Severe Acute Respiratory Syndrome, Research Paper Example

The 21^st century was considered a fairly safe time for the humanity in terms of medical care and understanding of the majority of infectious diseases. However, the outbreak of the severe acute respiratory syndrome (SARS) in 2003 in Foshan, Guandong province of the mainland China, appeared a serious challenge for the modern advanced medicine (Peiris et al. 2431). According to Du et al., SARS is the first new infectious disease identified in the 21^st century (226). Therefore, this new disease that usually occurs in the severe and acute form, and causes death because of the serious health complications, poses a new and unexplored threat for the humanity, since no effective cure has yet been identified, and the understanding of causes, epidemiology, and pathogenesis of SARS are still at the germinal level of development. The problem of SARS emergence was recognized as a serious public health concern by WHO, so nowadays, the clinical and theoretical research on identifying the ways in which SARS can be combated takes one of the forefront positions in the worldwide medical research.

The present research paper offers a detailed and comprehensive overview of data related to SARS causes, epidemiology, and the course of development of pathologies in humans diagnosed with SARS. The recent findings of the molecular epidemiologic studies, as well as the research of the SARS-CoV S protein properties present the key research interest in the present work. It also contains the information on the modern efforts conducted for SARS isolation, prevention, management, and vaccination.

Cause of SARS

SARS is also called the atypical pneumonia; its first recorded cause of outbreak occurred in Foshan, Guangdong Province, in the China mainland in November 2002 (Du et al. 226). Unfortunately, due to the ineffective and reactive Chinese policy of concealing and diminishing the danger of the SARS threat, SARS quickly spread to other countries before the international medical community managed to research it, and bring it under the epidemiological control (Tseng et al. 1). Peiris et al. mentioned the cases of SARS in Hong Kong, Vietnam, Singapore, and later in Canada and other countries in February and March 2003 (2431). It became possible to bring SARS under control only in the middle of 2003; the epidemics resulted into 8,000 reported SARS cases, 800 deaths of SARS, and the increasing age and co-morbidity being among risk factors that contributed to fatal cases (Tseng et al. 1).

Clinical research indicated that SARS is caused by the novel coronavirus SARS – CoV; coronaviruses are generally the group of “enveloped, single-stranded-RNA viruses causing disease in humans and animals, but the other known coronaviruses that affect humans cause only the common cold” (Peiris et al. 2431). The effect of the SARS-CoV on the human beings is explained by its genome RNA encoding a non-structural replicase polyprotein and structural proteins such as “spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins” (Du et al. 226). The SARS-CoV virus is considered a zoonotic virus residing in hosts that can form a natural reservoir for it (e.g. bats), but can also affect the intermediate hosts such as small animals before affecting humans (Du et al. 226). There is still a pronounced lack of understanding regarding the SARS-CoV coronavirus’ life cycle and pathogenesis, which prevents the medical community from formulating a concise and comprehensive strategy for tackling SARS and SARS-like viruses in future.

According to Peiris et al., SARS has also revealed the reverse-transcriptase polymerase chain reaction (RT-PCR), and manifested its non-confinement to the respiratory tract only by means of analyses made with the isolation of SARS from “respiratory secretions, feces, urine, and tissue specimens from lung biopsy” (Peiris et al. 2431). However, Tseng et al. insisted, “the clinical disease is similar to other severe acute respiratory infections, including influenza; the SARS case definition includes clinical, epidemiologic, and laboratory criteria” (1). It is also necessary to understand that SARS-CoV is capable of triggering a series of co-morbidities, including the dysfunctions of humoral and cellular immune nature (Du et al. 226).

In the context of discussing SARS, one has to note that the pathogen causing the acute and severe, at times mortal, disease is of the key interest for researchers and clinicians. As Du et al. characterized its structure, “the spikes of SARS-CoV are composed of trimers of S protein, which belongs to a group of class I viral fusion glycoproteins that also includes HIV  glycoprotein 160 (Env), influenza haemagglutinin (HA), paramyxovirus F and Ebola virus glycoprotein. The SARS-CoV protein encodes a surface glycoprotein precursor that is predicted to be 1,255 amino acids in length, and the amino terminus and most of the protein is predicted to be on the outside of the cell surface or the virus particles” (Du et al. 227).

