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Discussion On MERS Question: Critical review of the literature on one Emerging or Re-Emerging Communicable Disease Threat.   Answer: Introduction Middle East Respiratory Syndrome (MERS) is a respiratory syndrome that can be traced back to Saudi Arabia in 2012. It was initially restricted to persons who were traveling within the Middle East and/or their contacts, but later had a spill-over effect into other countries as demonstrated by outbreaks in countries out of the Middle East block such as the Republic of Korea (RoK), Austria, the Philippines, Thailand, France, Tunisia, Germany, Malaysia, Greece and the United Kingdom (World Health Organization (WHO), 2017; NSW Government, 2017). MERS is caused by Middle Eastern respiratory syndrome coronavirus (MERS-CoV). MERS is not a national notifiable in Australia, but it is at least classified as a notifiable condition in some parts of Australia, precisely South and Western Australia (Government of South Australia – SA Health, n.d.) and the US (Centers for Disease Control and Prevention (CDC), 2015). This paper is a discussion on MERS with focus on the role of agent, host and environmental factors in the development and spread of the condition and the corresponding potential policy responses to the same. This is achieved through discussions on three main sections. The first section discusses the epidemiology, transmission routes, risk factors and clinical features, while the second part is a discussion on the interaction between the causative agent, host and environmental factors in the production of the illness in individuals, and the last part discusses various responses towards the control of the spread of the virus. Discussion Epidemiology, Transmission Routes, Risk Factors And Clinical Features The MERS coronavirus belongs to the large and diverse family of coronaviruses which are known to cause ill health to both humans and animals. Four strains of coronaviruses that affect humans {human coronaviruses (hCoV)} are known to cause respiratory infections in human, with severity ranging from mild to moderate. These hCoVs include the alpha-coronaviruses hCoV-NL63 and hCoV-229E and betacoronaviruses hCoV-HKU and hCoV-OC43 (The Department of Health, 2014). In the class of beta-coronaviruses also lies the viruses causing MERS-CoV and severe acute respiratory syndrome coronavirus (SARS-CoV). However, according to The Australian Department of Health, these two viruses are genetically distinct from each other (The Department of Health, 2014). The MERS coronavirus was only identified in 2012 as a new variant of the coronavirus family that could lead to a rapid onset of severe respiratory illness in humans (Zaki, van Boheemen, Bestebroer, Osterhaus, & Fouchier, 2012). Most of MERS cases have been found to develop in persons presenting with other underlying conditions which predispose them to respiratory infections. While MERS-CoV is distinct from the SARS-CoV in humans, the MERS-CoV has some similarity to coronaviruses found in bats (The Department of Health, 2014).   Up to date, all cases of MERS in humans have been in persons who have been residents in or travellers to the countries in the Middle East or have had a close contact with persons presenting with the infection in the same region. The disease has been predominantly reported in in travellers or residents in the United Arab Emirates (UAE), Jordan, Qatar and the Kingdom of Saudi Arabia (Who Mers-Cov Research Group., 2013). But as demonstrated in later years, the infection is not just restricted to the Middle East as evidenced by the reported cases in countries, not in the Middle East. This includes countries in Europe such as Italy, Germany, the United Kingdom, France, Tunisia, Malaysia, South Korea, the Philippines, Thailand and Greece (NSW Government, 2017). South Korea reported the largest outbreak in 2015, which was a multi-centre hospital outbreak which was traced to a traveller from the Middle East (WHO, 2015; CDC, 2015). Notably, Australia has so far reported zero MERS-CoV cases. (NSW Government, 2017). A MERS situation update by WHO for the months of January and February 2017 states that as of the beginning of March 2017, a total of 1,916 laboratory confirmed cases of MERS have been reported to WHO and a total of 702 persons have died, translating to a case-fatality rate of 36.6%  (WHO, 2017). According to the same update, a total of 27 countries worldwide have reported MERS cases. Transmission Routes The epidemiologic aspects of the MERS-CoV have not been adequately defined, but the most recognized means of transmission is the human-to-human transmission of the virus, in healthcare settings. However, just like other coronaviruses, the spread of the virus is thought to occur through contact with an infected individual’s secretions. The exposure in healthcare facilities could be justified by the 2015 outbreak in South Korea and Saudi Arabia, whose point of introduction is always a single introduction of MERS, probably zoonotic (Al-Abdallat, et al., 2014). According to the WHO, MERS-CoV is a zoonotic virus which enters the sphere of humans through contact with infected dromedary camels in the Middle East (WHO, 2016). The restriction that it is dromedary camels in the Arabian Peninsula can be supported by negative findings of the virus in tested camels from other parts of the world (Chan, et al., 2015). Studies have demonstrated strong indicators of both direct and indirect exposure to camels to causing the infections. This hypothesis is supported by at least one group in which the camels also tested seropositive (WHO, 2017). Outstandingly, a review of