SARS epidemic: epidemiology, transmission, and clinical management

¶ … Acute Respiratory Syndrome

SARS epidemic created a medical emergency and a healthcare crisis with the loss of hundreds of lives in a short span of time. The knowledge of the etiology of the disease and the genome sequence of the virus provided new impetus in treatment of the disease. The crisis was successfully managed through an international cooperative effort and today we are better prepared to handle possible future outbreaks of the epidemic.

SARS is an acute infectious respiratory disease with all the symptoms of atypical pneumonia like fever, breathlessness that caused severe casualties in a short period of time. The first instance of SARS infection was reported in November 2002 in the Guangdong province of china. The SARS epidemic created a panic worldover and the World Health Organization issued a global alert on March 12th 2003 about the rapid spread of symptoms of atypical pneumonia. Symptoms of atypical pneumonia were reported in China and Hong Kong in February and March of 2003 and SARS created panic at the global level with 774 deaths and more than 8000 infected people. China, Taipei, Canada and Hong Kong suffered the most from the epidemic while sporadic SARS infections were found in many European nations and North America. Hundreds of people exhibiting symptoms were quarantined and treated for the complications until the SARS outbreak was fully contained. In July 2003 China officially announced the successful treatment of the last 12 cases of SARS. The present problem however is the early detection of the virus as the currently available diagnostic tools are either time consuming (ELISA and Immunofluorescence) or highly sensitive without any conclusive detection. (PCR). A discussion of the epidemiology, transmission, and the latest research results and treatment methods would provide a better understanding of the disease.

The SARS Virus

Ever since the spread of the epidemic in February 2003 laboratories worldwide were involved in research to hasten the identification of the agent that was responsible for the symptoms of atypical pneumonia. The World health organization instituted a combined research by eleven laboratories on March 17th to speedup the research, as by then, the virus was starting to take its toll. By the end of March researchers in Hong Kong managed to find out traces of a novel coronavirus in the affected patients. By means of cell culture, electron microscopy and immuno-fluroscent antibody tests researchers in United States and Germany also confirmed the existence of a special type of coronavirus. Coronavirueses have the largest genome size ranging from 27 kb to 32 kb and have been well-known to cause respiratory disorders in animals. Coronoviruses are easily transmitted by way of droplets, touch and small particulates in the air. They also have very short incubation periods as is the case with the SARS virus which has an incubation period between 2 and 7 days. On April 12th 2003 scientists working at the Michael Smith Genome Sciences center sucesfully mapped out the genetic sequence of the SARS virus making way for improvements in early detection and finding effective pharmacological treatment methods.

Clinical Course of SARS

There are two distinct phases observed in an infected person. The initial phase is that's of acquisition of the virus and the rapid multiplication of the same inside the host. The next phase is charaterized by persistence of symptoms due to immunological damage. During this stage symtoms may worsen and as a study by peris etal showed around 20%-36% of the affected people may require intensive care while 13 to 26% may require ventilator support for breathing. It is estimated that the IGg seroconversion starts around the 10th day and this is followed by rapid fall in the viral load.. The worsening of the symptoms during this phase is mainly due to the adverse response of the overactive immune system. [D SC Hui]

Symptoms and diagnostics

Typical symptoms for the SARS disease include raise in temperature (above 38 degrees), sore throat, breathing difficulty which becomes progressively acute, myalgia or muscle pain, sputum formation etc. There is a considerable drop in blood platelets and lymphopenia is commonly observed. All symptoms are manifest within the first two weeks of the onset of the infection. In severe cases (10 to 20%) there may be a need for mechanical ventilation to facilitate breathing as the lung function is severely impaired. Diagnostic procedures include a chest X-ray which would clearly indicate patchy appearance in the lungs. However chest X-rays taken during the initial few days would not show much differentiation from that of a healthy person and hence identification of lung infection by means of chest X-rays would only be possible in the later stages. [after a week] Finally, diagnosis in co-morbid conditions is difficult as the presence of other infections, may suppress the manifestation of symptoms.

