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Middle Eastern Respiratory Syndrome (MERS)

3.00 Contact Hours
A score of 80% correct answers on a test is required to successfully complete any course and attain a certificate of completion.
Author:    Pamela Downey (MSN, ARNP)

Outcomes

MERS-CoV is the acronym for Middle East Respiratory Syndrome Coronavirus, the virus that causes MERS. When referring to the virus and not the illness, the Centers for Disease Control and Prevention (CDC) uses this acronym. When referring to the illness, the CDC uses MERS. The virus was first reported in 2012 in Saudi Arabia. It is different from any other coronaviruses that have previously been found in individuals.

Objectives

After completing this course, the learner will be able to meet the following 16 objectives:

  1. Describe the epidemiology and geographic distribution of MERS-CoV including notable cases and clusters of MERS-CoV globally.
  2. List the possible sources and modes of transmission of MERS-CoV.
  3. Describe the signs and symptoms of a progressively worsening MERS-CoV infection.
  4. Describe common laboratory and diagnostic tests ordered to confirm or refute the diagnosis of MERS-CoV infection.
  5. Relate the clinical management goals and interventions used in care of the MERS-CoV infected individual.
  6. Compare and contrast infection prevention and control practices in healthcare settings, homecare settings and in the community.
  7. Relate reporting procedures for confirmed cases of MERS-CoV and patients under investigation for MERS-CoV infection to local/state health departments, the CDC and the WHO.
  8. Relate the survival rate of a MERS-CoV infected individual.

Introduction

In September 2012, a case of novel coronavirus infection was reported involving a Saudi Arabian gentleman who had been admitted to a hospital in June 2012 with pneumonia and acute kidney injury. A few days later, a separate report appeared of an almost identical virus detected in a second individual with acute respiratory syndrome and acute kidney injury. The second individual initially developed symptoms in Qatar but had traveled to Saudi Arabia before he became ill. He then sought care in the United Kingdom. Many subsequent cases and clusters of infections have been reported.

This novel coronavirus, initially termed human coronavirus-EMC (for Erasmus Medical Center), has been named Middle East respiratory syndrome coronavirus (MERS-CoV).

Virology

Middle East respiratory syndrome coronavirus (MERS-CoV) or EMC/2012 (HCoV-EMC/2012) is a positive-sense, single-stranded RNA novel species of the genus Betacoronavirus, lineage C.  It is different from the other human betacoronaviruses (severe acute respiratory syndrome coronavirus (SARS), OC43 and HKU1) but closely related to several bat coronaviruses. Initially called novel coronavirus 2012 or simply novel coronavirus, it was first reported in 2012 after genome sequencing of a virus isolated from sputum samples from an individual who fell ill in a 2012 outbreak of a new flu.

MERS-CoV genomes are phylogenetically classified into two clades, clade A and B.  The earliest cases of MERS were of clade A clusters (EMC/2012 and Jordan-N3/2012). New cases are genetically distinct (clade B).

The Taxonomy of MERS-CoV is as follows:

  • Scientific name: Middle East Respiratory Syndrome Coronavirus
  • Common name: MERS-CoV
  • Synonym: Severe acute respiratory syndrome coronavirus
  • Other names:
    • novel coronavirus (nCoV)
    • London1 novel CoV/2012
    • Human Coronavirus Erasmus Medical Center/2012 (HCoV-EMC/2012)
  • Lineage:
    • Viruses
      • ssRNA viruses
      • Group: IV; positive-sense, single-stranded RNA viruses
      • Order: Nidovirales
      • Family: Coronaviridae
      • Subfamily: Coronavirinae
      • Genus: Betacoronavirus
      • Species: Betacoronavirus 1
  • Commonly called:
    • Human coronavirus OC43
    • Human coronavirus HKU1
    • Murine coronavirus
    • Pipistrellus bat coronavirus HKU5
    • Rousettus bat coronavirus HKU9
    • Severe acute respiratory syndrome-related coronavirus
    • Tylonycteris bat coronavirus HKU4
  • Virus hosts:
    • Homo sapiens (human)
    • Camels
    • Bats

MERS-CoV is distinct from the SARS coronavirus and distinct from the common-cold coronavirus and known endemic human betacoronaviruses HCoV-OC43 and HCoV-HKU1. Until 23 May 2013, MERS-CoV had frequently been referred to as a SARS-like virus or simply the novel coronavirus and earlier it was referred to colloquially on message boards as the "Saudi SARS". MERS-CoV is closely related to several bat coronaviruses.

An electron micrograph of a thin section of MERS-CoV, showing the spherical particles within the cytoplasm of an infected cell.

An electron micrograph of a thin section of MERS-CoV, showing the spherical particles within the cytoplasm of an infected cell.

 Middle East respiratory syndrome 3-D image

Tropism

Viral tropism is defined by the specificity of a virus for a particular host tissue determined in part by the interaction of viral surface structures with receptors present on the surface of the host cell.

In humans, MERS-CoV has a strong tropism for nonciliated bronchial epithelial cells. It has been shown to effectively evade the innate human immune responses and antagonize interferon (IFN) production in these cells. This tropism is unique in that most respiratory viruses target ciliated cells.

Dr. Gary Whittaker, professor of Virology, and Jean Millet at Cornell’s Biological Safety Level 3 facility located in the Animal Health Diagnostics Center discovered that a common protease enzyme known as furin activates the MERS-CoV to fuse with cell membranes and enter host cells. Whittaker and Millet suggest that blocking furin at a specific point in the host cell entry process could lead to a treatment by preventing the virus from getting into cells, where it uses the cell’s reproduction mechanism to make new viruses.

Coronaviruses have a spike protein that is activated by a protease and mediates membrane fusion and entry into a host cell. The location on the spike protein where a protease activates this process is called a cleavage site. The researchers found there were two cleavage sites for MERS-CoV, each activated by furin at different times:

  1. After a new virus is assembled inside a host cell which occurs when the virus makes its way out of the host cell to the cell surface and
  2. When the released virus finds a new cell and is taken up into the membrane.

MERS-CoV particles as seen by negative stain electron microscopy. Virions contain characteristic club-like projections emanating from the viral membrane.

Whittaker and Millet concluded that this might be a situation where that extra cleavage site is allowing more spread in animals or humans. With MERS, “the primary infection is in the lungs, and even there it infects additional cell types, including immune cells, which could allow dissemination throughout the body”.

Dipeptidyl peptidase 4 (DPP4, also known as, CD26), which is present on the surfaces of human nonciliated bronchial epithelial cells, is a functional receptor for MERS-CoV. Expression of human and bat DPP4 in nonsusceptible cells enables infection by MERS-CoV. The DPP4 protein displays high amino acid sequence conservation across different species including the sequence that was obtained from bat cells.

Further research identified DPP4 as a functional cellular receptor for MERS-CoV. Unlike other known coronavirus receptors, the enzymatic activity of DPP4 is not required for infection. As would be expected, the amino acid sequence of DPP4 is highly conserved across species and is expressed in the human bronchial epithelium and kidneys. Bat DPP4 genes appear to have been subject to a high degree of adaptive evolution as a response to coronavirus infections, so the lineage leading to MERS-CoV may have circulated in bat populations for a long period of time before being transmitted to humans.

To jump to humans, animal viruses such as these novel coronaviruses, and avian and swine flu viruses, must evolve to be able to latch onto proteins on the surfaces of human cells. In a paper published in Nature, Stalin Raj at the Erasmus Medical Centre in Rotterdam, the Netherlands, and a largely European team reported that spikes on the surface of HCoV-EMC bind to DPP4, a well-known receptor protein on human cells. When the binding site for the virus on DPP4 was blocked using antibodies, the virus could not infect cells. Conversely, when DPP4 was expressed on the surface of normally non-susceptible cells, HCoV-EMC could now infect them.