literature also indicates cases where the infections resulted even in the absence of a history of prior exposure to other animals. This perspective rather suggests the likelihood of the virus being introduced through multiple channels as opposed to a single zoonotic case. The primary hypothesis in the transmission and resulting outbreaks of MERS has been a hypothesised link to some animals serving as either the reservoir or intermediate host(s), with dromedary camels as the primary suspects. They are known to produce a significant amount of MERS-CoV RNA in their lungs and the urinary tract (Khalafalla, et al., 2015). The droplet transmission route is claimed to play a significant role in the transmission of the virus. The exact source from which people acquire the virus from camels has not been clearly defined but it is postulated that there is an intricate interplay of both animal and human behaviours as demonstrated in the figure below. Source: (Mackay & Arden, 2015) Figure 1: Speculated transmission routes of MERS-CoV and how humans and camels contribute to epidemics. Human-to-human transmission of the virus has also been observed especially in healthcare settings, among family workers, and among co-workers. The usually suspected transmission mechanisms in human-to-human transmission have been suspected to be either respiratory (sneezing, coughing) or direct physical contact with the affected individual or contamination of the environment by the infected individuals, but this is yet to be fully demonstrated. The only definitive comment made by the WHO is that the virus is not easily transmitted from an individual to another unless there is close contact between the two, as demonstrated in the provision of unprotected care to an infected patient (WHO, 2017). Cases of human-to-human transmission have only been documented in the health care environment and nowhere else. Notably, the origins of MERS-CoV virus are yet to be fully understood, but analysis of the virus genomes have demonstrated that the virus could have originated in bats and was transmitted to dromedary camels during early ages.   Risk Factors The distribution of the disease among the already reported cases is demonstrated to be skewed heavily to middle-aged persons and the elderly. The risk is heightened in persons who are elderly, are immunocompromised, or present with other comorbidities (WHO, 2017). For MERS associated with the health care environment, the risk for infection among healthcare workers is magnified among those who have close contact with patients infected with the virus, especially radiology technicians and nurses (Alraddadi, et al., 2016). In addition, according to the same authors, health care workers with a history of smoking had 3 times increased risk for the infection compared to non-smokers. This association further arouses the curiosity of the role that smoking plays in the risk profile, unluckily, there is no literature addressing the same. This requires further research. Males aged above 60 years are also claimed to be at increased risk of contracting the virus. The risk is further heightened if they suffer from underlying conditions such as renal failure, hypertension, and diabetes (WHO, 2017). A twist to this association could rather suggest that instead of a sex-specific difference in biologic susceptibility, males have exhibit social and behavioural factors which increase their exposure to the virus compared to females. This can be supported by an observation by Mackay and Arden, (2015) in which males infected by MERS-CoV present with a more severe disease compared to females of the same class. Clinical Picture The mean incubation period for MERS-CoV has been determined to be 5 to 6 days, ranging from 2 to 16 days, with 13-14 days between when one person develops the diseases and spreads it to another (Assiri, et al., 2013; Memish, Zumla, Al-Hakeem, Al-Rabeeah, & Stephens, 2013). For cases with progressive illness, the median death is 11-13 days (Assiri, et al., 2013; Ki, 2015). Early symptoms of the illness include fever, myalgia, chills and gastrointestinal symptoms, which subsequently decline, only be substituted with more severe systemic and respiratory syndrome, severe pneumonia with acute respiratory distress syndrome and multi-organ failure (Kraaij-Dirkzwager, et al., 2014; Mailles, et al., 2013). The Interaction Between The MERS-CoV, Host And Environmental Factors To Produce MERS Majority of camels in the Arabian Peninsula are dromedary camels and their contact with humans ranges between little to close. This contact serves as the gateway to the transmission and the corresponding outbreaks; hence it is significant to illustrate the interplay of the agent, the reservoir and the environmental factors that predispose the host to the virus and consequential development of the syndrome.  