It is also valuable for microbiological research to have identified the receptor of SARS-CoV in the human organism – it is the angiotensin-converting enzyme (ACE2). Hence, it is possible to admit that SARS-CoV in both humans and animals depends directly on the ACE2 in terms of cell entry. The SARS CoV in animals is able to evolve and change to affect humans afterwards; one of such cases may be illustrated by the “chimeric recombinant SARS-CoV that bears the S protein of civet SARS-CoV (icSZ16-S) can adapt to human airway epithelial cells and displays enhanced affinity for human ACE2” (Du et al. 227). SARS-CoV plays the vital role in the formation of bonds with receptors, and facilitates the further changes between the viral envelope and the host cell membrane in the infected organism (Du et al. 227).

The origin of the SARS outbreak of 2003 was intensely researched, but there is still very fragmented and unsupported information on the true epidemiology of the 2003 health crisis. Peiris et al. indicated that the possible cause of disease development is that SARS used to be an exclusively animal disease, and crossed the barrier between the animal and human organism only recently (2431). The present supposition was supported by the exposure to live, caged animals considered exotic “game food”, and culinary delicacies in China. The animals diagnosed with SARS included Himalayan palm civets, raccoon dogs, ferrets and cats, etc. (Peiris et al. 2432). Hence, more caution is needed in the wild animal trade and live game animals’ business, especially in the Asian regions.

Epidemiology of SARS

There are many epidemiologic studies of SARS, mainly dedicated to the outbreak and epidemiology of SARS in a particular state. For instance, Vartti et al. devoted their article to the investigation of the Finnish and Dutch SARS outbreaks, and concluded that Finns were more knowledgeable about SARS issues, and were more worried about the probability of SARS outbreak in their country; they also had poor personal efficacy beliefs regarding their personal ability to prevent SARS (41). The Dutch revealed low levels of confidence in the ability of physicians to tackle issues, challenges, and questions related to SARS, and but at the same time searched the Internet more frequently, and had more confidence in the Internet information about SARS than Finns did (Vartti et al. 41).

SARS was often associated with the low socio-economic status, which was researched by Bucchianeri in the article “Is SARS a Poor Man’s Disease?”; the author based arguments on the assumption that the link between health and the socio-economic status (SES) of people is pronounced nowadays, and that the SARS epidemic of 2003 provided an example of a low-probability and high-cost threat of an infectious disease (1-2). The findings of Bucchianeri suggest that the SES-SARS link was the most stable in the criterion of income, while the relation of occupation to SARS prevalence was very complex, and the high rate of SARS incidence was not simply confined to the medical personnel (Bucchianeri 11).

Lai and Tan studied the epidemiology of SARS in Singapore, and admitted that the first SARS case was registered on March 1, 2003; the total number of SARS cases reached 238, and 33 cases (14%) became fatal for the Singapore residents (77). The first case occurred with the 22-year-old female Singaporean at Tan Tock Seng Hospital; she had just returned from Hong Kong where she had been infected by Dr. Liu later detected as the super-spreader of SARS (Lai and Tan 77). The latter recovered from SARS, but caused a large number of SARS cases, many of which ended lethally for patients. The overall account of the SARS outbreak in Singapore indicates that 8 persons (3%) obtained their SARS  infection during their stay abroad, while 97 cases (41%) were reported among healthcare workers (Lai and Tan 77-78).

As for the quantitative assessment of the SARS epidemiologic potential and the evaluation of control measures’ effectiveness, a study of Peiris et al. targeted the issue closely (2432). The researchers indicated that SARS-CoV has a much lower potential for transmission than it was initially suggested, but it is characterized by the super-spreading events under which a small number of infected individuals can cause a much larger number of disease transmissions. The incubation period of SARS varies considerably from 2 to 10 days, approximately equaling the 4-7-day period, as the statistical analysis of reported cases suggests (Peiris et al. 2432). The WHO-established baseline for SARS intervention is 10 days, which has proven successful in interrupting the chain of adverse microbiological reactions caused in the human organism after the intrusion of the SARS CoV virus.