In a cell line susceptibility study, MERS-CoV infected several human cell lines, including lower (but not upper) respiratory, kidney, intestinal and liver cells, as well as, histiocytes. The range of tissue tropism in vitro was broader than that for any other known human coronavirus. In another study, human bronchial epithelial cells were susceptible to infection. MERS-CoV can also infect nonhuman primate, porcine, bat, civet, rabbit and horse cell lines. Further study is necessary to determine whether these in vitro findings will translate to broader species susceptibility during in vitro infections.

Because of a large increase in cases in Saudi Arabia in the spring of 2014, concern arose that MERS-CoV might have mutated to become more transmissible or virulent. However, cell culture experiments of viruses isolated during these outbreaks showed no evidence of changes in viral replication rate, immune escape, interferon sensitivity or serum neutralization kinetics compared with a contemporaneous but phylogenetically different virus recovered in Riyadh or the original MERS-CoV isolate from 2012.

Genetic Analysis

In an analysis of the full or partial genomes of MERS-CoV obtained from 21 individuals with MERS-CoV infection in Saudi Arabia between June 2012 and June 2013, there was sufficient heterogeneity to support multiple separate animal-to-human transfers. Moreover, even within a hospital outbreak in Al-Hasa, Saudi Arabia, there was evidence of more than one virus introduction. By estimating the evolutionary rate of the virus, the authors concluded that MERS-CoV emerged around July 2011 (95% highest density July 2007 to June 2012).

Phylogenetic analysis during the spring of 2014 showed that viruses from individuals in Jeddah, Saudi Arabia, were genetically similar, suggesting that the outbreak in Jeddah was caused by human-to-human transmission. Of 168 specimens that were positive for MERS-CoV during the outbreak in Jeddah, 49% came from a single hospital, King Fahd Hospital. Isolates from individuals in Riyadh, Saudi Arabia, during the spring of 2014 belonged to six different clades, suggesting that these infections resulted from increased zoonotic activity or transmission from humans in other regions. One cluster of infections observed in a single hospital in Riyadh was associated with a single clade, suggesting nosocomial transmission.

Evolution

At least one individual who had fallen sick with MERS was known to have come into contact with camels or recently drank camel milk.

In 2013 MERS-CoV was identified in three members of a dromedary camel herd held in a Qatar barn, which was linked to two confirmed human cases who have since recovered. The presence of MERS-CoV in the camels was confirmed by the National Institute of Public Health and Environment (RIVM) of the Ministry of Health and the Erasmus Medical Center World Health Organization Collaborating Center, the Netherlands. None of the camels showed any sign of disease when the samples were collected.

The Qatar Supreme Council of Health advised in November 2013 that individuals with underlying health conditions, such as heart disease, diabetes, kidney disease, respiratory disease, the immunosuppressed and the elderly, avoid any close animal contacts when visiting farms and markets, and to practice good hygiene, such as washing hands.

In December 2013, a further study on dromedary camels from Saudi Arabia revealed the presence of MERS-CoV in 90% of the evaluated dromedary camels (total 310), suggesting that dromedary camels not only could be the main reservoir of MERS-CoV but also the animal source of MERS.

According to the 27 March 2014 MERS-CoV summary update, recent studies support that camels serve as the primary source of the MERS-CoV infecting humans, while bats may be the ultimate reservoir of the virus. Evidence includes the frequency with which the virus has been found in camels to which human cases have been exposed, seriological data which shows widespread transmission in camels and the similarity of the camel CoV to the human CoV.

Warnings

On 13 February 2013, the World Health Organization (WHO) stated "the risk of sustained person-to-person transmission appears to be very low." The cells MERS-CoV effects in the lungs only account for 20% of respiratory epithelial cells, so a large number of virions are likely needed to be inhaled to cause infection.

As of 29 May 2013[update], the WHO warned that the MERS-CoV virus is a "threat to the entire world." However, Dr. Anthony S. Fauci of the National Institutes of Health (NIH) in Bethesda, Maryland, stated that as of now MERS-CoV "does not spread in a sustained person-to-person way at all." Dr. Fauci stated that there is potential danger in that it is possible for the virus to mutate into a strain that does transmit from person-to-person.

The infection of healthcare personnel (HCP*) has led to concerns of human-to-human transmission.

* HCP refers to all individuals, paid and unpaid, working in healthcare settings whose activities potentially place them at risk for exposures to an individual with MERS-CoV. Examples of such activities include those that require direct contact with patients and exposure to the patient-care environment, including being in the patient room or in a triage or examination room or other potentially contaminated areas and handling blood, body fluids (except sweat), secretions, or excretions or soiled medical supplies, equipment or environmental surfaces.

The Centers for Disease Control and Prevention (CDC) lists MERS as transmissible from human-to-human. "MERS-CoV has been shown to spread between people who are in close contact.” Transmission from infected individuals to healthcare personnel (HCP) has also been observed. Clusters of cases in several countries are being investigated." There was also a New York Times article which provided some correlative context for this.

Epidemiology

The first confirmed case of MERS was reported in Saudi Arabia in September 2012.  Egyptian virologist Dr. Ali Mohamed Zaki isolated and identified a previously unknown coronavirus which was isolated from the sputum of a gentleman in Jeddah, Saudi Arabia, who was admitted to the hospital with pneumonia and acute kidney injury in June 2012. Dr. Zaki then posted his findings on 24 September 2012 on ProMED-mail, an internet-based reporting system that helps disseminate information about infectious disease outbreaks worldwide. The isolated cells showed cytopathic effects (CPE), in the form of rounding and syncytia formation.

A second case was found in September 2012. A 49-year-old gentleman living in Qatar presented with acute respiratory syndrome and acute kidney injury who had recently traveled to Saudi Arabia. A sequence of the virus was nearly identical to that of the first case. In November 2012, similar cases appeared in Qatar and Saudi Arabia. Additional cases were noted, with deaths associated, and rapid research and monitoring of this novel coronavirus began.

A study by Ziad Memish of Riyadh University and colleagues suggests that the virus arose sometime between July 2007 and June 2012, with perhaps as many as 7 separate zoonotic transmissions. Among animal reservoirs, CoV has a large genetic diversity yet the samples from individuals suggest a similar genome, and therefore common source, though the data are limited. It has been determined through molecular clock analysis, that viruses from the EMC/2012 and England/Qatar/2012 date to early 2011 suggesting that these cases are descended from a single zoonotic event. It would appear MERS-CoV had been circulating in the human population for greater than one year without detection and suggests independent transmission from an unknown source.

Subsequent cases and clusters* of infections have been reported (Figure 1). Since April 2012, more than 1,400 cases of MERS-CoV infection have been reported. The actual number of cases is likely to be higher. The median age is 48 years (range 9 months to 94 years) and 64% of the cases have been male.

* A cluster is defined as two or more individuals with onset of symptoms within the same 14 days period and who are associated with a specific setting such as a classroom, workplace, household, extended family, hospital, other residential institution, military barracks or recreational camp.

Figure 1

Epidemic Curve of MERS-CoV Cases in Humans Reported to the WHO as of 5 February 2015 (n = 971)

Reprinted from WHO, Middle East respiratory syndrome coronavirus (MERS-CoV): Summary of current situation, literature update and risk assessment - as of 5 February 2015.

The number of cases in the Middle East increased dramatically in March and April 2014 then declined sharply in mid-May 2014. A smaller increase in cases occurred during March and April 2013. An outbreak of more than 180 cases occurred in the Republic of Korea in May and June 2015. In this index case*, the gentleman had recently traveled to several countries in the Arabian Peninsula.

