra and Nipah viruses,
metapneumoviruses, respiratory syncytial virus, measles virus,
Myocoplasma pneumoniae,and Chlamydia pneumoniae[14].
Evaluation
of Vero E6 cells infected with coronavirus isolated from a patient
with SARS revealed viral cytopathic effect that included occasional
multinucleated syncytial cells but no obvious viral inclusions.
Immunohistochemical assays with various antibodies reactive with
coronavirus from antigenic group I, including human coronavirus
229E, feline infectious peritonitis virus 1, and porcine
transmissible gastroenteritis virus, and with an immune serum
specimen from a patient with SARS demonstrated strong cytoplasmic
and membranous staining of infected cells. No staining was
identified with any of several monoclonal or polyclonal antibodies
reactive with coronavirus in antigenic group II (human coronavirus
OC43, bovine coronavirus, and mouse coronavirus) or group III
(turkey coronavirus and infectious bronchitis virus). Electron-microscopical
examination of a bronchoalveolar-lavage specimen from one patient
revealed many coronavirus-infected cells[14].
Ksiazek and
colleagues[5] noticed that the primary histopathological
lesions are consistent with a nonspecific acute response to lung
injury that can be caused by infections, trauma, drugs, or toxic
chemicals. The multinucleated syncytial cells without viral
inclusions seen in the lungs of two patients, however, are
suggestive of a number of viral infections including measles and
parainfluenzavirus, respiratory syncytial virus, and Nipah virus
infection. Multinucleated syncytial cells associated with some human
coronavirus infections have occasionally been observed in cell
culture, but most often in cell cultures inoculated with animal
coronaviruses. To detect this novel coronavirus antigen, the
investigators used an extensive panel of antibodies against
coronaviruses that are representative of the three antigenic groups,
including several group 1 antiserum specimens that reacted against
Urbani SARS-associated coronavirus infected tissue-culture material.
A possible explanation for the failure of this antiserum to react
with antigens in these patients on immunohistochemical analysis is
that the host immune response has cleared the virus from these
tissues. The tissues were available late in the course of the
illness, 14 to 20 days after its onset. For many viral respiratory
infections, viral antigens and nucleic acids are cleared within two
weeks after the onset of disease.
Electron
microscopic examination showed that virus-like particles with
100-150 nm in diameter were found in cytoplasm and dilated reticular
endoplasm of the infected alveolar epithelial cells and endothelial
cells[5, 15-17]. Other agents, such as paramyxovirus,
metapneumovirus and chlamydia, were also identified in the pulmonary
tissues[16,22]. It could be that the coronavirus may by
itself produce the disease but it may also open the door for other
viruses, or nonviruses, to aggravate the disease.
The
pathogenesis of this disorder remains to be determined. However, the
mechanism of acute lung injury could involve direct damage by the
virus to the alveolar wall by targeting either endothelial cells or
epithelial cells. Alternatively, the virus could infect inflammatory
cells with the injury mediated through cytokines, interleukins, or
tumor necrosis factor-alpha. It is also possible that the tissue
damage in SARS is not directly related to viral infection in tissues
but is a secondary effect of cytokines or other factors induced by
viral infection proximal to but not within the lung tissue. In
influenza infections, viral antigens are seen predominantly in
respiratory epithelium of large airways and are only rarely
identified in pulmonary parenchyma, despite concomitant and
occasionally severe interstitial pneumonitis.
LESIONS
IN DIGESTIVE ORGANS
As previously described, most coronaviruses cause either a
respiratory or an enteric disease, which is also transmitted by the
faecal-oral route. During this outbreak of SARS, symptoms of
gastrointestinal tract in the patients were noticed. Many
investigators[13,19,24] found that gastrointestinal
symptoms are not uncommon at presentation, including diarrhea (19-50
percent), nausea and vomiting (19.6 percent), and abdominal pain (13
percent) manifested in SARS patients.
As
many as 66 % of the patients in the Amoy Garden SARS outbreak in
Hong Kong also had diarrhea, contributing to a significant virus
load being discharged in the sewerage, which caused 361 cases of
SARS[3]. During hospitalization, some patients were
present with mildly elevated aminotransferase levels (indicating
liver damage), or developed dysfunction of the liver at the later
stage of the disease. Some patients presented with severe acute
abdominal pain requiring exploratory laparotomy. All these patients
developed typical SARS. These clinical findings suggest that SARS
virus does involve the digestive system, especially the epithelial
cells of intestinal mucosa.
Patholologic
evaluation of the fatal cases showed that, except the lung changes,
hepatocytes underwent fatty degeneration, cloudy swelling, apoptosis
and dot necrosis, with Kupffer cell proliferation and portal
infiltrates of lymphocytes[15,16]. There were regional
hemorrhages, vascular congestion and lymphocytic infitration in
gastrointestinal walls of the patient. Suckling mice inoculated with
SARS-infected samples also demonstrated hepatocytic lesions,
including swelling, vacuolar and hydropic degenerations, focal
cellular condensation and necrosis. But no coronavirus-like
particles were found in hepatocytes.
Epidemiologic investigation also showed that the virus
could survive in stools for at least two days and in diarrhoeal
stools, which has a higher pH, for up to four days. It can also
survive on plastic surfaces for up to 48 hours, but it is not yet
known how big a dose of the virus is required to cause infection[18].
According
to the experience of Prince of Wales Hospital in Hong Kong[20],
where SARS outbreak happened, the difficulty of making a firm
diagnosis until chest radiographic changes appear has important
implications for health-care personnel and for surveillance. Three
major reasons for spread of infection to health-care workers are:
failure to apply isolation precautions to cases not yet identified
as SARS, breaches of procedure, and inadequate precautions. Every
patient must now be assumed to have SARS, which has major long-term
implications for the health-care system. Another reason for spread
among health-care workers is infected workers continuing to work
despite symptoms, such as mild fever. Such individuals must now
cease working. However, staying at home can also have disastrous
consequences for exposed family members. Potential cases therefore
require early isolation from both workplace and household. Extreme
measures are required to protect health-care workers, who account
for about 20 % of cases. Therefore, gastroenterologists and
hepatologists should pay more attention when contacting the
patients.
SARS has
been appropriately elicited because current knowledge regarding the
transmission of this disease is rapidly evolving and clinicians must
provide patient care while dealing with a degree of uncertainty. The
Centers for Disease Control and Prevention have published and
regularly update logical recommendations for preventing the spread
of the causative agent. The causative organism appears to spread
predominantly by contact and droplets and may spread
by airborne routes as well. The use of N-95 masks, gowns,
double gloves, hand hygiene, and eye protection seem well advised
and appear to have substantially curtailed spread within hospitals.
Global
efforts have described this new syndrome with dramatic speed, and
identified and sequenced the apparent etiologic agents. With
expedited efforts to develop a specific diagnostic test, effective
infection-control techniques, and to develop effective therapies and
vaccines for SARS-associated coronavirus, and to create a true
global health network, there is much reason for optimism. To be
prepared for that challenge, health care professionals must not
forsake their patients, the research community must help provide
answers to the unanswered questions, and health care leadership must
take the knowledge from that research to rapidly implement whatever
strategies necessary to better combat this newly emerging infectious
disease[28].
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