Diagnostic methods became much easier after the SARS genome was successfully sequenced. Today we have Elisa, PCR (polymerase chain reaction) and the immunofluorescence array tests to identify the presence of the SARS virus. However, unlike other common virus infections, in the case of the SARS, virus shedding in excretion is very little in the early stages of the infection and hence detection by these tests is difficult. Since the currently available testing methods are not able to detect these small traces of virus shedding in the early phase of the disease, infection management still presents a huge problem. Of the three available diagnostic procedures the ELISA test detects the SARS antibodies in the specimen but only after a minimum of 21 days after the symptom manifestation and hence it is not much helpful from disease control perspective. Immunofluorescence assay test is comparatively quicker and takes 10 days to detect the antibodies but requires an immunofluorescence microscope. The best diagnostic is the PCR which can detect the presence of the viral DNA from any specimen such as stools, sputum, blood and other tissue samples. At present, in the absence of standard reagents for viral and antibody detection, we are largely dependent on epidemiological and clinical findings for diagnosing SARS in the early stages of the infection. [Kamps]

Epidemiology of SARS

Though the first instance of SARS was supposed to have occurred in November 2002 in Guangdong province of China, the first reported case of SARS was in February 2003 in Hanoi and in a few weeks patients exhibiting similar symptoms of atypical pneumonia were reported in Toronto, Hong Kong and Singapore. Initially the infection spread quickly because of poor understanding of the symptoms and the delay in hospitalization. However the Chinese government swung into action and immediately stepped up the preventive measures. Once the contagious nature of the disease was identified quarantine measures were employed and the disease was significantly controlled. Facial masks were advised to prevent the transmission through respiratory secretions. The disease outbreak was more or less confined to people working in close proximity with the infected person. With improved infection control methods, reduced contacts and hospitalization of infected people and quarantining of exposed people the spread of the disease was controlled to a great extent.

China and Hong Kong

China was the most affected by the SARS outbreak. With only 37 SARS cases (as of April 19) in Beijing, the epidemic was believed to have been under control. However the Chinese health care officials were shocked when more than 400 SARS cases were reported between April 20th and 21st. The WHO cleared China from the list of regions "with recent local transmission' on June 24 but by this time SARS took a heavy toll with 5300 affected patients and 349 deaths. Infection in Hong Kong began in early march and towards the end of March peaked to a maximum rate of around hundred infections per day until it gradually subsided towards the end of April. By the middle of June there were 1755 people affected by SARS and 295 patients were dead. An important fact is that 30% of the infected people were healthcare workers. Taiwan was the third worst affected region after china and Hong Kong with a total of 671 infected cases (as of July 11th 2003) and 84 deaths. [Kamps]

Toronto, Vietnam and Singapore

As per data available on June 2nd 2003, when the world health organization removed Toronto from the list of places with "recent local transmission" of the disease there were a total of 251 cases with 43 casualties. In Vietnam, the Hanoi region was most affected with a total of around 70 cases but the epidemic was totally contained by the end of April. In Singapore the first instance of SARS infection occurred around the end of February and between 25th February and 30th April there were a total of 238 SARS cases of which 33 were fatal. 76% of the infections in Singapore occurred within the hospice environment. The WHO cleared Singapore from the list of "recent local transmission" on the 31st of May. [Kamps]

Treatment for SARS

The search for effective antiviral drugs is still underway and here we shall discuss the treatment methods that were used during the outbreak of the disease in 2003 and also touch upon the latest developments in the search for a potent drug for the virus. Treatment for the SARS CoV was based primarily on a theoretical approach and physicians had to modify their treatment depending on the response to the particular drugs that were administered. As a precautionary measure antibiotics were used to ward off any respiratory infections from common pathogens. Several types of antiviral drugs were administered though there were no clear-cut evidence as to their effectiveness against SARS CoV.

