Middle East respiratory syndrome coronavirus infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

MERS-CoV is a viral respiratory illness caused by a lineage C betacoronavirus, an enveloped, spherical (120 nm in diameter), single-stranded, positive-strand RNA virus that belongs to the family Coronaviridae. Its clinical significance was initially described following an outbreak in 2012 in Jeddah, Saudi Arabia. To date, little is known about MERS-CoV virus. The natural reservoir of MERS-CoV is unknown, but either bats or camels are thought to be the most likely natural reservoir with unconfirmed potential for sustained human-to-human transmission. MERS-CoV has been associated with residence in 9 countries in the Middle East and in South Korea. Approximately, 1,300 cases have been reported with a case-fatality rate reaching 30-40%. Following exposure, patients with MERS-CoV often remain asymptomatic during the viral incubation period for 5 to 14 days. Patients typically develop non-specific flu-like symptoms, such as high-grade fever, myalgia, sore throat, and cough. Many patients experience spontaneous self-resolution of symptoms a few days following the onset of symptoms. Individuals with systemic chronic comorbidities and immunosuppression are at high risk of developing worsening clinical features, such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), pericarditis, disseminated intravascular coagulopathy (DIC), septic shock, and death. According to the Centers of Disease Control and Prevention (CDC), laboratory confirmation of MERS-CoV infection requires either a positive PCR test of ≥ 2 specific genomic targets or a single positive target followed by successful sequencing of a second. Serologic testing is recommended in patients when PCR is not available. Additional lab testing is not diagnostic buy may be useful to monitor for the development of complications. Antiviral therapy against MERS-CoV is not yet recommended. Supportive care is the mainstay of management of MERS-CoV, but monitoring for and early management of MERS-CoV-associated complications are equally important. While there is no vaccine available for MERS-CoV, at-risk individuals are advised to implement infection control measures to prevent the spread of the infection in hospitals and in the communities.

The index case of MERS-CoV infection was reported in Saudi Arabia in September, 2012. Dr. Ali Mohamed Zaki, an Egyptian virologist, was the first to attribute MERS-CoV to coronavirus.

MERS-CoV has a strong tropism for the non-ciliated bronchial epithelium. The virus has the capacity to evade the innate immune system and inhibit interferon production. It uses the DPP4 (or CD26) receptor to bind to the host cell and to release viral nucleocapsid into the cellular cytoplasm. Once inside the cell, viral replication follows and proteins are expressed. The viral genes encode 4 structural proteins and 5 accessory proteins.

MERS-CoV is caused by a lineage C betacoronavirus, an enveloped, spherical (120 nm in diameter), single-stranded, positive-strand RNA virus that belongs to the family Coronaviridae of the order Nidovirales. The natural reservoir of MERS-CoV is unknown, but bats are thought to be the most likely natural reservoir. MERS-CoV is thought to have a zoonotic activity, whereby transmission occurs from animals to humans. Limited data is available to confirm or rule out human-to-human transmission.

MERS-CoV must be differentiated from other respiratory tract infections that cause flu-like symptoms, such as influenza virus, respiratory syncytial virus (RSV), and other coronaravirus infections.

MERS-CoV has been associated with residence in 9 countries in the Middle East and in South Korea. However, cases with a history of recent travel had been reported in several countries worldwide. As of June 2015, 1289 laboratory-confirmed cases of MERS-CoV infection have been reported. The case fatality rate of MERS-CoV ranges between 30% to 40%. The median age at infection is 47 years with no age preponderance to MERS-CoV infection (range: 9 months to 94 years). Approximately 2/3 of infected patients are males.

Risk factors in the development of either MERS-CoV infection or MERS-CoV-associated complications include recent travel to the Arabian Peninsula, exposure to patients with suspected or confirmed MERS-CoV infection, immunocompromised status, and history of prior systemic comorbidities, such as diabetes mellitus, hypertension, active malignancy, chronic kidney disease, respiratory disease, liver disease, and chronic cardiac disease.

