Emergence of SARS: During November 2002, an outbreak of acute community acquired pneumonia occurred in the Guangdong province of China and by February 2003, more than 300 such cases were reported in that region.
The disease took a pandemic turn when a physician came from the outbreak affected area to Hong Kong Special Administrative Region (HKSAR) and stayed in a hotel. He transmitted the infection to several other residents of that hotel. These secondary cases when went back to their respective countries developed the clinical manifestations. This led to the occurrence of similar cases (as that of the Guangdong province of China) in the USA, UK, Canada, Singapore, Vietnam, Philippines and also in China.
The disease came to the limelight when a WHO physician, Carlo Urbani who was working in Vietnam reported the outbreak of severe pneumonia to the World Health authorities. In March 2003, WHO issued a global alert and the clinical syndrome was named “severe acute respiratory syndrome” (SARS). The unknown pathogen was then detected to be a novel Coronavirus and named severe acute respiratory syndrome (SARS) virus.
Since then, cases were reported from 37 countries worldwide affecting a total of 8098 cases and 774 deaths with a mortality rate of »10%. The last human chain transmission was declared to be over in July 5th 2003.
Origin of SARS Virus
SARS virus is zoonotic in origin. Bats are the reservoir of SARS virus. The virus is believed to be transmitted from bat to civet cat, raccoon, dog and possibly to several other animals.
These animals are thought to be the source of virus to humans. Once the virus has infected the human host, transmission of virus from infected person to other individual through respiratory route has acted as the primary mode of transmission amongst the human host (Fig. 1).
Fig1. Emergence and transmission of SARS virus
SARS CoV was isolated from Chinese horseshoe bat which was genetically similar to the SARS CoV of human and palm civet. Bats act as reservoir of several other viruses without manifesting the disease and have been associated with zoonotic transmission.
The virus has also been isolated from several animals like palm civet, raccoon dogs and Chinese ferret badgers. These animals are available in the Chinese wet market, providing an ecologically suitable environment for transmission of virus to humans.
The initial SARS cases occurred in animal handlers. Infected human developed pneumonia-like illness and the disease then transmitted from person-to-person through respiratory route.
Modes of Transmission
Transmission through infected droplets is the main mode of person-to-person transmission. A large number of secondary cases are seen within the family members, health care workers and other close contacts. Direct or indirect contact with infected fomite is the major way of droplet infection.
In health care setting, handling the invasive procedure, nebulizer, suction, intubation or any procedure generating a large amount of respiratory droplets are mostly associated with disease transmission.
Airborne transmission has been documented in a localized residential setting in Hong Kong. The source of infection was traced to an infected patient’s toilet from where the contaminated aerosols generated through exhaust fan were transmitted to the upper floors infecting hundreds of individuals in the residential complex. However, in general, airborne transmission is not considered as a common mode of transmission.
The presence of virus in the fecal sample and occurrence of diarrhea in around 40% infected patients raises the possibility of feco-oral transmission.
Clinical Features
The average incubation period is 2–10 days. Disease mainly manifests as prodromal phase and respiratory phase.
Prodrome phase: Disease starts with influenza like symptoms, such as fever, malaise, myalgia.
Early respiratory phase: After a few days of illness, respiratory symptoms start with dry non-productive cough, mild shortness of breath, tachypnea. Unlike other atypical pneumonia, features of upper respiratory tract such as rhinorrhea and sore throat are less common.
Chest physical signs are less marked as compared to chest radiograph like other atypical pneumonia. During the early respiratory phase, chest CT shows prominent ground glass consolidation in periphery and subpleural region of lower zone.
Late respiratory phase: In around two-thirds of cases, respiratory symptoms gradually progress to severe dyspnea and hypoxia, deterioration in chest sign with development of diarrhea during the second week of illness. In around 10–20% of cases, disease progresses and respiratory failure develops. Chest radiograph shows the progression of original consolidation to unilateral or bilateral consolidation. The case fatality rate is near 10%.
