Severe system, a necessity in a cell’s performance

Severe Acute Respiratory Syndrome (SARS) is considered the first pandemic of the 21st century. Within months after emerging in the Guangdong province in mainland China, it had affected more than 8000 patients, causing 774 deaths in 26 countries over five continents. This paper reviews the causes, epidemiology, and the clinical features of the disease.The Respiratory System Overview and Connections to Severe Acute Respiratory Syndrome The process of absorbing Oxygen and releasing Carbon Dioxide is fulfilled through the respiratory system, a necessity in a cell’s performance and the removal of the waste products from cell respiration. Several organs are needed to carry out the action of breathing, entering through the mouth or nose, travelling down the trachea where it reaches the lungs, which are large cone-shaped sacs on either side of the heart. Once at the lungs, a system of small pipes, known as bronchi, allow the air to travel throughout the lungs until they form thin air sacs, better known as alveoli. These bubbles are the sight of the most important part of the gas exchange; where the Oxygen can diffuse into the bloodstream through the network of capillaries surrounding each one. As the lungs are vascular organs, they receive a large amount of blood from the pulmonary arteries from the right side of the heart. This allows a quick exchange of low oxygen and high carbon dioxide blood into the lungs, meaning the waste product from cell respiration can be disposed of in a streamlined fashion. It also allows oxygen-rich blood to flow from the lungs to the left side of the heart, which can then flow through the body. The act of breathing in, medically known as inspiration and expiration, is conducted through the use of muscles, diaphragm and intercostal, and made efficient through pleurae. A thin membrane, the pleurae, layers the outside of the lungs, visceral, and the inside of the chest cavity, parietal, removing the friction that would be associated with the movement of the lungs and also ensures the lungs expand as the ribcage does. The diaphragm is the large muscle, running across the chest below the ribcage, that contracts and expands as you breathing, forcing the ribcage in and out. Without these aspects, respiration would not be possible, as there would be no agent to take in the needed air. Being a form of pneumonia, SARS-CoV course through the lungs takes a similar toil. Once the virus enters the body, it begins to travel through the lungs, as it is usually inhaled or inflicted orally, then reaches the alveoli. These small sacs are thin and delicate, so disruption of any sort can be extremely detrimental, but a powerful illness such as this can completely destroy their ability to conduct gas exchange. The lung tissues become scarred and inflamed, inhibiting the capillaries function of bringing oxygen in and carbon dioxide out, creating a surplus of waste in the body and an insufficient amount of oxygen.  This also creates an exudate, which is a mass of cells or fluid, in the respiratory tract, decreasing the amount of air able to be taken in. Autopsied lungs have been found to be of an abnormal weight and edematous, or filled with fluid. There have also been effects of SARs-CoV found in the necrosis of the spleen and atrophy of the white pulp, a microscopic region of the spleen, and the lack of lymph nodes in patients. This shows its role in the immune system, as the spleen acts as a filter of blood and storage white blood cells and platelets, often one of the main organs fighting certain bacteria, such as pneumonia. It has also been autopsied and revealed in brain tissue and cerebrospinal fluid, meaning an infection of the nervous system, with it also spreading to the urogenital tract with necrosed kidneys and reduced germ cell, and lastly inflammation of the intestines in showing the effects of SARS-CoV in the gastrointestinal tract. The extent of SARS-CoV within the body is immense, not only affecting certain systems but bone marrow, liver and skeletal muscle as well. The areas reached shows the power of this virus and its ability to almost completely take over those with the ailment.Researched Causes of Severe Acute Respiratory Syndrome In November of 2002, an anomalous form of pneumonia emerged in Foshan, Guangdong Province, mainland China. The disease spread across Eastern Asia, beginning in Hong Kong and then to Vietnam, Singapore, Canada, and so on (Fig. 1) in February and March 2003.  Severe Acute Respiratory Syndrome is now known to be caused by a coronavirus, which are a family of enveloped viruses, meaning it has an outer layer or coat made from the plasma membrane, which allows it to infect other cells and survive,  with a positive single-stranded RNA. These viruses can cause diseases associated with respiratory, gastrointestinal, liver and neurologic tracts in humans and animals, but are most frequently linked with the common cold. Severe Acute Respiratory Syndrome Coronavirus, SARS-CoV, presence has been illustrated through the use of reverse transcriptase polymerase chain reaction (RT-PCR) and the isolation of the virus from respiratory secretions, feces, urine, and lung biopsy tissue specimens. Reverse transcriptase is mainly associated with retroviruses, such as SARS, and is an enzyme used to generate complementary