In june 2012

In june 2012 , a new corona virus was isolated from a male patient in Saudi Arabia who was suffering with severe respiratory illness & later died in a hospital in Jeddah. This virus was initially named as human coronavirus–EMC and later named as Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) (Mohd H et al, 2016). MERS-CoV is known to cause severe hypoxemic respiratory failure with multi organ failure and often requires admission to the intensive care unit (ICU) (Al-Dorzi HM et al, 2016). Since June 2012 , multiple outbreaks have been reported in or been epidemiologically linked to the Arabian Peninsula (Mohd H et al, 2016 ). Till 27 September 2016, there were 1806 laboratory confirmed cases reported by World Health Organization (WHO), which includes 643 related deaths. The majority of MERS cases are reported from Saudi Arabia (Al-Dorzi HM et al,2016). The continuous MERS epidemic in the Arabian peninsula is believed to be related to the failure to control the zoonotic sources. Many healthcare associated outbreaks have been reported with the largest such outbreak being reported from Republic of Korea in 2015, where 186 cases including 36 deaths occurred. The index case had a travel history to Arabian peninsula (Zhou J et al, 2015).
2. GEOGRAPHICAL DISTRIBUTION
MERS cases have been reported from 27 countries which include few from European, Asian, North American and African continent. Majority of the cases have been reported from the endemic region of MERS which is Middle East. Recent reports of MERS case from Korea indicated the rapid spreading potential of this virus & not checked by early detection and infection control measures (Min J et al,2016). After Saudi Arabia, Korea has the second highest number of MERS cases (n=185) and United Arab Emirates (UAE) in third with 83 cases. There are at least 13 cases of MERS reported from UAE, Jordan, Philippines, Malaysia, Algeria, Egypt, Greece, Netherlands, Qatar, United States and Turkey which were reported to be spread via travelers who visited Saudi Arabia (Min J et al,2016).
Travel related MERS cases have also been reported from United kingdom, Italy, France, Germany, Tunisia & Iran (Cunha CB et al,2014). Patients reported outside the middle east, all had a history of travel to the middle east or had contact with a primary case (Zumla A et al,2015).
3. VIROLOGY
Corona viruses are large enveloped single stranded RNA viruses (Guery B et al, 2013). The glycoprotein spikes surrounding the spherical virion give the viruses its characteristic “halo appearance” on electron microscopy (Cunha CB et al,2014 ). Corona viruses have the ability to infect and cause disease in many animal species including bats, mice, birds, dogs, pigs and cattle (Guery B et al, 2013 ).
Human corona viruses belong to two genera: Alpha coronaviruses and Beta coronaviruses. The genus Beta coronaviruses consists of 4 lineages, A, B, C and D. Severe acute respiratory syndrome(SARS-CoV) belongs to lineage B but MERS-CoV belongs to lineage C beta coronaviruses. Sequence analysis shows that MERS-CoV is closely related to the bat coronaviruses HKU4 and HKU5. Severe acute respiratory syndrome coronavirus (SARS-CoV) was also derived from bat coronaviruses. MERS-CoV has a similar phylogeny and is considered a cousin of SARS-CoV but both have distinct biology, such as the use of different human receptors. (Shirato K et al. 2014, Berban R, et al. 2013).
Since the discovery, various names have been attributed to MERS-CoV like human coronavirus – Erasmus medical center (hCoV-EMC), human beta coronaviruses 2c England Qatar, human beta coronaviruses 2c Jordan N3, beta coronavirus England 1 and novel coronaviruses (NCoV). Currently the international committee on Taxonomy and the coronaviruses study group (CSG) has decided the name to be Middle East Respiratory Syndrome Corona Virus (MERS- CoV) (Shirato K,2014 ).