Following exposure, patients with MERS-CoV remain asymptomatic during the incubation period for 5 to 14 days. If left untreated, patients typically develop non-specific flu-like symptoms, such as high-grade fever, myalgia, sore throat, and cough. Many patients experience spontaneous self-resolution of symptoms a few days following the onset of symptoms. Patients with systemic chronic comorbidities and immunosuppression are at high risk of developing worsening clinical features, such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), pericarditis, disseminated intravascular coagulopathy (DIC), and septic shock. Approximately 30-40% of patients die following MERS-CoV infection.

Symptoms of MERS-CoV typically include high-grade fever, cough, headache, dyspnea, and myalgia. Gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain may also be present.

Patients with MERS-CoV infection typically present with vital signs derangement, such as high-grade fever, tachycardia, tachypnea, and decreased oxygen saturation. Signs on physical examination may include decreased breath sounds, crackles, dullness on percussion, and increased tactile fremitus on pulmonary auscultation. Signs of complications may also be present, such as profound hypotension (suggestive of shock) or pericardial rub (suggestive of pericarditis).

Laboratory findings of MERS-CoV may include leukopenia, lymphopenia, thrombocytopenia, elevated inflammatory markers, and elevated lactate dehydrogenase (LDH) levels.^[1] Lab findings are not diagnostic of MERS-CoV but are useful to monitor for the development of MERS-CoV infection.

Radiographic findings MERS-CoV infection include unilateral or bilateral patchy densities or opacities, interstitial infiltrates, consolidation] and pleural effusions on chest x-ray.

On chest CT-scan, patients with MERS-CoV may demonstrate changes similar to patients with ARDS. CT scan may demonstrate bilateral airspace abnormalities with ground glass opacities, predominantly located at the bases of the lungs, suggestive of organizing pneumonia.^[2]

Laboratory confirmation of MERS-CoV infection requires either a positive PCR test of ≥2 specific genomic targets or a single positive target followed by successful sequencing of a second.^[1] If a patient has a positive serologic test, but no PCR or sequencing test, the individual is considered a probable case.

Antiviral therapy against MERS-CoV is not yet recommended. Supportive care is the mainstay of management of MERS-CoV. Monitoring for and early management of MERS-CoV-associated complications is also important.

Implementation of infection prevention and control measures is critical to prevent the possible spread of MERS-CoV in hospitals and communities. Hospitalized patients should be admitted to airborne infection isolation rooms. All healthcare personall should also wear personal protective equipment, including gloves, gowns, and eye and respiratory protection, when exposed to patients with MERS-CoV. Patients evaluated for MERS-CoV infection who do not require hospitalization may be treated and isolated at home to prevent the nosocomial spread of infection. Isolation at home is defined as the separation or restriction of activities of an ill person with a contagious disease from those who are well.^[1]

There is no vaccine available for the prevention of MERS infection. All individuals should implement precaution measures including washing hands with soap, avoiding personal physical contact or sharing utensils with sick individuals, and avoiding drinking raw food that may be contaminated with animal products.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2], João André Alves Silva, M.D. [3]

The index case of MERS-CoV infection was reported in Saudi Arabia in September, 2012. Dr. Ali Mohamed Zaki, an Egyptian virologist, was the first to attribute MERS-CoV to coronavirus.

• The index case of MERS-CoV infection was reported in Saudi Arabia in September, 2012. The index patient was a middle-aged man who presented with pneumonia and acute kidney injury.
• The virus was first termed human coronavirus-EMC (Erasmus Medical Center), then it was termed human coronavirus England 1 following the isolation of the virus from a patient in the United Kingdom who had recently traveled to the Middle East.^[1][2]
• On June 13 2012, Egyptian virologist, Dr. Ali Mohamed Zaki, identified the coronavirus responsible for the syndrome in Saudi Arabia.^[3]
• On September 2012, the virus was first reported outside Saudi Arabia in Qatar in a 44 year old man who had recently traveled to Saudi Arabia.
• It was later determined that viruses from the EMC/2012 and England/Qatar/2012, date to early 2011, suggesting that these cases had likely descended from a single zoonotic event.^[4]
• During the 2012-2013 outbreak, the World Health Organization (WHO) International Health Regulations Emergency Committee determined that MERS-CoV did not meet the criteria for a “public health emergency of international concern”, but was nevertheless of “serious and of great concern”.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

MERS-CoV has a strong tropism for the non-ciliated bronchial epithelium. The virus has the capacity to evade the innate immune system and inhibit interferon production. It uses the DPP4 (or CD26) receptor to bind to the host cell and to release viral nucleocapsid into the cellular cytoplasm. Once inside the cell, viral replication follows and proteins are expressed. The viral genes encode 4 structural proteins and 5 accessory proteins.