The findings of Peiris et al. also support the epidemiological study of Syed et al., stating that the majority of reported cases of SARS infection occurred in the healthcare settings with the patients who expressed the symptoms of the severe, acute SARS course. Hence, the assumption about the peak epidemic load on the 10^th day of the epidemic outbreak was also supported by clinical evidence. There is no evidence documenting transition of SARS before the clear manifestation of symptoms in the infected person; the majority of SARS infection cases occurred during close contacts with the infected individuals in taxis, in airplanes, in the workplace, etc. Moreover, it is notable that the RT-PCR test can detect the SARS-CoV virus in the human organism within 30 days after the onset of the illness, but the virus cannot be isolated from the organism after the third week of the illness’ course (Peiris et al. 2433).

Pathogenesis and Diagnosis of SARS

Proceeding to diagnosing SARS, one has to note that people of all age groups were susceptible to SARS. As for gender, female patients dominated slightly; immuno-compromised patients and pregnant women were also diagnosed with SARS in some rare cases (Peiris et al. 2434). The most commonly reported symptoms of SARS with which patients turned to medical establishments included fever, myalgia, malaise, and chills or rigor; cough was also often reported as a symptom, but shortness of breath, tachypnea, or pleurisy were detected only at the later stages of SARS development in patients (Peiris et al. 2434). Rhinorrhea and sore throat traditionally noted in cases of pneumonia were not registered with SARS patients, since the SARS-CoV virus is different in its effect on the human organism from the viruses associated with atypical pneumonia cases, i.e., mycoplasma or Chlamydia. Moreover, the respiratory signs commonly associated with pneumonia were much lower in intensity in SARS patients even as compared with the expectations drawn from the chest radiography made for them in hospitals (Peiris et al. 2434).

Among other symptoms indicating the SARS infection, one has to note the lymphocytopenia manifestations, and increased levels of “alanine aminotransferase, creatine kinase, and lactase dehydronase” (Peiris et al. 2434). The course of disease is also specific for SARS patients:

“one third of patients with SARS have improvement, with defervescence and resolution of radiographic changes. The other two thirds have persistent fever, increasing shortness of breath, tachypnea, oxygen desaturation, worsening of chest signs on physical examination, and the onset of diarrhea. Serial chest radiographs or CT scans reveal the progression of the original abnormality into unilateral or bilateral multi-focal air-space consolidations” (Peiris et al. 2434).

Additional adverse impacts on the human respiratory system include the shifting or fluctuating radiographic shadows, pneumomediastinum, subpleural pneumonic process, fibrosis and formation of cysts the rupture of which causes air leak, etc. (Peiris et al. 2434).

Yang, Lin, Jim and Guo conducted a study on SARS pathogenesis, and assumed that SARS is commonly associated with the multiple organ damage, but the pathogenesis of this infection still remains controversial. The authors investigated the

“pathogenesis of pancreatic lesions and glucose intolerance in SARS patients by determining whether biochemical parameters measuring involvements of liver, kidney, heart, lung, and the endocrine part of pancreas after hospitalization were predictors for death and whether these involvements (especially in the endocrine part of pancreas) were associated with tissue-specific ACE2 expression” (Yang et al. 194).

The findings at which Yang et al. arrived indicate that SARS has a multi-system nature, and caused hyperglycemia that ultimately became an adverse contributing factor to death outcomes (Yang et al. 197-8). Overall, the authors clarified that SARS caused major damage to kidneys, heart, lungs, and the endocrine system of the human organism; these manifestations of damage represented the key contributors to patient mortality, together with the ACE2 expression in multiple organs. Some additional autopsy findings suggest that the patients who died within the 10-day period from the SARS onset had such complications as “diffuse alveolar damage, desquamation of pneumocytes, an inflammatory infiltrate, edema, and hyaline-membrane formation” (Peiris et al. 2435).