The human-camel contact is commonplace in the Arabian Peninsula and may result from various ways (as illustrated in the figure above). Most of the countries in the Middle East (with special reference to Saudi Arabia due the fact that it has so far recorded the highest number of cases), has several large well-attended festivals, parades, sales and races which feature dromedary camels and also, these camels are bred and reared close to populated areas (Al-Mukhtar & Estimo, 2014; Hemida, et al., 2015)127-128. In addition, inhabitants of these countries have the tendency to consume milk and meat from camels after the Hajj pilgrimage (Mackay & Arden, 2015). Notably, however, reports of infections of MERS-CoV are much lower compared to the frequent habits of preparing, drinking, eating products from dromedary camels. It is also established that some tribes in Saudi Arabia consume fresh unpasteurised milk from dromedary camels, alongside their urine which is claimed to be having some health benefits. It is however interesting to note that butchers make up a larger proportion of the local occupations, and neither them nor any of the associated risk groups have ever been identified among MERS cases (Mackay & Arden, 2015). A logical explanation to explain the same is that there is a heightened likelihood to be a reporting issue and not just an unexplainable absence of the illness. This association can be corroborated by evidence from a 2015 case-control study that concluded that the onset of MERS is as a result of direct contact with dromedary camels and not the ingestion of products from these animals (Alraddadi, et al., 2014). Some researchers hold a different hypothesis that there is the likelihood of humans infecting dromedary camels, contrary to the already established hypothesis.  This divergent proposition has been instigated by laboratory finding in which whenever cases of MERS have been reported, the camel population is also found to have nasal colonisation of the virus alike. This hypothesis is however yet to be studied and proven.   Camels often calve during the winter months that run between late October and late February and this season may be characterised by an increased risk of spill-over of the virus to humans because new infections are often likely to occur within the camel populations (Hemida, et al., 2015). The role played by maternal camel antibody in delaying infection in the calves is yet to be established (Memish, et al., 2013; Hemida, et al., 2015). Young camels have been found to host active infection more often compared to their parents, and as a result of the inclination to choose camels aged 5 years or older for sacrificial slaughter, and this is accompanied with an insignificant risk of exposure to the virus. This conclusion draws reference back to the fact that slaughterhouse workers stand out as a high-risk occupational group. The survivability of MERS-CoV in the environment is also important towards understanding the association between the various parameters leading to the development of the illness. Laboratory experiments have demonstrated that adding the virus to milk from either a camel, goat or cow, and storing it at low temperatures (4 degrees Celsius), the virus could still be recovered at least seventy-two hours later, and if stored at 22 degrees Celsius (almost room temperature), the virus could still survive up to 48 hours (van Doremalen, Bushmaker, & Munster, 2013). On the survivability of the virus in the environment in the absence of a milk medium, a study by van Doremalen, Bushmaker, and Munster, (2013) was able to demonstrate that even at high ambient temperatures (about 30 degrees Celsius) and low relative humidity (30%), the virus still remains viable for up to 24 hours. This demonstrates quite a significant survivability rate compared to other well-known and efficiently transmitted respiratory virus such as influenza A virus which cannot be recovered even after four hours under the same conditions to those survived by MERS-CoV (van Doremalen, Bushmaker, & Munster, 2013). However, the survival of MERS-CoV is still said to be inferior compared to that of SARS-CoV (Chan, et al., 2011). MERS outbreaks have been so far experienced in health care settings as opposed to community settings. It is therefore hypothesized that the hospital environmental facilitates environments that promote super-spreading of MERS-CoV. The above-demonstrated survivability characterised therefore plays a significant role in the development of these outbreaks. For purposes of understanding how they contribute to this, it is an established fact that pathogenic bacteria can remain viable and airborne for three-quarters of an hour in a coughed aerosol and can spread for four metres (Mackay & Arden, 2015). The ability of MERS-CoV to remain viable for extended times gives it the capacity of thoroughly infecting surfaces of rooms occupied by either infected or symptomatic patients (Knibbs, et al., 2014). It is however unknown whether the virus can remain truly airborne. These findings help paint a clear picture of the possibilities of aerosols to transmit the virus in various settings such as hospital waiting rooms, treatment rooms, private patient rooms, emergency departments and open intensive care facilities. It is thus of significance to consider the variable or air exchange, circulation and filtration as variable in measuring and reducing the risk of MERS-CoV spread, and the use of negative pressure rooms in the containment of known cases. Human-to-human transmission is attributed to droplet spread as demonstrated in both outbreaks in Saudi Arabia and South Korea (Assiri, et al., 2013; Assiri A. , et al., 2013; Al-Tawfiq & Memish, 2014; Zumla & Memish, 2014). As a result, environmental control in terms of risk measurement and reduction efforts directed at curbing the spread should be targeted at aerosols-generating events that involve camels (urination, defecation, and preparation and consumption of camel products), and the formulation of personal protective equipment worn by healthcare workers working with infectious cases.   Policy Responses To MERS-CoV The response to MERS can be categorized to either individual countries or as a cumulative response by the World Health Organisation. Notably, however, no specific policies have been designed to control the virus, but rather various guidelines are available for the control of the same.  