DNA from an RNA template.The technique of RT-PCR is commonly used in molecular biology to detect RNA expression by using the ability of RT to synthesize a complementary DNA from mRNA transcripts, then using PCR to amplify regions of interest. This indicates the infection is not unique to the respiratory tract, but affects other systems, like digestive and excretory. An experimental infection of SARS-CoV was conducted on Cynomolgus macaques, an important non-human primate in biomedical research, who Osterhaus, Fouchier, and Kuiken (2004) found to have “developed a disease comparable to SARS in humans”(p.1). The results of this experimental infection suggest the causation of SARS in humans can be traced back to the necessary presence of SARS-CoV, although it is not confirmed if the transmissibility or severity of the disease can be enhanced by microbes or other cofactors. All of these factors prove that SARS-CoV is a new group within the coronavirus family (Fig.1). Around six months after the disease was first recognized, the World Health Organization (WHO) coordinated an international investigation, with the causative agents of SARS being one of the main research priorities.  Due to seroepidemiological data, or data involving the identification of antibodies to specific antigens in populations, indicating that the SARS-CoV was not a human-originated endemic, it seemed probable that this virus had crossed the species barrier from animal to human. Studies were focused mainly on wild animals captured and marketed for culinary purposes due to the fact that the majority of the early cases had reportedly occurred in people handling these wild animals sold as exotic foods. A live animal retail market was investigated in Shenzhen, a major city in the Guangdong province, where animals, mainly wild, with one domestic, were sampled. These animals originated from different regions of southern China, only coming into contact with their arrival to the market, and had remained in the markets for irregular amounts of time.  Nasal and fecal samples were taken, stored in medium 199, a solution used to encourage virus production, with bovine serum albumin, a protein concentration derived from cows, and antibiotics, as well as blood samples for serology. Anonymous samples from the traders were also taken, with informed consent, and animals were examined by veterinary surgeons beforehand to ensure they were free of apparent disease, as well as samples submitted from routine laboratory tests of patients for non-respiratory diseases. This data was then compared. Using RT-PCR, the nasal and fecal swabs were tested for the viral nucleic acid of SARS-CoV, specifically the N gene of the human SARS-CoV. Four of the six Himalayan palm civet swabs tested positive in the RT-PCR assay and all cells were introduced into FRhK-4, an epithelial cell from a monkey’s kidney, for virus isolation.  Four of the Himalayan palm civet inoculated cells were observed to have a cytopathic effect, meaning the SARS-CoV was damaging to the cells. Morphology of one of the infected cells, viewed with electron microscopy, showed particles compatible with the coronavirus. These tests demonstrate the SARS-CoV virus originated in animals, particularly live game animals found in markets, and is capable of interspecies transmission. These findings allow researchers to further understand the genetic life of the virus and its epidemiology.Diagnosis of Severe Acute Respiratory Syndrome Being a rapid progressing viral pneumonia, the initial manifestations of SARS are not specific, resulting in a difficulty in clinically differentiating the virus from other acute cases of pneumonia. Diagnosis can be difficult as other diseases, such as influenza, have similar outbreaks and symptoms, which means contact history of other patients that may have SARS-CoV is heavily relied on. One case originating in Taiwan, who has substantial business ties with Hong Kong and mainland China, where several of the original SARS cases originated, began with an index patient, who was a worker at the hospital. The worker had living quarters on site and remained on duty and often socialized with patients and staff, despite his worsening symptoms. He reported fever, diarrhea, and as the virus progressed, he was admitted to a private ward with the diagnosis of infectious enteritis, often known as food poisoning. Stool samples revealed leukocytes, a type of white blood cells responsible for counteracting foreign substances and disease, but his cultures tested negative. The patient was treated with intravenous antibiotics, but later became short of breath. A chest radiograph, colloquially chest x-ray, showed bilateral pulmonary infiltrates and the patient was moved to an isolation room in the intensive care unit and treated for possible SARS-CoV, where a PCR test proved positive for the disease. Although this patient did eventually die, due to the time in which he was treated, this case gave insight into the possible route the virus progresses in. Not every case presents itself in the same way, but there are common aspects. The patient usually becomes ill within 2-10 days of exposure, the most common symptom is a fever, 38°C, accompanied by a headache, myalgias, malaise, chills, and rigor. At around 2-7 days,  respiratory issues start to occur, and around 35% of patients do suffer