  • *Index case is the first case or instance of a patient coming to the attention of health authorities.

Geographic Distribution

Since April 2012, more than 1,400 laboratory-confirmed human infections with MERS-CoV have been reported to the WHO. These occurred primarily in countries in the Arabian Peninsula* (Figure 2). The majority of cases have occurred in Saudi Arabia including some case clusters.

  • *Countries considered in the Arabian Peninsula and neighboring the Arabian Peninsula include: Bahrain, Iraq, Iran, Israel, the West Bank and Gaza, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Syria, the United Arab Emirates (UAE) and Yemen.

Figure 2

Countries Reporting MERS-CoV Infection as of 5 February 2015

MERS-CoV: Middle East respiratory syndrome coronavirus.World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV): Summary of current situation, iterature update and risk assessment–as of 5 February 2015. http://www.who.int/csr/disease/coronavirus_infections/mers-5-february-2015.pdf?ua=1 (Accessed on March 04, 2015). Copyright © 2015 World Health Organization.

Cases have also been reported from other regions of the world including North Africa, Europe, Asia and North America (Table 1). In countries outside of the Arabian Peninsula, individuals developed illness after returning from the Arabian Peninsula or through close contact with infected individuals.

Countries in or near the Arabian Peninsula with Laboratory-Confirmed Cases

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

Countries with Travel-Associated Laboratory-Confirmed Cases

  • Algeria
  • Austria
  • China
  • Egypt
  • France
  • Germany
  • Greece
  • Italy
  • Malaysia
  • Netherlands
  • Philippines
  • Republic of Korea (South Korea)
  • Thailand
  • Tunisia
  • Turkey
  • United Kingdom
  • United States

Notable Cases and Clusters

Notable cases and clusters which have been reported to the WHO are summarized as follows:

April 2012

  • The two earliest laboratory-confirmed cases were subsequently reported from Jordan. Both individuals died during a cluster of acute respiratory illness in April 2012, which included 10 healthcare workers. Serologic testing suggested that seven surviving hospital contacts had MERS-CoV infection.

June 2012

  • The index case was a gentleman in Jeddah, Saudi Arabia, who was hospitalized with pneumonia. He developed acute respiratory distress syndrome (ARDS) and acute kidney injury and died. MERS-CoV was isolated from his sputum.

September 2012

  • A nearly identical coronavirus was detected in a gentleman who also had ARDS and acute kidney injury requiring admission to the intensive care unit. He initially developed symptoms in Qatar but had recently traveled to Saudi Arabia and sought care in the United Kingdom.

October and November 2012

  • A cluster of MERS-CoV infections occurred in four gentlemen in one family in Riyadh, Saudi Arabia. Two died. None of the 24 other family members who lived with the infected individuals or 124 healthcare workers who had contact with them became ill.

January 2013

  • A resident of the United Kingdom who had traveled to Saudi Arabia and Pakistan developed a severe respiratory illness and diagnostic tests of respiratory specimens were positive for both MERS-CoV and H1N1 influenza A. He died in March 2013.

February 2013

  • The individuals son (refer to January 2013 above), who had underlying medical conditions, died from MERS-CoV infection after being in close contact with his father. Another family member developed a mild illness and was also found to have MERS-CoV. Neither of these individuals traveled to the Middle East, strongly suggesting that they acquired the virus via human-to-human contact.

April 2013

  • A cluster of 23 laboratory-confirmed MERS-CoV infection cases and 11 probable cases of MERS-CoV was detected in Al-Hasa in the Eastern Province of Saudi Arabia. Almost all cases were directly linked to human-to-human exposure, most of them in the hemodialysis (nine cases) or intensive care (four cases) units of a single hospital. There were only two proven cases in healthcare workers and only three family members (all of whom had visited the hospital) were proven infected despite a survey of over 200 household contacts.

May 2013

  • An individual in France developed MERS-CoV infection after returning to France from a vacation in the United Arab Emirates. A second individual was diagnosed with MERS-CoV after sharing a hospital room with the first individual. The first individual died and the second individual was critically ill. Both individuals were immunocompromised, one a renal transplant recipient and the second on daily glucocorticoids. No cases of secondary transmission were detected in more than 100 healthcare workers despite the lack of use of personal protective equipment.

March and April 2014

  • A sharp increase in the number of cases was reported in Saudi Arabia and the United Arab Emirates. Of the over 500 cases reported, the majority represented hospital-based outbreaks in the Saudi Arabian cities of Jeddah (255 cases), Riyadh, Tabuk, Madinah and in Al Ain City, Abu Dhabi, United Arab Emirates. Cases included healthcare workers, individuals admitted for other medical problems, visitors and ambulance staff. During this time period, up to 75% of cases appeared to have been acquired from exposure to individuals known to be infected. However, there has been no clear evidence of sustained human-to-human transmission of MERS-CoV in community settings. Many of the secondary infections that occurred in healthcare workers were either mildly symptomatic or asymptomatic but 15% of healthcare workers presented with severe disease or died.
  • The first case in the United States was reported in an American healthcare worker in his sixties who lived and worked in Riyadh, Saudi Arabia but traveled to Indiana in April 2014 where he sought healthcare. It was subsequently concluded by the CDC that he had tested negative for MERS-CoV after completing additional and more definitive tests using a neutralizing antibody assay.

May 2014

  • A second imported case in the United States was confirmed in Florida in an individual who was visiting from Saudi Arabia.

September 2014

  • The first laboratory-confirmed case of MERS-CoV infection was diagnosed in Vienna, Austria.This case involved a 29-year-old female citizen of the Kingdom of Saudi Arabia who travelled to Vienna, Austria on a flight from Doha, Qatar. The woman was symptomatic with an upper respiratory infection and fever prior to arrival in Austria.

May 2015

  • The first case in the Republic of Korea occurred. The index case was a gentleman who had recently traveled to Bahrain, the United Arab Emirates, Saudi Arabia and Qatar.
  • An additional case of MERS-CoV infection was reported from Oman. This laboratory-confirmed case involved a 75-year-old male who developed symptoms and was admitted to the hospital. He was treated symptomatically and discharged on 20 May. His symptoms worsened and he was readmitted to the same hospital.
  • China reported one laboratory confirmed case of MERS-CoV infection. This case involved a 44-year-old gentleman from the Republic of Korea. He is the son of the third MERS-CoV case and the younger brother of the fourth MERS-CoV case that were previously reported. He developed symptoms on 21 May but flew to China, Hong Kong Special Administrative Region on 26 May and subsequently travelled to Huizhou through the point of entry in Shenzhen City, Guangdong Province. He was hospitalized in a Chinese hospital for isolation.
  • Iran reported one additional case of MERS-CoV infection involving a 61-year-old gentleman from Kahnooj city who developed symptoms and was admitted to the hospital. He was subsequently transferred to another hospital in Kerman city. The gentleman was discharged from the hospital. Follow-up contact tracing of household and healthcare contacts occurred.
  • Qatar reported one additional case of MERS-CoV infection. This involved a 73-year-old gentleman from Doha city who developed symptoms and sought medical care at a hospital. He was treated symptomatically and sent home on the same day. He returned as symptoms worsened and was admitted to the same hospital. He tested positive for MERS-CoV. The gentleman was reported in critical condition in the ICU. Contact tracing of household contacts and healthcare contacts followed.

June 2015

  • The first case of MERS-CoV infection in Thailand was reported in a 75-year-old gentleman who had traveled from Oman to Bangkok. He was discharged from the hospital having recovered clinically and after repeat laboratory testing showed no evidence of residual infection.