4. VIRAL GENOME AND PROTEIN
The genome structure of MERS-CoV is similar to that of other coronaviruses. The RNAs are capped and polyadenylated with the 5′ two thirds of the genome encoding the non-structural proteins (NSPs) involved in viral replication and the remaining 3′ third of the genome encoding the structural genes. The surface of virion has a heavily glycosylated, petal shaped, large protein known as spike (S) glycoproteins (Shirato K,2014 ).
Dipeptidyl peptidase 4 (DPP4) is also called CD26 is a 766-aa type II trans membrane glycoprotein that has been shown to be the functional receptor for MERS-CoV in permissive cell lines (Shirato K, 2014 ). MERS-CoV can bind to DPP4 from several species. In addition to humans and camels non-human primates, rabbits, goats, sheep, and horses, among other animals, are thought to be susceptible to infection (Zumla A et al., 2015 ). DPP4 is expressed on the cell surface in the lungs, kidneys, small intestine, liver, parotid gland, spleen, testes, prostate and activated leucocytes. This explains the capacity of MERS-CoV to infect cells of these organs. MERS-CoV can also bind to bat DPP4 (Shirato K,2014).
5. EPIDEMIOLOGY
MERS-CoV is considered as the second coronavirus after SARS-CoV that can cause a pandemic (Min J et al,2016). Like many other corona viruses , MERS-CoV is believed to be originated from bats (Figure 1). This is based on the isolation of other lineage C beta-coronaviruses that are very closely related to MERS-CoV on phylogenetic analysis. But still it is difficult to prove that bats are the direct source of human disease (Mohd H et al, 2016 ). Several other animal species like dromedary camels (Camelus dromedarius), cows, goats and sheep have been assessed for serological evidence of MERS-CoV infection. MERS-CoV specific antibodies were only found in dromedary camels. The first detection of MERS-CoV was reported in dromedary camels on a farm in Qatar that had been linked to human cases of the disease. (Zumla A et al,2015, Mohd H et al, 2016, Haagmans BL, et al. 2014 ).
Investigation has revealed that dromedary camels are so for the only reservoir of MERS-CoV (Wernery U et al,2017 ). Adult dromedary camels have almost 100% sero positivity against MERS-CoV while virus is found mainly in dromedary calves. In contrast to human infection, MERS-CoV causes no or mild disease in dromedaries (Wernery U et al,2017 , Zumla A et al,2015). Evidence in literature shows that there is a possibility of transition from camels to human & camels are the only confirmed zoonotic source for human infection (Zumla A et al,2015, Aleanizy F.S et al, 2017, Azhar E.I, et al. 2014 ). MERS is a zoonotic viral disease that can be transmitted from dromedaries to human beings in which it causes severe respiratory disease with a high case fatality (Wernery U et al,2017). Seroprevalence of MERS-CoV antibodies was significantly higher in camel-exposed individuals than in general population (Muller MA, et al. 2015). Epidemiological and genomic studies of cases associated with hospital and household MERS outbreaks have confirmed human to human transmission with high risk of infection seen in patients with immunosuppression or coexisting illnesses. (Zumla A et al,2015, Drosten C et al,2014, Assiri A et al. 2013 , Memish ZA et al.2013). The rate of secondary transmission among household contact of patient with MERS-CoV has been approximately 5% (Drosten C et al,2014 ). Regarding seasonality, it was previously hypothesized from the high incidence of cases during spring and early summer months and this has been postulated that this may be correlated to the camel birthing pattern; young newborn camels encountering MERS-CoV for the first time may get ill and transmit the virus to humans. However, this hypothesis was nullified after outbreaks of MERS were spotted in latter half of 2015 & early 2016 in other seasons. International analysis about the difference in outcomes for MERS cases have shown different fatality rates based on location. African & Middle East countries showed a MERS fatality rate of 41% where as in Europe it was 47% & Asian countries showed an atypical 20.3% case fatality (Min J et al,2016 ).