• The incubation period for MERS infection is 5–7 days, with a range of 2–14 days.^[1][2]
• Immunocompromised patients can present with longer incubation periods of up to 20 days.

• The virus has the capacity to evade the innate immune system and inhibit interferon production.^[3][4]
• Due to the similarities between the MERS-CoV and the SARS-CoV, it was initially proposed that the MERS-CoV possible uses the same cellular receptor for infection, as the SARS-CoV, namely the angiotensin converting enzyme 2^[5][6][7], however, the cellular receptor for MERS-CoV was later identified to be dipeptidyl peptidase 4 (DDP4) or CD26.^[4]
• The amino acid sequence of this receptor is a highly conserved sequence across species, being expressed in human bronchial epithelium and kidneys, and its enzymatic activity is not required for the process of infection.^[4][8]
• DDP4 is a neutrophil chemorepellent. Its loss from the cell surface results in cellular alteration of the composition of the immune cell infiltrate and subsequent alteration of the natural history of the infectious state.^{[5][9][10][11]}
• When MERS-CoV binds to its cellular receptor, a series of reactions involving host proteases, such as cathepsin B, are triggered. These include the excision of the surface glycoprotein, which will ultimately:^[5][12]
• Expose fusion peptide
• Allow fusion between virus and cell membrane
• Lead to the release of the viral nucleocapsid into cellular cytoplasm

The betacoronavirus contains a genome composed of 30,119 nucleotides that encodes structural and non-structural proteins. The genome is considered the largest among all RNA virus genomes, reaching 27-32 kb in size.

The structural proteins expressed by the betacoronavirus include:^[5][13]

• 1 Nucleocapsid (N) protein is required for encapsidation and viral replication
• 1 Glycoprotein is required for viral entry into the host cell
• 2 membrane proteins required for viral structure and assembly

All 4 structural proteins are encoded by genes located at the 3′ end of the RNA chain. In addition to the 4 structural proteins, the genome encodes 5 accessory proteins involved in viral assembly and evasion of the host immune system.^[14][13]

• MERS-CoV has a strong tropism for the non-ciliated bronchial epithelium.
• Less commonly, MERS-CoV may primarily infect cells of the GI tract or the neurological system.

• MERS-CoV is thought to have a zoonotic activity, whereby transmission occurs from animals to humans.
• Although bats are the natural host of the betacoronavirus, it is unknown if MERS coronavirus transmission to humans is through bats, through an intermediate animal hosts following crossover and subsequent adaptation, or through a completely different host.
• Limited data is available to confirm or rule out human-to-human transmission.

• Co-infection of MERS-CoV with other respiratory viruses such as:^[15]
  • Parainfluenza virus
  • Rhinovirus
  • Influenza A or B virus
  • Respiratory syncytial virus
  • Enteroviruses
  • Human metapneumovirus
  • Nosocomial bacterial infections.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

MERS-CoV is caused by a lineage C betacoronavirus, an enveloped, spherical (120 nm in diameter), single-stranded, positive-strand RNA virus that belongs to the familyCoronaviridaeof the orderNidovirales. The natural reservoir of MERS-CoV is unknown, but bats are thought to be the most likely natural reservoir. MERS-CoV is thought to have a zoonotic activity, whereby transmission occurs from animals to humans. Limited data is available to confirm or rule out human-to-human transmission.

MERS-CoV is caused by a lineage C betacoronavirus.

Betacoronavirus is an enveloped, spherical (120 nm in diameter), single-stranded, positive-strand RNA virus that belongs to the family Coronaviridae of the order Nidovirales.

The betacoronavirus contains a genome composed of 30,119 nucleotides that encodes structural and non-structural proteins. The genome is considered the largest among all RNA virus genomes, reaching 27-32 kb in size.

• MERS-CoV has a strong tropism for the non-ciliated bronchial epithelium.
• Less commonly, MERS-CoV may primarily infect cells of the GI tract or the neurological system.