July 2015

  • The Republic of Korea reported a total of 186 secondary and tertiary MERS-CoV cases among household and hospital contacts, including 36 deaths. One of the 186 cases was the case that was confirmed in China (see May 2015 above). This individual was the first reported case in China.
  • The median age of the Korean cases was 55 years (ranging from 16 to 87 years of age). The majority of cases were men (59%). Twenty-six cases (14%) were healthcare professionals. To date, all cases have been linked to a single chain of transmission and are associated with healthcare facilities.
  • The Republic of Korea reported that at the end of July there were no additional cases of infection and no new deaths had occurred related to MERS-CoV.
  • The Philippines reported one laboratory-confirmed case of MERS-CoV. This case involved a non-national, 36-year-old gentleman who developed symptoms of MERS-CoV infection and had a laboratory-confirmed positive result for the virus. He was discharged from the Research Institute for Tropical Medicine (RITM) in Manila following two negative tests, 48 hours apart, which demonstrated that he was no longer infectious. He recovered and is reported to be well.

August 2015

  • The Kingdom of Saudi Arabia reported 19 additional cases of MERS-CoV infection, including 1 death. Fifteen of these reported cases were associated with a MERS-CoV outbreak which occurred in a hospital in Riyadh. Contact tracing of household and healthcare contacts was ongoing.
  • The Kingdom of Saudi Arabia reported the deaths of four prior MERS-CoV cases.

The current outbreak situation as of 24 August 2015 is:

Total confirmed cases

  • Republic of Korea: 185
  • China: 1
  • Total deaths: 36
  • Global laboratory-confirmed total: 1,432
  • Global deaths: 507

Possible Sources and Modes of Transmission

MERS-CoV is a zoonotic virus that is transmitted from animals to humans. The origins of the virus are not fully understood but, according to the analysis of different virus genomes, it is believed that it has been present in bats for some time and had spread to camels by the mid-1990s. The virus appears to have spread from camels to humans in the early 2010s. The original bat host species and the time of initial infection in this species has yet to be definitively determined.

Bats

Early research suggested the virus is related to one found in the Egyptian tomb bat. In September 2012 Ron Fouchier speculated that the virus might have originated in bats. Work by epidemiologist Ian Lipkin of Columbia University in New York showed that the virus isolated from a bat looked to be a match to the virus found in humans. 2c betacoronaviruses were detected in Nycteris bats in Ghana and Pipistrellus bats in Europe that are phylogenetically related to the MERS-CoV virus.

Other research has shown that MERS-CoV is closely related to the Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5. Serological evidence shows that these viruses have infected camels for at least 20 years. The most recent common ancestor of several human strains has been dated to March 2012 (95% confidence interval December 2011 to June 2012).

Studies performed in Europe, Africa and Asia, including the Middle East, have shown that the coronavirus RNA sequences are found frequently in bat fecal samples and that some of these sequences are closely related to MERS-CoV sequences. In a study from Saudi Arabia, 823 fecal and rectal swab samples were collected from bats and, using real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay, many coronavirus sequences were found. Most were unrelated to MERS-CoV, but, notably, one 190 nucleotide sequence in the RNA-dependent RNA polymerase (RdRp) gene was amplified that had 100% identity with a MERS-CoV isolate cloned from an index individual with MERS-CoV infection. This sequence was detected from a fecal pellet of a Taphozous perforatus bat captured from a site near the home of the index individual. MERS-CoV grows readily in several bat-derived cell lines.

Although bats might be a reservoir of MERS-CoV, it is unlikely that they are the immediate source for most human cases because human contact with bats is uncommon.

Camels

The route of transmission from animals to humans is not fully understood, but camels are likely to be a major reservoir host for MERS-CoV and an animal source of infection in humans. Strains of MERS-CoV that are identical to human strains have been isolated from camels in several countries, including Egypt, Oman, Qatar and Saudi Arabia.

It seems likely that dromedary camels are the primary animal host for MERS-CoV.  The strongest evidence of camel-to-human transmission of MERS-CoV comes from a study in Saudi Arabia in which MERS-CoV was isolated from a gentleman who died of laboratory-confirmed MERS-CoV infection after close contact with camels that had rhinorrhea. Full-genome sequencing demonstrated that the viruses isolated from the gentleman and his camel were identical. The study had the following findings:

  • A previously healthy 44-year-old gentleman was admitted to the intensive care unit of a hospital in Jeddah, Saudi Arabia with severe dyspnea. He initially developed fever, rhinorrhea, cough and malaise eight days prior to admission. He then became dyspneic three days prior to admission. He owned a herd of nine dromedary camels and had visited the camels daily until three days prior to admission. Four of the camels had been ill with nasal discharge during the week before the onset of his illness. He had applied a topical medicine to the nose of one of the ill camels seven days before he became ill. The gentleman died 15 days after hospital admission.
  • Nasal swabs collected from the gentleman on hospital days 1, 4, 14 and 16 were all positive for MERS-CoV by rRT-PCR. The first nasal specimen collected from one symptomatic camel was also positive by rRT-PCR. A repeat nasal specimen collected 28 days later was negative. Nasal specimens that were collected from the other camels on day 1 (seven camels) and day 28 (eight camels) were negative by rRT-PCR. Milk, urine and rectal specimens collected from all camels were negative by rRT-PCR.
  • Separate Vero cell cultures inoculated with the first specimens obtained from the gentleman and from the rRT-PCR-positive camel both grew MERS-CoV strains which, on full-genome sequencing, were identical.
  • A serum specimen collected from the gentleman on day 1 was negative for MERS-CoV antibodies (<1:10) by immunofluorescence assay, whereas the specimen collected on day 14 had an antibody titer of 1:1280. Paired serum specimens from the infected camel also showed a greater than 4-fold increase in the antibody titer. Four other camels had increases in antibody titers and the remaining four camels had high, stable antibody titers to MERS-CoV.
  • These results suggest that MERS-CoV infection was transmitted through close contact with an infected camel.

Other phylogenetic analyses comparing portions of the MERS-CoV genome obtained from camels to MERS-CoV obtained from humans with epidemiologic links to the camels have demonstrated that the viruses were similar.

Serologic studies have also suggested that camels are an important source of MERS-CoV:

  • Of 203 serum samples collected in 2013 from dromedary camels in various regions of Saudi Arabia, 150 (74%) had antibodies to MERS-CoV by enzyme-linked immunosorbent assay. The rate of seropositivity was higher in adult than juvenile camels (greater than 95% among camels older than 2 years of age versus 55% in camels 2 years of age or younger. Using stored serum samples from 1992 to 2010, antibodies to MERS-CoV were detected as early as 1992. No MERS-CoV specific antibodies were detected in domestic sheep or goats in Saudi Arabia.
  • Almost all adult camels (greater than 90%) from countries in the Arabian Peninsula, Jordan, Egypt, Nigeria and Ethiopia show antibody evidence of prior MERS-CoV infection. Adult camels in other countries of the region (Kenya, Tunisia, Spain, Canary Islands) are also MERS-CoV antibody positive but at a lower prevalence. Camels in other parts of Europe and in the Americas do not have MERS-CoV antibodies. No other domestic animals tested have shown evidence of infection.
  • The journal of Emerging Infectious Diseases records research showing the coronavirus infection in dromedary camel calves and adults, 99.9% matching to the genomes of human clade B MERS-CoV.
  • A report in the journal The Lancet Infectious Diseases (9 August 2013) showed that 50 out of 50 (100%) blood serum from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against the MERS-CoV spike protein. Blood serum from European sheep, goats, cattle and other camelids had no such antibodies. Countries like Saudi Arabia and the United Arab Emirates produce and consume large amounts of camel meat. The possibility exists that African or Australian bats harbor the virus and transmit it to camels. Imported camels from these regions might have carried the virus to the Middle East.
  • In another study, three dromedary camels inoculated with MERS-CoV intratracheally, intranasally and conjunctivally shed large quantities of the virus from the upper respiratory tract. The infectious virus was detected in nasal secretions for 7 days post-inoculation and viral RNA for up to 35 days post-inoculation.