Ribavirin

Ribavirin is a guanosine analogue and possesses immunosuppressive properties. It has been tested to be useful against a variety of DNA and RNA viruses. This drug was extensively used in conjunction with corticosteroids during the SARS epidemic. However ribavirin has not shown any positive in vitro activity against SARS virus and there is still no conclusive evidence as to its effect against SARS CoV in vivo. So ribavirin is primarily used as a preventive drug against other viral pathogens. It has been observed from clinical studies that SARS patients show acute symptoms during the 3rd and fourth week of the disease even though the viral load is found to be substantially reduced at this time. This is attributed to the severe reactions of the immune system. Ribavirin has been proved to be a powerful inhibitor of proinflammatory mediators that are triggered by the viral invasion. Hence the efficacy of the drug (if at all) has been ascribed to restricting the acute response from the immune system. There is a marked reduction in macrophage activation and increase in production of Th1 cytokine and simultaneous reduction in levels of Chapter 2 cytokines. High concentrations of this drug has been shown to have serious side effects like bradycardia (slowing down of heart rate) and anemia. [Kamps]

Lopinavir-ritonavir

This drug is used in fight against AIDS as a potential Protease inhibitor and is useful in halting the virus replication process. It is believed that the use of Lopinavir-ritonavir combinational drug would inhibit SARS CoV protease formation, and consequently arrest the virus replication. So this drug is potentially more useful if it is administered at an early stage before the virus has replicated much.

Immunomodulatory Treatment

As discussed earlier, part of the problem with SARS infection is dealing with the acute reaction of the immune system. During the acute stages of the disease there is a high level of proinflammatory cytokines which results in alveolar macrophages. That is, even after the initial stage of viral replication is halted and the viral load has been substantially reduced from the system the immune system continues to be hyperactive and this results in lung damage. Immunomodulatory agents such as corticosteroids have the effect of suppressing this hyperactive reaction from the immune system and provide relief from symptoms that are bought about by the excessive release of proinflammatory cytokines. However there is a hidden danger in the use of corticosteroids as their efficacy in relieving symptoms is time Specific. If the corticosteroids are administered before the immune system begins to be over active there is a danger of allowing the viral replication unchecked. On the contrary too much delay would allow the cytokine overflow and consequent damage to the lungs and worsening of the symptoms. So in order for corticosteroids to be effective they must be administered in a timely manner and over a required period of time. The dosage also needs to be carefully planned in accordance with the physical characteristics of the each person. Inappropriate prescription of these drugs would result in immunosuppression and make the host susceptible for opportunistic infections. Other immunomodulatory agents that are also used for this purpose include Thymosin alpha 1, cyclophosphamide etc. [Kamps]

Interferons

Interferons have shown their positive effect in arresting viral replication. In vitro experiments conducted in Germany have revealed that interferon ? is very effective in this regard. So, interferons maybe highly effective during the initial days of the attack as they can halt the replication of the virus. Since ribavirin had little effect on preventing the replication of the virus inside the host, in future medics may use interferons as an effective medicine to contain the viral load inside the host. Cinatl et.al 2003 proved the antiviral potency of interferons, Quoting from the study "We showed that interferons inhibit SARS-CoV replication in vitro. Interferon ss was most potent, showing prophylactic protection and antiviral potential after infection. Interferon ss could be the drug of choice, alone or in combination with other antiviral drugs," [J Cinatl]