Pathogenesis
SARS CoV enters the target cells through binding to host cell receptor angiotensin converting enzyme 2 (ACE-2) present on the surface of the target cell. The surface spike protein (S protein) of SARS CoV mediates the binding and fusion with the host cell. ACE-2, a metallopeptidase, which acts as the receptor for SARS CoV is present on the human lungs epithelial cells, enterocytes of small intestine and tubular epithelial cells of kidney indicating the tropism of SARS CoV for these organs. The receptor ACE-2 is also present in endothelial cells of vessels and arterial smooth muscle cells.
Besides ACE-2, lymph node and dendritic cell specific ICAM3 grabbing non-integrin (LSIGN and DC-SIGN) have also been found as the receptors for SARS CoV.
The disease pathogenesis in SARS CoV is multifactorial.
Role of ACE-2: ACE-2 by its normal function inhibits ACE and angiotensin II, both of which are responsible for inducing the lungs failure. SARS CoV when binds to ACE-2 downregulates it, leading to inhibition of the inhibitory action of ACE-2 on ACE and angiotensin II which in turn leads to lungs failure.
Direct viral effect: Replication of virus in the infected cells causes direct damage to the cells and induces local inflammation leading to injury of type II pneumocytes.
Immune cells: The role of the immune cells in disease pathogenesis is not very conclusive. Infection of the immune cells probably contributes to the disease pathogenesis by disseminating the infection to various organs. Destruction of infected immune cells may lead to immune suppression which exacerbates the severity of disease.
Increased level of cytokines and chemokines has been found in severe cases of SARS CoV patients. Overexpression of gene expression of various chemokines also has been demonstrated in SARS CoV infected cells. Based on these observations, it has been hypothesized that the infected pneumocytes and dendritic cells induce the release of proinflammatory cytokines and chemokines that are responsible for causing lung injury.
Antibody against the surface protein of SARS CoV has been found to cross-reacting with the pulmonary epithelial cells. Autoantibodies against the pulmonary epithelial cells have been found in SARS patients. These autoantibodies have been shown to induce the cytotoxic injury to the epithelial and endothelial cells.
LAB DIAGNOSIS
Nasal/nasopharyngeal or throat aspirate or swab is the primary sample for detection of SARS CoV. Specimens collected in swabs are put in to the viral transport medium (VTM). Stool, urine and tissue sample can also be collected depending on the clinical condition. All samples are to be transported to the laboratory in cold chain.
Serum is tested for demonstration of four fold rise of antibody titer.
Isolation of virus, virus nucleic acid detection, antigen detection and demonstration of fourfold rise in antibody titer confirm the diagnosis. Virus culture and neutralizing antibody detection require biosafety level-3 facility and also time consuming. Therefore, viral nucleic acid detection is the most common and preferred method of diagnosis.
Viral nucleic acid detection: This is done by conventional reverse transcriptase PCR or by real-time PCR. The latter (real-time PCR) shows higher sensitivity and specificity as compared to conventional PCR. Virus Orf1b gene or nucleoprotein gene is the common target used.
As the viral load is higher during the second week of illness, sensitivity of PCR increases during this period. Therefore, if a sample is negative during early part of illness, the test should be repeated after a few days. Positive reaction by conventional PCR should be repeated with a second sample or a second PCR using a different target to confirm the result.
Virus antigen detection: Enzyme immune assay has been developed to detect the virus N protein using the specific antibody from serum samples. The sensitivity of this test is maximum during the 1st week of illness which gradually decreases with the appearance of antibodies.
Antibody detection: Detection of antibody can be done by immunofluorescence (IF) method or neutralization assay. Detection of antibody is most helpful during the second week of illness. Demonstration of fourfold rise in titer is considered as confirmatory in retrospective confirmation. IgM antibody detection is usually not
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