Human-to-Human

The virus does not appear to pass easily from human-to-human unless there is close contact such as providing unprotected care to an infected individual. There have been clusters of cases in healthcare facilities, where human-to-human transmission appears to be more probable, especially when infection control and prevention practices are inadequate. Thus far, no sustained community transmission has been documented.

The virus appears to be circulating throughout the Arabian Peninsula, primarily in Saudi Arabia, where the majority of cases (greater than 85%) have been reported since 2012. Several cases have been reported outside the Middle East. Most of these infections are believed to have been acquired in the Middle East and then exported outside the region. The ongoing outbreak in the Republic of Korea is the largest outbreak outside of the Middle East, and while concerning, there is no evidence of sustained human-to-human transmission in the Republic of Korea. For all other exported cases, no secondary or limited secondary transmission has been reported in countries with exported cases.

Serologic studies have shown a low prevalence of MERS-CoV antibodies in humans in Saudi Arabia. A broad antibody survey of 10,009 individuals representative of the general population of Saudi Arabia found seropositivity in 15 (0.15%), all but one of whom resided in five interior provinces (of 13 total provinces). In a separate survey included in the same report, 87 camel shepherds and 140 slaughterhouse workers were tested of whom 7 (3.1%) were seropositive.

Among 5,235 adult pilgrims from 22 countries who visited Mecca, Saudi Arabia, for Hajj in 2013, none had a positive MERS-CoV polymerase chain reaction (PCR) from the nasopharynx. 3,210 individuals were screened pre-Hajj and 2,025 were screened post-Hajj.

Case clusters in the United Kingdom, Tunisia, Italy and in healthcare facilities in Saudi Arabia, France, Iran and the Republic of Korea strongly suggest that human-to-human transmission occurs (Figure 3). The number of contacts infected by individuals with confirmed infections, however, appears to be limited. An exception to this was the outbreak in the Republic of Korea in May and June 2015 where many secondary and some tertiary cases occurred.

Figure 3

Epidemic Curve of 536 Laboratory-Confirmed MERS-CoV Patients by Case Type (Primary versus Secondary; as of May 8, 2014)

MERS-CoV: Middle East Respiratory Syndrome Coronavirus; WHO: World Health Organization. Reproduced with permission from: World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) summary and literature update – as of 9 May 2014.

Secondary cases have tended to be milder than primary cases and many secondary cases have been reported to be asymptomatic. Possible modes of spread include droplet and contact transmission.

More than half of all laboratory-confirmed secondary cases have been associated with healthcare settings. The majority of cases in the spring of 2014 in Saudi Arabia were acquired through human-to-human transmission in healthcare settings likely due, at least in part, to systemic weaknesses in infection control.

In a report describing a hospital outbreak in the Republic of Korea in May and June 2015, 37 infections were associated with the index case, who was hospitalized from May 15 to May 17. Twenty-five cases were secondary and 11 were tertiary. The overall median incubation period was six days, but it was four days for secondary cases and six days for tertiary cases. The Korean outbreak clearly demonstrated the importance of "super spreaders," several of whom were identified in an epidemiologic analysis and were responsible for a high proportion of cases. As an example, a single individual infected at least 70 other individuals between May 27 and May 29 while being treated in the emergency room of a single hospital in Seoul, the Republic of Korea.

Secondary transmission has also occurred in the household setting. Among 280 household contacts of 26 index individuals with MERS-CoV infection, 12 probable cases of secondary transmission were detected by rRT-PCR of a pharyngeal swab and/or serology. However, it is possible that some of the index cases and probable secondary cases may have acquired MERS-CoV from a common source, particularly since three of seven contacts tested positive for MERS-CoV by rRT-PCR only four days after illness onset in the index cases. Some secondary cases may also have been missed since only 108 of 280 contacts had samples available for serologic testing longer than 3 weeks after the onset of symptoms in the index case.

MERS-CoV is most easily found in lower respiratory tract samples (tracheal aspirates, sputum, or bronchoalveolar lavage fluid) of symptomatic individuals, and this shedding may persist for as long as two weeks. Prolonged shedding was also detected by rRT-PCR in an asymptomatic healthcare worker. The healthcare worker was initially tested following occupational exposure to MERS-CoV. Serial rRT-PCR testing revealed ongoing shedding for six weeks. These findings raised concerns that asymptomatic individuals could unknowingly transmit the infection to others.

In a study that evaluated the transmissibility and epidemic potential of MERS-CoV based upon 55 laboratory-confirmed cases detected by late June 2013, the reproduction number (R0; defined as the average number of infections caused by one infected individual in a fully susceptible population) was estimated to be between 0.60 and 0.69. The finding of an R0 less than 1 suggests that MERS-CoV does not yet have pandemic potential. Others have pointed out that the R0 might be higher in the absence of infection control measures.

Case Definitions

The following MERS-CoV infection case definitions have been proposed by the WHO:

Confirmed Case – An individual with laboratory confirmation of MERS-CoV infection irrespective of clinical signs and symptoms. Confirmatory laboratory testing requires a positive PCR on at least two specific genomic targets or a single positive target with sequencing on a second.

Probable Case - A patient under investigation (PUI) with absent or inconclusive laboratory results for MERS-CoV infection who is a close contact* of a laboratory-confirmed MERS-CoV case. Examples of laboratory results that may be considered inconclusive include a positive test on a single PCR target, a positive test with an assay that has limited performance data available or a negative test on an inadequate specimen.

A probable case is defined by the following criteria:

  • A febrile acute respiratory illness with clinical, radiographic or histopathologic evidence of pulmonary parenchymal disease (e.g., pneumonia or acute respiratory distress syndrome) and
  • A direct epidemiologic link with a confirmed MERS-CoV case and
  • Testing for MERS-CoV is unavailable, negative on a single inadequate specimen, or inconclusive

OR

  • A febrile acute respiratory illness with clinical, radiographic or histopathologic evidence of pulmonary parenchymal disease (e.g., pneumonia or acute respiratory distress syndrome) and
  • The individual resides in or traveled to the Middle East or countries where MERS-CoV is known to be circulating in dromedary camels or where human infections have recently occurred and
  • Testing for MERS-CoV is inconclusive

OR

  • An acute febrile respiratory illness of any severity and
  • Direct epidemiologic link with a confirmed MERS-CoV case and
  • Testing for MERS-CoV is inconclusive

 

  • * A close contact is defined as being within approximately 6 feet (2 meters) or within the room or care area for a prolonged period of time (e.g., healthcare personnel, household members) while not wearing recommended personal protective equipment (i.e., gowns, gloves, respirator, eye protection) OR having direct contact with infectious secretions (e.g., being coughed on) while not wearing recommended personal protective equipment (i.e., gowns, gloves, respirator, eye protection).

The WHO criteria for laboratory confirmation require detection of viral nucleic acid or acute and convalescent serology. The presence of nucleic acid can be confirmed by positive results from at least two sequence-specific real-time reverse-transcriptase polymerase chain reactions (rRT-PCRs) or a single sequence-specific rRT-PCR test and direct sequencing from a separate genomic target. A case confirmed by serology requires demonstration of seroconversion in two samples ideally collected at least 14 days apart using at least one screening assay (enzyme-linked immunoassay, immunofluorescence assay) and a neutralization assay.