• MERS-CoV is thought to have a zoonotic activity, whereby transmission occurs from animals to humans.
• Although bats are the natural host of the betacoronavirus, it is unknown if MERS coronavirus transmission to humans is through bats, through an intermediate animal hosts following crossover and subsequent adaptation, or through a completely different host.
• Limited data is available to confirm or rule out human-to-human transmission.

• The natural reservoir of MERS-CoV is unknown.
• The following are thought to be the natural reservoirs of MERS-CoV:
  • Bats (The majority of reports hypothesized that bats are the natural reservoir of MERS-CoV)
  • Camels
  • Goats

• 
  TEM reveals ultrastructural morphology of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural morphology of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural morphology of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). From Public Health Image Library (PHIL). ^[1]
• 
  Middle East Respiratory Syndrome Coronavirus (MERS-CoV) viral particles. From Public Health Image Library (PHIL). ^[1]
• 
  Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virion. From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural details exhibited by three spherical-shaped Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virions. From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural details exhibited by a number of spherical-shaped Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virions. From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural details exhibited by a number of red-colored, spherical-shaped Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virions. From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural details exhibited by five spherical-shaped Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virions, which were colorized yellow. From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural details exhibited by a single, spherical-shaped Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virion. From Public Health Image Library (PHIL). ^[1]
• 
  TEM reveals ultrastructural details exhibited by a single, spherical-shaped Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virion. From Public Health Image Library (PHIL). ^[1]
• 
  SEM reveals ultrastructural details at the site of interaction of two spherical-shaped Middle East Respiratory Syndrome Coronavirus (MERS-CoV) viral particles, colorized blue, that were on the surface of a camel epithelial cell, colorized red. From Public Health Image Library (PHIL). ^[1]
• 
  SEM reveals ultrastructural details at the site of interaction of numerous yellow-colored Middle East respiratory syndrome Coronavirus (MERS-CoV) viral particles on the surface of a Vero E6 cell (blue). From Public Health Image Library (PHIL). ^[1]

• Middle East respiratory syndrome coronavirus

• Emergence of the Middle East Respiratory Syndrome Coronavirus
• MERS-CoV Complete Genome
• Emerging viruses
• Molecular Illustration of MERS-Coronavirus
• Philippines still MERS-CoV free – DOH

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

MERS-CoV must be differentiated from other respiratory tract infections that cause flu-like symptoms, such as influenza virus, respiratory syncytial virus (RSV), and other coronaravirus infections.

The differential diagnosis of MERS-CoV include the following:^[1][2]

• Influenza virus infection
• Parainfluenza virus infection
• Respiratory syncytial virus (RSV) infection
• Adenovirus infection
• Rhinovirus infection
• Infection with other coronaviruses
• Metapneumovirus infection
• Acute respiratory distress syndrome
• Community-acquired pneumonia
• Brucellosis

Life threatening infection with 2019-nCoV, MERS-CoV and SARS-CoV should be differentiated from each other. The following table differentiates infection from these coronaviruses:^{[3][4][5][6][7][8][9][10][11][12][13][14]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2], Alejandro Lemor, M.D. [3]

MERS-CoV has been associated with residence in 9 countries in the Middle East and in South Korea. However, cases with a history of recent travel had been reported in several countries worldwide. As of June 2015, 1289 laboratory-confirmed cases of MERS-CoV infection have been reported. The case fatality rate of MERS-CoV ranges between 30% to 40%. The median age at infection is 47 years with no age preponderance to MERS-CoV infection (range: 9 months to 94 years). Approximately 2/3 of infected patients are males.

• As of June 2015, 1289 laboratory-confirmed cases of MERS-CoV infection have been reported in 25 countries.

• As of January 2015, 356 MERS-CoV-related deaths have been reported. The case fatality rate of MERS-CoV ranges between 30% to 40%.

• There is no age preponderance to MERS-CoV infection (range: 9 months to 94 years).
• Among infected patients, the median age is 47 years.

• There is a male preponderance to MERS-CoV infection. The male-to-female ratio is 1.6 to 1.0.