For instance, the Saudi Arabian Ministry of health has responded with both outbreak control policies touching on notification of suspected cases, risk assessment, investigation procedures and treatment protocols. WHO has likewise taken various steps and also projected steps to be undertaken later on. WHO works with various countries, and has notably worked with CDC to develop policies aimed at improving the efficiency of surveillance (Banerjee, Rawat, & Subudhi, 2015), and the Saudi Arabian Ministry of Health (MoH) to develop specific guideline for the control and prevention of infections by the virus for both health care workers, patients and their family members contained under the Scientific Advisory Board’s Infection Prevention and Control Guidelines for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection (Saudi Arabia Ministry of Health, 2014; Scientific Advisory Board, 2015). Neither CDC nor Saudi Arabia MoH has prescribed specific guidelines for the control of the agent, but have rather made recommendations for quarantine measures for infected individuals and have also prescribed guidelines to be followed before the infected person resumes regular activities following recovery. Both the CDC, Saudi Arabian MoH and various agencies from most countries (Australia included) have also prescribed guidelines for airport staff on the management of suspected MERS cases, and likewise developed advisories and precautionary statements for travellers into and out of the countries. The WHO Director-General convened the International Health Regulations (IHR) Emergency Committee on MERS which is chaired by Australia’s Chief Medical Officer (The Department of Health, 2016). In the case of Australia, the country’s Communicable Diseases Network Australia has also developed a national guideline for the public health management of MERS, and these guidelines have also been endorsed by the Australian Health Protection Principal Committee (AHPPC). In addition, as from 2015, information is provided on the disease to both the public, clinicians, laboratory and public health personnel and general practitioners. State and territorial AHPPC and its standing committees work in tandem with the Australian department with regard to this. Among these recommendations, it is stipulated by the Public Health Laboratory Network that the ideal diagnosis of the infections should be done using PCR-based tests. In addition, the government through the Department of Foreign Affairs and Trade (DFAT) has issued a Smartraveller bulletin on MERS alongside country-specific advice for travelling to the affected countries. As the coordinating body, the WHO strives for the development and application of universal standard infection control precautions and transmission-based precautions when dealing with MERS (The Department of Health, 2016). Conclusion MERS-CoV stands as one of the emerging infectious agents responsible for a significant amount of respiratory illness across three continents. MERS was originally restricted to countries in the Arabian Peninsula but as a result of human dynamics, it has successfully caused outbreaks outside of the Middle East with the most notable one being a healthcare-associated in South Korea in which 186 persons were infected and a total of 36 died. The main transmission routes for MERS-CoV are camel-to-human and human-to-human. Dromedary camels remain as the primary reservoir of the virus which is claimed to have been sourced from paths. Several epidemiologic aspects of MERS are however yet to be known. Hospital environments are characterised to be bearing ideal conditions for the spread of the virus, hence liable to the health care outbreaks so far. Regardless of the infection having been reported across 27 countries, neither individual countries nor the WHO have developed any specific policies aimed at controlling the virus, but rather various guidelines have been provided.   References Al-Abdallat, M., Payne, D., Alqasrawi, S., B, R., Tohme, R., Abedi, G., . . . Haddadin, A. (2014). Hospital-associated outbreak of Middle East respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description. Clin Infect Dis. , 1225-33. Al-Mukhtar, R., & Estimo, R. (2014). Link between MERS virus and camels worries breeders. Alraddadi, B. M., Al-Salmi, H. S., Jacobs-Slifka, K., Slayton, R. B., Estivariz, C. F., Geller, A. I., . . . Haynes, L. (2016). Risk Factors for Middle East Respiratory Syndrome Coronavirus Infection among Healthcare Personnel. Emerg Infect Dis, 1915-1920. Alraddadi, B., Watson, J., Almarashi, G., Turkistani, A., Sadran, M., & Housa, A. (2014). Risk Factors for Primary Middle East Respiratory Syndrome Coronavirus Illness in Humans, Saudi Arabia. Emerg Infect Dis. Al-Tawfiq, J., & Memish, Z. (2014). Middle East respiratory syndrome coronavirus: transmission and phylogenetic evolution. Trends Microbiol., 573-9. Assiri, A., Al-Tawfiq, J., Al-Rabeeah, A., Al-Rabiah, F., Al-Hajjar, S., Al-Barrak, A., . . . M. Z. (2013). Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis., 752-61. Assiri, A., McGeer, A., Perl, T. M., Price, C. S., Rabeeah, A. A., Cummings, D. A., . . . Mad, H. (2013). Hospital Outbreak of Middle East Respiratory Syndrome Coronavirus. NEJM, 407-416. Assiri, A., McGeer, A., Perl, T., Price, C., Al Rabeeah, A., & Cummings, D. (2013). Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl JMed, 407-16. Banerjee, A., Rawat, R., & Subudhi, S. (2015). 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Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med, 1814-20. Zumla, A., & Memish, Z. (2014). Middle East respiratory syndrome coronavirus: epidemic potential or a storm in a teacup? Eur Respir J, 1243-8.

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