Clinical Assessment

Incubation Period

In an outbreak of MERS-CoV infection in Saudi Arabia that resulted in laboratory-confirmed MERS-CoV in 23 individuals, the median incubation period was 5.2 days (95% confidence 1.9 - 14.7 days). In one secondary case that occurred in an individual in France who shared a room with an infected individual, the incubation period was estimated at 9 - 12 days. In an outbreak in the Republic of Korea, the median incubation period was 6.3 days (95th percentile 12.1 days).

Based on current data, the incubation period* for MERS is usually about 5 or 6 days, but can range from 2 - 14 days. In MERS-CoV confirmed cases, the median time from illness onset to hospitalization is approximately 4 days. In critically ill individuals, the median time from onset to intensive care unit (ICU) admission is approximately 5 days and median time from onset to death is approximately 12 days.

  • * Incubation period is defined as the time between when an individual is exposed to MERS-CoV and when they start to have symptoms

The median incubation period for secondary cases associated with limited human-to-human transmission is approximately 5 days (range 2 - 14 days).

The WHO and the CDC recommend that an evaluation for MERS-CoV be considered in individuals with a syndrome of MERS who returned from travel to the Arabian peninsula or neighboring countries within the past 14 days.

Comorbidities

Based on what researchers know so far, individuals with pre-existing medical conditions (also called comorbidities) may be more likely to become infected with MERS-CoV or have a severe case. The virus also appears to cause more severe disease in older individuals.

Most MERS-CoV cases have been reported in adults (98%) (median age approximately 50 years, male predominance), although children and adults of all ages have been infected (range 0 to 99 years, n=1,335)). Most hospitalized MERS-CoV infected individuals have had chronic comorbidities. Among confirmed MERS-CoV cases reported to date, the case fatality proportion is approximately 35%.

It is unclear whether individuals with specific conditions are disproportionately infected with MERS-CoV or MERS-CoV is more severe in these individuals. In a study of 47 individuals with MERS-CoV infection in Saudi Arabia, 45 (96%) had the following underlying comorbidities:

  • Diabetes mellitus (68%)
  • Hypertension (34%)
  • Chronic cardiac disease (28%)
  • Chronic kidney disease (49%)
  • One individual was receiving long-term immunosuppressive therapy with glucocorticoids

The high rate of comorbidities which were reported should be interpreted with caution, since diabetes mellitus was frequently observed in a study of more than 6,000 individuals presenting to an outpatient clinic in Riyadh, Saudi Arabia and because approximately half of the 47 individuals described were part of an outbreak in a hemodialysis unit where the rates of chronic kidney disease and hypertension would be expected to be high.

In a study of 12 critically ill individuals with MERS-CoV infection, each individual had at least one comorbid condition. The median number of comorbid conditions was 3 (range 1 to 6). In a case-control study that included 17 case individuals with MERS-CoV infection and 82 controls, case individuals were more likely than controls to be overweight, have diabetes mellitus and to have end-stage renal disease.

Other comorbidities include:

  • Cancer
  • Chronic lung disease
  • Weakened immune systems

Health History

Healthcare providers should evaluate individuals for MERS-CoV infection based on recommendations issued by the CDC for investigation of possible cases in the United States. These recommendations include those individuals who meet the following criteria for being a PUI:

Fever and pneumonia or ARDS (based on clinical or radiologic evidence) and either:

  • Epidemiologic Risks:
    • History of travel from countries in or near the Arabian Peninsula within 14 days before symptom onset or
    • Close contact with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula or
    • History of being in a healthcare facility (as a patient, worker or visitor) in the Republic of Korea within 14 days before symptom onset or
    • A member of a cluster of individuals with severe acute respiratory illness (e.g., fever and pneumonia requiring hospitalization) of unknown etiology in which MERS-CoV is being evaluated, in consultation with state and local health departments

OR

  • Fever and symptoms of respiratory illness (not necessarily pneumonia; e.g., cough, shortness of breath):
  • Epidemiologic Risks:A history of being in a healthcare facility (as a patient, worker or visitor) within 14 days before symptom onset in a country or territory in or near the Arabian Peninsula in which recent healthcare-associated cases of MERS-CoV have been identified

OR

  • Fever or symptoms of respiratory illness (not necessarily pneumonia; e.g. cough, shortness of breath):
  • Epidemiologic Risks: A history of being in close contact wit h a confirmed MERS-CoV case while the individual was ill.

Signs and Symptoms

A wide clinical spectrum of MERS-CoV infection ranges from no symptoms (asymtomatic) to mild upper respiratory symptoms rapidly progressing to pneumonitis, respiratory failure, septic shock and multi-organ failure resulting in death. Limited clinical data for MERS-CoV infected individuals are available. Most published clinical information to date is from critically ill individuals.

Asymptomatic and Mild Infections

Several individuals with asymptomatic infection have been identified among contacts of individuals with symptomatic infection. As an example, the Saudi Arabian Ministry of Health screened more than 3,000 close contacts of individuals using rRT-PCR testing of nasopharyngeal swabs and identified seven healthcare workers with MERS-CoV infection, two of whom were asymptomatic and five of whom had mild upper respiratory tract symptoms.

Many individuals who have been reported to be asymptomatic have in fact had signs and symptoms of illness. In a study of a healthcare facility-associated outbreak in Jeddah, Saudi Arabia, in the spring of 2014, there were 255 laboratory-confirmed cases of MERS-CoV infection. Of 64 individuals who were initially identified as being asymptomatic, 33 of the 64 individuals (52%) were available for a telephone survey. Of these 33 individuals, 79% reported at least one symptom during the month before testing and 70% reported more than one symptom. Unexpectedly, 36% of the individuals reported the presence of signs and symptoms as the reason for undergoing MERS-CoV testing, even though they had been identified as being asymptomatic.

There have been reports describing individuals with a mild respiratory illness not requiring hospitalization. In one report, an individual developed a dry cough on the 10th day of illness followed by dyspnea and hypoxia on the 11th day of illness. Prior to that, he had only nonspecific signs and symptoms which included malaise, myalgias and low-grade fevers.

A typical presentation of MERS-CoV infection includes:

  • Shortness of breath
  • Pneumonia (a common finding, but not always present)
  • Gastrointestinal symptoms, including diarrhea

Atypical presentations including mild respiratory illness without fever and diarrhea preceding the development of pneumonia have been reported.

Progression of MERS-CoV Infection

Upon hospital admission, common signs and symptoms of individuals who were laboratory-confirmed to have MERS-CoV infection may include:

  • Fever
  • Sore throat
  • Coryza
  • Non-productive cough
  • Sputum production
  • Dyspnea
  • Myalgia
  • Pneumonia (a common finding, but not always present)
  • Gastrointestinal symptoms including:
    • Anorexia
    • Abdominal pain
    • Nausea
    • Vomiting
    • Diarrhea

Individuals who progressed from requiring admission to being transferred to an ICU often had a history of a febrile upper respiratory tract illness with rapid progression to pneumonia within a week of illness onset. Severe illness can cause respiratory failure that requires mechanical ventilation and support in an ICU. Approximately 36% of reported individuals with MERS-CoV have died.

Individuals who progressed from requiring admission to being transferred to an ICU often had a history of a febrile upper respiratory tract illness with rapid progression to pneumonia within a week of illness onset. Severe illness can cause respiratory failure that requires mechanical ventilation and support in an ICU. Approximately 36% of reported individuals with MERS-CoV have died.