The major threat of SARS-CoV is that it can replicate in several types of human organs and tissues, which causes a wide range of adverse health consequences for patients diagnosed with SARS (Du et al. 226). The virus can bind to host cells through alternative receptors including DC-SIGN and L-SIGN, which suggests that the ACE2 is not a vitally important agent of SARS-CoV, and the DC-SIGN and L-SIGN receptors can be bound with S protein of the infection without its activation. The mechanism of SARS pathogenesis stems directly from the SARS-CoV life cycle represented by the following stages:

• SARS-CoV enters the target cells through an endosomal pathway
• S protein establishes the initial binding with the cellular receptor angiotensin-converting enzyme 2 (ACE2), with the further transfer of the ACE2-virus complex to endosomes (S protein is cleaved by the endosomal acid proteases, such as cathepsin L) to become active for the viral fusion process
• Release of the viral genome and its translation into viral replicase polyproteins pp1a and 1ab, with their further cleaving into small products by viral proteinases
• Synthesis of subgenomic negative-strand templates from the discontinuous transcription on the plus-strand genome, their functioning as templates for mRNA synthesis
• Production of the full-length negative-strand template as a template for genomic RNA
• Assemblage of viral nucleocapsids from genomic RNA and N protein in the cytoplasm, with further budding into the lumen of the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC)
• Release of virions from the cell through the process of exocytosis (Du et al. 228).

The transmission of SARS from one person to another one commonly occurs by means of a direct or indirect contact of the mucous membrane of eyes, nose, or mouth with the infected droplets or fomites emitted by an infected person in a respiratory way. Hence, the respiratory treatment procedures conducted in hospitals, such as the endotracheal intubation, bronchoscopy, etc. increased the risk of SARS dissemination to the immediate surroundings, increasing the cases of SARS infection up to 100 cases from one patient at a time (Peiris et al. 2433). It is also necessary to keep in mind that the SARS virus is stable to the existence in the atmosphere when it dries on various surfaces, which means that SARS is a much more stable virus from the series of other similar respiratory viruses that lose their infectious force when disseminated into the atmosphere.

Management and Prevention of SARS

The emergence of SARS as a worldwide pandemic in 2003 and the rapid identification of its severe, acute, and often lethal nature have led to the comprehensive and intense efforts to detect the pathogen causing the disease, and to generate a range of tools for management and prevention of SARS (Tseng et al. 7). Besides control in the major sites of occurrence and at the points of international significance, the effort was directed at developing vaccines for control of the new coronavirus’ dissemination. The present evidence is supported by the fact that the latest case of reported SARS occurred in April 2004; however, the threat of SARS’ returning as an epidemic is not fully annihilated (van den Worm et al. 1). Van den Worm et al. insisted that there is a real danger of SARS re-emerging in some of its natural reservoirs, which is possible either in its original form that the humanity came across in 2002-2003, or in an even more virulent and pathogenic form with an event higher lethal potential (van den Worm 1). The research brought about contradictory and often ambiguous results, but work is still conducted in the field of designing an efficient SARS-CoV vaccine.

At the time when SARS broke out as an epidemic of an unexplainable infectious and fatal disease in 2002-2003, there was no treatment known by the medical community, and SARS was conventionally managed with the help of broad-spectrum antibacterial drugs conventionally considered effective again the typical and atypical acute community-acquired pneumonia (Peiris et al. 2437). This was mostly done because the SARS symptoms and course of disease resembled the atypical pneumonia course, and the reliance on the medications was made mostly due to these similarities. Before discovering the SARS-CoV as a causative agent of SARS, the anti-viral drug commonly used for patients with SARS was ribavirin (Peiris et al. 2437).