from issues at the onset of the fever. Nonproductive cough associated with laboured breathing, or dyspnea, can be one of the first symptoms of the lower respiratory tract, followed by rhinorrhoea and sore throat in the upper respiratory tract. Diarrhea can occur in patients, with 25% – 35% suffering from this symptom, but this is linked to the fecal-oral/respiratory transmission of SARS-CoV. However, findings on chest radiographs do not always correlate with the severity of rales, small airways and alveoli collapsing due to fluid, exudate, or lack of aeration, causing a popping noise, and rhonchi, caused by obstructions or secretions in the large airway, with respiratory signs present in less than one-third of cases. Atypical symptoms, such as lack of fever, can occur in elderly patients and those with chronic illness, but it has been found SARS-CoV presents itself milder in children. There is also a correlation between the results of RT-PCR and immunofluorescent serologic testing, which is the use of fluorescent light microscopy to analyze antibodies in the blood. In the first five weeks after the first generation diagnostic tests were completed and made available in Hong Kong, 1,048 cases and their diagnosis were investigated, one of the laboratories being the Department of Microbiology of Queen Mary Hospital. Clinical specimens for the viral RNA detection included nasopharyngeal aspirates, throat and nose swabs, saliva, sputum, endotracheal aspirates, feces, and urine, which were then categorized as “clinical SARS,” “suspected SARS,” and “not SARS” depending on the responses to antimicrobial therapy, the inhibition or killing of microorganisms, for bacterial pathogens. Virus isolation, viral RNA detection, and serologic testing were performed with these samples, whose results helped to further the understanding of SARS-CoV effect on the body. After a total of 5,310 were tested, results found that viral RNA could be found in the respiratory tract within the first four days of the illness, although it took five days for feces samples and seven days for urine samples to have detectable RNA. These samples peaked at 11 days into the illness, with the viral RNA progressively increasing. Nasopharyngeal aspirates and throat and nose swabs prove to be the most productive specimen, as they show results within the first four days. These tests yield evidence that the nasopharyngeal aspirates and throat and nose swabs are the most useful in early diagnosis of SARS-CoV (Chan, 2004, p. 3) and viral RNA could still be detected in them after 30 days. Serology and virus isolation proved to be not as effective, as results could only be seen after the first two weeks of testing. The data gathered from these tests depict that the diagnosis of SARS-CoV is mainly reliant on the state of RNA and how it reacts to RT-PCR testing, isolation, or serology. There is information to be gained on the physical status of the patient, like coughing, sickness, or issues breathing, but since the viral pneumonia is similar to other respiratory illness, the study of the causative bacterial pathogens is needed to correctly identify SARS. Management and Prevention So far, the treatment of SARS-CoV is a controversial topic due to the lack of randomised controlled testing for treatments. Many results are anecdotal, however, because of its similarities to Bronchiolitis Obliterans Organizing Pneumonia (BOOP), which is sensitive to steroid therapy, Ribavirin and a steroid have been the main regime. This broad-spectrum antiviral agent, Ribavirin, interferes with the synthesis of viral mRNA and is often used as a first line medicine. Being a prodrug, meaning it metabolizes into a pharmacologically active drug, it is able to have improved absorption and distribution in the body. Many of the cases in Hong Kong and Toronto have stabilized and improved with this therapy, introduced  2003. This treatment is administered orally, except with patients suffering advanced dyspnoea treated intravenously, along with a corticosteroid and hydrocortisone for those in advanced stages.  Ribavirin has been proven to have adverse effects, including the destruction of red blood cells, hemolytic anemia, and electrolyte disturbances, but corticosteroids, specifically methylprednisolone, have shown to be favourable with little risk. Other methods include ensuring sufficient amounts of oxygen are supplied to the lungs, respiratory auxiliary ventilation,  and anti-inflammatory and immunosuppressive drugs. SARS-CoV replication has also been obstructed through the introduction of human interferon cells, which are clusters of signalling proteins, released by the presence of pathogens by host cells. Interferon ? has been proven to have prophylactic, intended to prevent disease  and has antiviral tendencies in vitro studies after infection. The combination of this protein with other antiviral drugs is a strong option for management of SARS-CoV. There has also been substantial evidence in regards to the effect of natural herbal medicine in the treatment of SARS-CoV. Traditional Chinese medicine has often been used with western medicine to auxilirate the healing process and has been extensively employed as part of the treatment of SARS-CoV. The Ministry of Health of China recommended several anti-SARS-CoV formulae to be used as a complementary component to the current