For many individuals with MERS-CoV infection more severe complications usually rapidly follow including:

Pulmonary Complications

  • Pneumonia
  • Acute Respiratory Failure
  • Acute Respiratory Distress Syndrome (ARDS)
  • Refractory hypoxemia

Extrapulmonary Complications

  • Acute kidney failure
  • Pericarditis
  • Disseminated intravascular coagulation (DIC)
  • Septic shock
  • Multi-organ failure

The following clinical findings were observed among 47 individuals with MERS-CoV infection in Saudi Arabia:

  • Fever (greater than 38°C) – 46 patients (98%)
  • Fever with chills or rigors – 41 patients (87%)
  • Cough – 39 patients (83%)
  • Shortness of breath – 34 patients (72%)
  • Hemoptysis – 8 patients (17%)
  • Sore throat – 10 patients (21%)
  • Myalgias – 15 patients (32%)
  • Diarrhea – 12 patients (26%)
  • Vomiting – 10 patients (21%)
  • Abdominal pain – 8 patients (17%)
  • Abnormal chest radiograph – 47 patients (100%)

Of these 47 individuals, 42 (89%) required ICU and 34 (72%) required mechanical ventilation. The median time from presentation for medical care to mechanical ventilation was 7 days (range 3 - 11 days) and to death was 14 days (range 5 - 36 days).

Children

There is only one published description of MERS-CoV infection in children. Of 11 infections, 9 were asymptomatic, all discovered during contact investigations of older individuals. Both symptomatic cases were in children with underlying conditions (cystic fibrosis and Downs’s syndrome).

Effect on Fetuses

One stillbirth at five months' gestation was reported in a woman with MERS-CoV infection. The woman developed vaginal bleeding and abdominal pain on the 7th day of illness with MERS-CoV. She spontaneously delivered a stillborn infant. In another MERS-CoV infection in pregnancy occurring near term, a woman in the United Arab Emirates gave birth to an apparently healthy baby but the mother died after delivery.

Clinical Findings in Animal Models

Several studies have shown that nonhuman primates develop MERS-CoV infection after inoculation with MERS-CoV and can therefore be used as animal models for studying MERS-CoV infection. In contrast, mice, ferrets and guinea pigs do not appear to be susceptible to MERS-CoV infection.

In one study, six rhesus macaques were inoculated with MERS-CoV through a combination of intratracheal, intranasal, oral and ocular routes. Within 24 hours, all animals developed anorexia, fever, tachypnea, cough, piloerection and hunched posture. Chest radiographs showed localized infiltrates and increased interstitial markings. After the animals were euthanized, postmortem examinations showed multifocal to coalescent lesions throughout the lungs. Histopathology demonstrated infiltrates of neutrophils and macrophages, compatible with acute interstitial pneumonia.

In another study by the same group, following inoculation with MERS-CoV, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, inflammatory changes on histology and cytokine and chemokine profiles peaked one day after infection and decreased rapidly over time. In nasal swabs and bronchoalveolar lavage (BAL) fluid specimens, viral loads were also highest on day 1 post infection and decreased rapidly. Two of three animals were still shedding virus from the respiratory tract on day 6 (the same day they were euthanized). MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring primarily in type I and II alveolar pneumocytes.

Laboratory and Diagnostic Tests

Real-Time Reverse-Transcriptase Polymerase Chain Reaction (rRT-PCR) Assay and Sequencing

Data from the cases sampled indicate that lower respiratory tract specimens e.g., sputum, tracheal aspirates, bronchoalveolar lavage (BAL) fluid are more sensitive for detection of MERS-CoV by rRT-PCR testing than those from the upper respiratory tract (combined nasopharyngeal and throat swab and nasopharyngeal aspirates). However, upper respiratory tract specimens are still useful for diagnosing MERS-CoV. For example, in a series of 47 individuals with MERS-CoV, the majority were diagnosed using nasopharyngeal swabs.

In a detailed analysis of an individual with multiple myeloma and MERS-CoV infection who succumbed after developing ARDS and septic shock, high concentrations of MERS-CoV were detected by rRT-PCR from respiratory specimens (BAL fluid or tracheobronchial secretions), peaking at 1.2 x106 copies/mL. MERS-CoV was also detected from oronasal secretions, stool and urine but at low concentrations. Only one of two oronasal specimens was positive by rRT-PCR (5,370 copies/mL). No virus was detected from the blood of this individual but it had been detected from the blood of another reported individual. The CDC performed rRT-PCR testing on serum samples.

Three rRT-PCR assays for routine detection of MERS-CoV have been developed:

Assay targeting a region upstream of the E protein gene (upE)

Assay targeting the open reading frame 1b (ORF 1b)

Assay targeting the open reading frame 1a (ORF 1a). In some cases, sequencing should be performed for confirmation.

An emergency use authorization was issued by the United States Food and Drug Administration in 2013 for the rRT-PCR assay developed by the CDC on clinical respiratory, blood and stool samples.

Preferred Tests and Specimen Types

Lower respiratory tract specimens should be the first priority for collection and real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) testing, since rRT-PCR testing of lower respiratory specimens appears to be more sensitive for detection of MERS-CoV than testing of upper respiratory tract specimens.

Given the potential severity of MERS-CoV infections, the risk for human-to-human transmission and the limited data about the sensitivity of each diagnostic test, the CDC recommends that:

  • Multiple specimens be collected from different sites and at different times after symptom onset to increase the likelihood of detecting MERS-CoV.
  • Ideally, lower respiratory tract, upper respiratory tract and serum samples should be obtained. Priority should be given to respiratory specimens (lower tract if obtainable and in all cases of severe disease; upper tract if disease is mild and lower tract specimens cannot be obtained).
  • A serum sample should also be obtained for serologic testing.
  • The number of days between specimen collection and symptom onset should be recorded.
  • Symptoms at the time of specimen collection should be recorded.
  • Proper infection prevention and control (IPCs) practices should be maintained when collecting specimens.
  • Approved collection methods and equipment should be used when collecting specimens.
  • Appropriate protocols should be followed when handling, storing and shipping specimens.

The following diagnostic approach has been adapted from guidelines issued by the CDC and the WHO:

  • If symptom onset for a PUI with respiratory symptoms was less than 14 days ago, a single serum specimen, a nasopharyngeal and oropharyngeal (NP/OP) specimen and lower respiratory specimen should be collected for CDC MERS rRT-PCR testing.
  • If symptom onset for a PUI with an ongoing respiratory tract infection, especially lower, was 14 or more days ago, a single serum specimen for serologic testing in addition to a lower respiratory specimen and an NP/OP specimen are recommended.

Respiratory Specimens

Lower respiratory tract specimens such as sputum, tracheal aspirate, endotracheal aspirate or BAL fluid should be obtained for rRT-PCR testing in all cases of severe disease and from milder cases when possible. Lower respiratory tract specimens should be the first priority for collection and rRT-PCR testing, since rRT-PCR testing of lower respiratory tract specimens appears to be more sensitive for detection of MERS-CoV than testing of upper respiratory tract specimens.  The MERS-CoV virus can be detected with higher viral load and longer duration in the lower respiratory tract compared to the upper respiratory tract and has been detected in feces, serum and urine. However, very limited data are available on the duration of respiratory and extrapulmonary MERS-CoV shedding.