There are a number of vaccines generated for targeting SARS in case it emerges in future again. The agents to be targeted when tackling SARS, the major part thereof considered within the replication cycle of SARS-CoV. In this context, the use of fusion inhibitors and protease inhibitors is highly recommended (Peiris et al. 2437). However, according to the research findings of Tseng et al., the anti-SARS vaccines can also lead to adverse physical consequences, such as pulmonary immunopathology. Tseng et al. conducted a study with a mouse model of SARS, a VLP vaccine, the vaccine that was given to ferrets and NHP, the whole virus vaccine, and the rDNA-produced S protein (1). As a result of their tests, the SARS-CoV vaccines used in the study “all induced antibody and protection against infection with SARS-CoV. However, the challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced” (Tseng et al. 1). Therefore, the conclusion at which the researcher arrived is that there is a need for caution regarding the use of the SARS-CoV vaccine in humans because of the possibility of the immunopathology development.

The work on finding an active and efficient SARS-CoV vaccine was actively conducted right upon the end of the epidemic, in the fear of its repetition. Liu et al. described their research effort in finding the disease-specific B cell epitopes by means of panning the phage-displayed random peptide libraries on serum immunoglobulinum (Ig) G antibodies from patients with SARS (797). The clinical findings of the researchers are as follows:

“Synthetic peptide binding and competitive-inhibition assays further confirmed that patients with SARS generated antibodies against SARS CoV. Immunopositive phage clones and epitope-based peptide antigens demonstrated clinical diagnostic potential by reacting with serum from patients with SARS. Antibody-response kinetics were evaluated in four patients with SARS, and production of IgM, IgC, and IgA were documented as part of the immune response” (Liu et al. 797).

The conclusions of the researchers indicate that the B cell epitopes of SARS corresponded to the SARS coronavirus, and that an epitope-serologic test may be effective in clinical detection of SARS, as well as the further study of SARS pathogenesis (Liu et al. 797).

The study of Du et al. was conducted in March 2009, when a considerable advancement in understanding the lifecycle and pathogenesis of the SARS-CoV was achieved. Hence, the researchers provided a much more detailed account of the vaccines and their typology to tackle various aspects of SARS-CoV, and to curb its development in the human organism from various perspectives. The first type of vaccines existing nowadays is that targeted at the SARS-CoV S protein (Du et al. 229). The generation of these vaccines is based on the understanding of the key role that S protein of SARS plays in receptor binding, and cell membrane fusion; hence, inducing the antibodies that can mitigate cell infusion and block receptor binding is seen as an effective way to tackle the SARS-CoV.

There are certain subdivisions of SARS-CoV vaccines: they may be based on the full-length S protein, and on RBD. As for the former, the study of Yang et al. cited by Du et al. was dedicated to the study of DNA vaccine encoding the full-length S protein, which induced both T-cell and neutralizing-antibody responses, and created protective immunity in a mouse model. However, this type of vaccines is also known for inducing adverse immune responses by causing liver damage of the vaccinated animals, and the enhanced infection after challenge with homologous SARS-CoV (Du et al. 229-230).

The vaccines based on RBD possess the potential of inducing neutralizing antibodies. Nevertheless, there are some alternative microbiological interventions designed to manage SARS; one of them includes the S-protein-based therapeutics comprising the use of peptides interrupting the RBD-ACE2 interaction, peptides interfering with the cleavage of S protein, and peptides blocking the HR1-HR2 interaction from forming a fusion-active core (Du et al. 230-232). Finally, the way to manage SARS was found in neutralizing mAbs that target the S protein of SARS; such methods include neutralizing mouse mAbs, and neutralizing human mAbs (generated from B cells of SARS patients) (Du et al. 232). The antiviral compounds and small molecules are also under research as possible ways of targeting SARS-CoV; they include the inhibitors of cathepsin L, and gene targeting with small interfering RNA (Du et al. 232-233).