Figure 1. Ecology and transmission of MERS-CoV
6. CASE DEFINITION
Case definition for confirmed and suspected cases have been defined by WHO ,the US centers for disease control and prevention and the ministry of health(MOH) of Saudi Arabia (Zumla A et al,2015 ). A conformed case is defined as any person with laboratory confirmation of MERS – CoV infection based on positive real – time polymerase chain reaction (RT-PCR) of MERS – CoV in swab samples collected by MOH in addition to any one of the following clinical definitions : Fever ( >38 C ), a cough , shortness of breath (SOB). sore throat, vomiting, diarrhoea , hemoptysis , chest pain and /or infection, respiratory failure , loss of consciousness , runny nose , and any asymptomatic outpatients with a history of contact with positive symptomatic cases are tested positive (Aleanizy F.S et al,2017 ).
7. IMMUNITY, PATHOGENESIS AND PATHOLOGY
MERS-CoV primarily infects human respiratory tract. It can effectively replicate in the airway epithelium of humans. Pulmonary endothelial cells are also highly susceptible to MERS-CoV . Human epithelial cells are stimulated to produce antiviral and pro inflammatory cytokines and chemokine to eliminate the invading pathogens. MERS-CoV infection failed to elicit strong pro inflammatory cytokines response in human primary respiratory epithelial cells and ex vivo respiratory tissues. The virus has evolved multiple antagonistic mechanisms to dampen or attenuate the host defense which contributed to the high pathogenicity in humans (Zhou J et al,2015 ). Type I interferon (IFN) expression is a crucial component of this initial response and corona viruses have developed strategies to prevent IFN induction. Type I IFN activates immune antiviral effectors such as natural killer (NK) cells, T CD8+ cells and macrophages , allowing viral clearance (Faure E et al,2014 ). There is evidence to suggest a consistent responsiveness of interferon treatment in vitro for MERS-COV (Aleanizy F.S et al,2017). The human immune cells that are involved in MERS-CoV infection are macrophages, dendritic cells and T lymphocytes (Zhou J et al,2015 ). In contrast to the inability to elicit the production of pro inflammatory cytokines in human respiratory epithelial cells , MERS-CoV is able to stimulate the induction of pro inflammatory cytokines/chemokine in human macrophages and dendritic cells (Zhou J et al,2015 ). MERS-CoV in characterized by their different patterns of disease; Sporadic cases, interfamilial transmission and health care associated infection (Al-Tawfiq JA et al,2016 ). There is also evidence to suggest the extra pulmonary organ involvement upon MERS-CoV infection. MERS-CoV viral RNA could be detected in blood, urine and stool specimens of some MERS patients suggesting viral dissemination . MERS causes an acute highly lethal pneumonia. Renal dysfunction or failure is common in patients (Zhou J et al,2015 ).The pathogenetic understanding comes from studies of experimentally infected animals. Studies have used several animals like macaques, marmosets and camels. Infected marmosets develop severe interstitial pneumonia and are useful model to study severe MERS, but their unavailability limits their utility. Neutrophil and macrophage infiltration and alveolar edema has been reported from affected lung tissue (Zumla A et al,2015 ). MERS mouse models have been generated by prior transduction of adenoviral vector expressing human DPP4. In the MERS-CoV permissible animal models, viral RNA can be detected from multiple organs of the infected animals. But there was failure in recovery of virus in most extra pulmonary organs (Zhou J et al,2015 ).
8. CLINICAL FEATURES
The clinical manifestations of MERS-CoV infection range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome, septic shock, and multi organ failure resulting in death (Zumla A et al,2015 ). Common symptoms at presentation includes fever with or without chills and/or rigor, cough, shortness of breath and myalgia. Gastrointestinal symptoms are also frequent which includes diarrhea, vomiting and abdominal pain (Assiri A et al.2013). The median incubation period for human to human transmission is approximately 5 days (Cunha CB et al,2014 ). 2 patients from France presented with similar clinical features which included fever, chills, and myalgia. Respiratory symptoms with cough and dyspnea soon became the