Only travel-associated MERS-CoV infection has also been reported in developed countries. At least one MERS-CoV case has been reported in the following countries:

• United States of America (USA)
• United Kingdom (UK)
• France
• Germany
• Italy
• Netherlands
• Austria
• Republic of Korea

MERS-CoV has been associated with residence in or recent travel to the following countries:

• Saudi Arabia
• United Arab Emirates (UAE)
• Qatar
• Jordan
• Oman
• Kuwait
• Yemen
• Lebanon
• Iran

Other countries with travel-associated MERS-CoV infection:

• China
• Algeria
• Egypt
• Malaysia
• Philippines
• Tunisia
• Turkey
• Greece
• Thailand

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2], Alejandro Lemor, M.D. [3]

Risk factors for the development of either MERS-CoV infection or MERS-CoV-associated complications include recent travel to the Arabian Peninsula, exposure to patients with suspected or confirmed MERS-CoV infection, immunocompromised status, and history of prior systemic comorbidities, such as diabetes mellitus, hypertension, active malignancy, chronic kidney disease, respiratory disease, liver disease, and chronic cardiac disease.

The following are risk factors for the development of either MERS-CoV infection or MERS-CoV-associated complications:

• The majority of MERS-CoV cases have been reported in the Arabian Peninsula.^[1]

• During the viral incubation period, individuals remain asymptomatic for up to 2 weeks following exposure and transmission.^[1]

• It is not confirmed if human-to-human MERS-CoV transmission is possible. Nonetheless, the majority of infected patients had not reported a recent exposure to animals that might suggest zoonotic activity. Accordingly, exposure to infected patients is suspected to increase the risk of MERS-CoV infection.^[1][2][3]

• Immunocompromised patients are at increased risk of developing MERS-CoV infection and MERS-CoV infection-associated complications.

• The rates of MERS-CoV infection and MERS-CoV-associated complications are significantly higher among patients with chronic systemic comorbidities, such as:
• Diabetes mellitus
• Hypertension
• Active malignancy
• Chronic kidney disease (CKD), especially end-stage renal disease (ESRD)
• Chronic cardiac disease
• Chronic liver disease
• Respiratory disease (e.g. COPD or cystic fibrosis)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Following exposure, patients with MERS-CoV remain asymptomatic during the incubation period for 5 to 14 days. If left untreated, patients typically develop non-specific flu-like symptoms, such as high-grade fever, myalgia, sore throat, and cough. Many patients experience spontaneous self-resolution of symptoms a few days following the onset of symptoms. Patients with systemic chronic comorbidities and immunosuppression are at high risk of developing worsening clinical features, such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), pericarditis, disseminated intravascular coagulopathy (DIC), and septic shock. Approximately 30-40% of patients die following MERS-CoV infection.

• The incubation period for MERS-CoV ranges from 5 to 14 days.^[1][2] During this time, individuals who have been exposed and acquired the infection will remain asymptomatic.

• Following transmission, patients typically first develop high-grade fever and non-specific flu-like symptoms, such as myalgia, dizziness, diaphoresis, sore throat, vomiting, diarrhea, cough, dyspnea, and abdominal pain.
• Although the majority of patients develop symptoms, 15-20% may experience no or mild clinical manifestations.

• If left untreated, the majority of patients experience spontaneous self resolution of the infection.
• Immunocompromised individuals or patients with significant comorbidities are at high risk of developing worsening symptoms and either pulmonary or extrapulmonary complications, including pneumonia, acute respiratory distress syndrome (ARDS), acute kidney injury, pericarditis, disseminated intravascular coagulopathy (DIC), septic shock, and death.

MERS-CoV-associated complications include the following:^{[3][4][4][5][6][7][8][9][10][11][12]}

• Pneumonia
• Pericarditis

• Acute respiratory distress syndrome (ARDS)
• Acute kidney injury
• Spontaneous abortion among pregnant women
• Disseminated intravascular coagulopathy (DIC)
• Septic shock
• Death

• If left untreated, the majority of patients experience self-resolution with excellent prognosis. Patients with systemic chronic comorbidities have a poorer prognosis and are at a higher risk of development of complications and death.
• Compared with other respiratory viruses, MERS-CoV is associated with higher risk of death (30% to 40%).^[13]

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