Conclusion

SARS is an acute and severe infectious disease; it is the fundamentally new disease discovered in the 21^st century and proving how unready the present-day global population is to the outbreaks of epidemic, dangerous infectious diseases. The SARS virus first emerged in 2002 in China, and quickly disseminated to a number of neighboring and distant countries through travelers and cargo transfers. SARS is a very complex and dangerous infectious disease associated with an atypical pneumonia, and often ending as a fatality for patients diagnosed with SARS. The large number of SARS cases and a high death toll in 2002-2003 resulted from the unwillingness of the Chinese government to share valid and precise information about the course of SARS dissemination on the country’s territory, which precluded taking the SARS virus under control before its catastrophic dissemination. Therefore, after robust clinical research and the understanding of the microbiological basis for SARS effect on the human organism, the epidemic was quickly curbed by the middle of 2003, though some sporadic outbursts of SARS cases were still registered in various corners of the world up to the end of 2003.

The key finding about the nature of SARS is that it is caused by the new type of viruses, the coronavirus SARS-CoV that used to affect animals, but transferred the border between the animal and human organisms due to its ability to evolve and mutate in the hosts’ organisms to form new bindings. In the human organism, the SARS-CoV is capable of intrusion into cells where it undertakes the virus fusion and affects different types of human organs and tissues. The damage to the human organism caused by SARS is severe and irreversible; therefore, the best variant to tackle the SARS virus is early diagnosis and intervention.

Fortunately, the active research and clinical work on tackling the threat of SARS was conducted in and after 2003, which enabled the identification of certain vaccines and medications to eliminate the threat of SARS. Some of them include the agents targeting the S protein of SARS, mainly because of its key role in the cell fusion and receptor binding. There are numerous S-protein-based therapeutics with the use of peptides attacking the S protein at different stages of its lifecycle. Another way of tackling SARS was found in neutralizing the human mAbs, and in using the inhibitors of cathepsin L. research still persists, since there is always a feasible threat of the virus’ return from its natural reservoirs in a modified form.

Works Cited

Bucchianeri, Grace Wong. “Is SARS a Poor Man’s Disease?” Forum for Health Economics and Policy 13. 2 (2010): 1-18.

Du, Lanying, Yuxian He, Yusen Zhou, Shuwen Liu, Bo-Jian Zheng, and Shibo Jiang. “The spike protein of SARS-CoV – a target for vaccine and therapeutic development”. Nature Reviews: Microbiology 7 (2009): 226-235.

Lai, Allen Yu-Hung, and Teck Boon Tan. “Combating SARS and H1N1: Insights and Lessons from Singapore’s Public Health Control Measures”. ASEAS – Australian Journal of South-East Asian Studies 5.1 (2012): 74-101.

Liu, I-Ju, et al. “Disease-Specific B Cell Epitopes for Serum Antibodies from Patients with Severe Acute Respiratory Syndrome (SARS) and Serologic Detection of SARS Antibodies by Epitope-Based Peptide Antigens”. Journal of Infectious Diseases 190 (2004): 797-809.

Peiris, S. M. Joseph, Kwok Y. Yuen, Albert D. M. E. Osterhaus, and Klaus Stöhr. “The Severe Acute Respiratory Syndrome”. The New England Journal of Medicine 349. 25 (2003): 2431-2441.

Tseng, Chien-Te, et al. “Immunizatiion with SARS Coronavirus Vaccines leads to Pulmonary Immunopathology on Challenge with the SARS Virus”. PLoS ONE 7. 4 (2012): 1-13.

Van den Worm, Sjoerd H. E., et al. “Reverse Genetics of SARS-Related Coronavirus Using Vaccinia Virus-Based Recombination”. PLoS ONE 7.3 (2012): 1-12.

Vartti, A. M., A. Oenema, M. Schreck, A. Uutela, O. de Zwart, J. Brug, and A. R. Aro. “SARS Knowledge, Perceptions, and Behaviors: a Comparison between Finns and the Dutch during the SARS Outbreak in 2003”. International Journal of Behavioral Medicine 16 (2009): 41-48.

Yang, Jin-Kui, Shan-Shan Lin, Xui-Juan Ji, and Li-Min Guo. “Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes”. Acta Biabetol 47 (2010): 193-199.