cures being tested and applied, many which have been found to reduce mortality rate and increase the amount of those cured and positive clinical outcomes. There are some ethical hoops to jump through pertaining to using herbal treatment, mainly due to the validity of the treatments. The idea that extremely sick patients are subjected to undergo experimental medicines and analysis is not one that goes smoothly, although the social value is high, that is the amount of gained knowledge, the risk to benefit ratio can be skewed and in need of justifying. Despite these, tests do prove that certain plants have anti complementary effects to SARS-CoV. It has been found that the bioactive flavonoids, a naturally occurring crystalline compound, often found in fruits, vegetables, and teas, has had the best results. Flavone has inhibitory effects on the virus replication of SARS-CoV and is therefore able to discourage the actions of several enzymes. The antioxidant principles of this compound is not fully understood, but it is known their ability to the signal receptors leads to the disruption of the viruses ability to spread. Glycyrrhizin, the reason behind the sweetness in licorice, has also linked with the inhibition of SARS-CoV replication. In results formulated by Cinati et al. (2003), it was determined “Glycyrrhizin affects cellular signalling pathways such as protein kinase C; casein kinase II; and transcription factors such as activator protein 1 and nuclear factor B.”(p.2), meaning the messages directed by the disease were not able to be received, as they were interrupted by the root. These two natural components do not have complete research, but at the time of SARS-CoV were beneficial to the exploration of the disease and have also been helpful with other illnesses, such as HIV-1 and Hepatitis C. For a disease such as SARS-CoV, the best management is to prevent it from spreading through communities. As there is a lack of a universal vaccine or cure, the prevention of SARS-CoV requires early case detection and isolation to ensure there is as little transmission possible. Precautions have been made, monitored by WHO, instructing droplet control to prevent nosocomial, originating in a hospital, transmission and strict hygiene to be promoted throughout affected countries, especially highly populated areas, such as hospitals, schools, and city centres. In a study conducted by the Advisors of Expert SARS group of Hospital Authority, it was concluded the use of masks, gowns, and proper handwashing techniques made those interacting with the SARS-CoV less susceptible to the disease, but the presence, or lack of, of gloves was not significant. It was also found “30% of non-infected staff did not use masks which supports that transmission is not airborne” (Yam, Yu, Lai, & Tsang, 2003). However, there is not a comprehensive evaluation of the precautions needed for the infection, only strong recommendation advising against the possibility of airborne and fecal-oral spread. Those with atypical symptoms and late admission or isolation create the majority of issues towards the spread, thus the level of control standards and suspicion held by medical centres is required to be increased. Public awareness is a huge factor in the management of SARS-CoV, resulting in large broadcasts and instructions appearing at the time of eruption in 2003. To manage and prevent an illness as prevalent as SARS-CoV is a difficult task, reliant on the cooperation of countries and the work of researchers. Data has revealed there are ways of controlling the replication of the disease once contracted through antiviral agents, namely Ribavirin, steroids, and a few herbs. These medicinal treatments are not able to fully cure SARs-CoV, with a reported fatality rate of 10% (Gu  &  Korteweg, 2007), but instead halt its ability to duplicate and relieve patients of certain symptoms. Many populations have relied on a strong ability to prevent the distribution of the illness outright through extensive precautions, promoting the isolation and fast diagnosis of patients to prevent spread. The Future of Severe Acute Respiratory Syndrome Having originated in 2003, much of the panic surrounding the eruption of SARS-CoV has greatly subsided. There is little new research in regards to furthering the understanding or finding a cure, but instead data is focussed on building on previously discovered aspects of the disease. Many reports have been written concerning how the initial outbreak was treated, the tests conducted, and the results from patients taking certain remedies, but little have original information. The results of the extensive research are the creation of  multiple remedies to SARS-CoV comparable diseases, such as ones that react to antiviral medications and steroids. This had become apparent in 2016 with the emergence of a WIV1-CoV virus, which binds to the same receptor as the SARS-CoV strain. Being animal born, found in horseshoe bats, and displaying similar symptoms, it is fair to assume the treatments may be alike as well. This was confirmed by researchers through tests, verifying the antibodies used to treat SARS-CoV were applicable to this virus in human and animal tissue. Although the specificities of SARS-CoV are no longer being investigated, what has been revealed leaves a beneficial starting point for other like illnesses.