Critical Care

In acute stages of the disease patients may experience severe breathing disorders necessitating both invasive and noninvasive forms of ventilation. It has been found now that the lung impairment which results in late stages of the disease is not due to the increase in viral load inside the host but more because of the hyperactive immune response to the virus resulting in immunopathological lung damage. Studies indicate that 20% of SARS patients manifested acute symptoms of dyspnea (breathing difficulty) and required intubation and mechanical ventilation. Noninvasive ventilation is preferred as a non-infecting and safer form of providing breathing support as invasive ventilation has been known to cause pneumoccocal infections, particularly in patients who are taking corticosteroids. However, for patients who do not improve with non-invasive ventilation it becomes necessary to use mechanical ventilation. Under these circumstances enough precautions must be taken to prevent the possibility of infection from endotracheal intubation. [Kamps]

SARS Vaccine [Latest Researches]

There are several ongoing researches for finding a good vaccine for SARS. China has already tested its SARS vaccine on humans and the results have proved to be encouraging. The U.S. has already developed 3 vaccines. Researchers working in the National Institute of allergy and infectious diseases (United States) have tested the latest SARS vaccine and experimented its efficacy by testing it on monkeys. The latest vaccine is directly delivered into the respiratory tract of the animal and it is effective in a single dose. Anthony S. Fauci, M.D., the director of NIAID says, "We now have three technologically unique approaches to restricting SARS replication in animals," These important studies of SARS vaccines demonstrate the outstanding progress we have made against this newly recognized and deadly disease.." [NIH]

The vaccine was formed by inserting the SARS S. genetic material into an impotent human parainfluenza virus. The vaccine is designed to target SARS-S protein which is present in the corona. For the test the researchers used two different types of the vaccine, one with SARS S. protein encoded in it and the other without the SARS spike protein. All the monkeys which inhaled the vaccine with the SARS S. protein developed antibodies for SARS virus and were resistant to infection by SARS virus while the rest of the monkeys continued to replicate the SARS virus upon exposure. Speaking about the new vaccine Dr. Brian R. Murphy, M.D said "This study shows that delivering the vaccine directly to the respiratory tract can effectively protect primates from SARS," With more research, we hope to develop a vaccine based on this approach that could be used to rapidly immunize first responders and other medical personnel, helping them control a potential outbreak." [NIH] Further tests also proved that only the SARS S. protein was involved in triggering the human immune response and hence the vaccine encoded with the SARS S. protein shows promising results.

Human Antibody

As said earlier the research is continuing at a very fast pace in the search for a best vaccine for SARS. Researchers from the Dana-Farber Cancer Institute have found out that a human antibody is very effective in containing the SARS virus after testing for and rejecting more than 27 billion potential candidates. Jianhua sui one of the researchers involved in the project said, "We hope a treatment will be tested in people by next winter. Our antibodies are human in origin so they should be well tolerated by patients. Human antibodies also have a long track record of safety so we don't envisage any major problems." The antibody that was chosen for this purpose was named 80R and in lab tests it had 100% prevention action. Wayne Marasco, another member of the project team said "It was one of those 'eureka' experiences, "It was pretty dramatic." This work is really a proof of principle for responding to emerging infectious diseases. If the international community works together, it can make a serious dent in the time it takes to develop protective treatments against these threats." [Danny Penman] These are just two instances of the medical research that are currently underway in our efforts at total prevention of the SARS infection. Research is also focused on developing diagnostic agents that can specifically and quickly identify the presence of the virus in a human specimen. This is very important as none of the currently available diagnostic testing tools are fully reliable.

Conclusion

The SARS epidemic created a worldwide health care crisis with the sudden onset of a hitherto unknown agent. The virulent and previously unknown nature of the virus took a heavy toll on human life. However the crisis was successfully managed through an international cooperative effort and the genetic sequence of the Coronavirus was finally mapped out paving way for creating more specific assays for detection and for developing effective counter drugs. The SARS epidemic has given us more experience in tackling another onset of the disease. Treatment methods continue to be refined and specific pharmacological agents are being developed by researchers. Our efforts in the quest for a SARS vaccine has already reaped rich rewards with many types of vaccines being tested successfully. With the present knowledge that we have gained we are certainly on our way to successfully contain and manage any possible future outbreaks.