  • Sputum Technique
    • Have the PUI rinse his/her mouth with water and then expectorate deep cough sputum directly into a sterile, leak-proof, screw-cap sputum collection cup or sterile dry container.
    • Refrigerate the specimen at 2 - 8°C up to 72 hours; if exceeding 72 hours, freeze at -70°C and ship on dry ice.
  • Tracheal aspirate, endotracheal aspirate, pleural fluid, BAL Technique
    • Collect 2 - 3 mL into a sterile, leak-proof, screw-cap sputum collection cup or sterile dry container.
    • Refrigerate specimen at 2 - 8°C up to 72 hours; if exceeding 72 hours, freeze at -70°C and ship on dry ice.
  • Upper respiratory tract specimens should be obtained for rRT-PCR testing and should be either a:
    • combined nasopharyngeal (NP) and oropharyngeal (OP) swab specimen
    • Use only two synthetic fiber swabs with plastic shafts and place the swabs immediately into sterile tubes containing 2 – 3 ml of viral transport media. NP/OP specimens can be combined, placing both swabs in the same tube.
    • Do not use calcium alginate swabs or swabs with wooden shafts, as they may contain substances that inactivate some viruses and inhibit rRT-PCR testing.
    • Techniques
      • NP swab: Insert a swab into the nostril parallel to the palate. Leave the swab in place for a few seconds to absorb secretions. Swab both nasopharyngeal areas.
      • OP swab (e.g., throat swab): Swab the posterior pharynx avoiding the tongue.
    • Refrigerate specimen at 2 - 8°C up to 72 hours; if exceeding 72 hours, freeze at -70°C and ship on dry ice.
  • Nasopharyngeal wash/aspirate or nasal aspirate
    • Collect 2 - 3 mL into a sterile, leak-proof, screw-cap sputum collection cup or sterile dry container.
    • Refrigerate specimen at 2 - 8°C up to 72 hours; if exceeding 72 hours, freeze at -70°C and ship on dry ice.
  • Obtaining upper respiratory tract specimens is especially important if the individual does not have signs or symptoms of lower respiratory tract disease or if the collection of lower respiratory tract specimens is not possible.

If initial testing of respiratory specimens is negative in an individual who is strongly suspected of having MERS-CoV infection, additional respiratory specimens should be obtained from multiple respiratory sites. Possible reasons for false-negative results include that the specimen was of poor quality, that it was collected late or very early in the illness, that it was not handled and shipped appropriately or that there were technical problems with the test.

In certain cases, the diagnosis should be confirmed by nucleic acid sequencing.

Repeat testing is helpful for confirming clearance of the virus. Respiratory specimens should be tested every two to four days until there are two consecutive negative results. If the discharge of the individual from an isolation ward requires negative rRT-PCR results, specimens can be obtained daily.

Laboratories with limited experience testing for MERS-CoV are encouraged to have their results confirmed by laboratories with greater experience (particularly negative specimens from individuals in whom MERS-CoV infection is thought to be likely).

Tests for Other Respiratory Pathogens

  • Co-infection with other respiratory viruses and a few cases of co-infection with community-acquired bacteria at admission have been reported. Nosocomial bacterial and fungal infections have been reported in mechanically-ventilated individuals.
  • Testing for MERS-CoV and other respiratory pathogens can be done simultaneously.
  • Testing for common respiratory pathogens by molecular or antigen detection methods (not by viral culture) is strongly recommended. Common respiratory pathogens include:
    • Influenza A, influenza B, respiratory syncytial virus, human metapneumovirus, human parainfluenza viruses, adenovirus, human rhinovirus and other respiratory viruses
    • Streptococcus pneumoniae, Chlamydia pneumophila, and other pathogens can also cause severe lower respiratory infections.

Clinical presentation, epidemiologic and surveillance information and season should be considered when selecting which pathogens to test for. A few MERS-CoV cases have had other respiratory pathogens detected, so identification of a respiratory pathogen prior to MERS-CoV testing should not preclude testing for MERS-CoV, especially if MERS is strongly suspected. If the laboratory does not have molecular or antigen testing capability for respiratory pathogens, the state laboratory should be contacted for assistance.

Serology

A serum sample (at least 0.2 ml of serum) should be obtained in the first 10 to 12 days after onset of illness for rRT-PCR testing and a second serum sample (also at least 0.2 ml of serum) should be collected at least 14 days after onset of illness for antibody detection. Serum samples are sent for rRT-PCR testing and for antibody testing.

Serum Specimens for rRT-PCR Testing

  • Serum for rRT-PCR testing is drawn for the detection of MERS-CoV itself and not the antibodies to the virus.
  • A single serum specimen should be collected optimally during the first 10 - 12 days after symptom onset.
  • Minimum serum volume needed: The minimum amount of serum required for MERS-CoV testing (either serologic or rRT-PCR) is 200 µL. If both MERS-CoV serology and rRT-PCR tests are planned, the minimum amount of serum required is 400 µL (200 µL for each test).
  • Children and adults: Collect 1 tube (5 - 10 mL) of whole blood in a serum separator tube.
  • Infant: A minimum of 1 mL of whole blood is needed for testing pediatric patients. If possible, collect 1 mL in a serum separator tube.
  • Serum separator tubes should be stored upright for at least 30 minutes, and then centrifuged at 1000 – 1300 relative centrifugal force (RCF) for 10 minutes before removing the serum and placing it in a separate sterile tube for shipping (such as a cryovial).
  • Refrigerate the serum specimen at 2 - 8°C and ship on ice-pack. Freezing and shipment of serum on dry ice is permissible.

Serum for Antibody Testing

  • Serologic testing on a single serum sample collected 14 or more days after symptom onset may be beneficial. Please be aware that the MERS-CoV serologic test is for research/surveillance purposes and not for diagnostic purposes. It is a tool developed in response to the MERS-CoV outbreak.
  • Several serology assays have been developed for the detection of MERS-CoV antibodies that would indicate an individual had been previously infected with the virus and had developed an immune response.
  • Serology for MERS-CoV antibodies includes three separate tests:
    • a screening test called an enzyme-linked immunosorbent assay (ELISA) followed   by
    • a confirmatory test called an indirect immunofluorescent assay (IFA) or microneutralization test
    • a slower, but more definitive confirmatory test called the neutralizing antibody assay.

According to the WHO, cases with a positive serologic test in the absence of rRT-PCR testing or sequencing are considered probable cases if they meet the other elements which comprise the case definition of a probable case.

Specimen Handling and Shipping

Specimens should reach the laboratory as soon as possible after collection. If there may be a delay of more than 72 hours in the laboratory receiving respiratory tract specimens, specimens should be frozen at - 70°C and shipped on dry ice. Repeated freezing and thawing of specimens should be avoided. Serum should be separated from whole blood and can be stored and shipped at 4°C or frozen and shipped on dry ice or liquid nitrogen. Avoid storage of respiratory and serum specimens in domestic frost-free freezers given the freezers wide temperature fluctuations. Each specimen container should be labeled with the individuals ID number, specimen type and the date the sample was collected.

For individuals in the United States, healthcare professionals seeking information about shipping or testing should contact the CDC Emergency Operations Center at 770-488-7100. Additional information can be found on the CDC's website.

Other Suggested Laboratory Tests

Among 47 cases of MERS-CoV infection in Saudi Arabia, laboratory abnormalities included:

  • Leukopenia (14%)
  • Lymphocytopenia (34%)
  • Lymphocytosis (11%)
  • Thrombocytopenia (36%)
  • Elevated aspartate aminotransferase (15%)
  • Elevated alanine aminotransferase (11%)
  • Elevated lactate dehydrogenase (49%)

Other reports have described:

  • Lymphocytopenia (with or without neutropenia)
  • Anemia and/or thrombocytopenia
  • Consumptive coagulopathy
  • Rising blood urea nitrogen (BUN)
  • Elevated serum creatinine (Cr)
  • Elevated lactate dehydrogenase (LDH)
  • Elevated liver enzymes (LFTs)
  • Disseminated intravascular coagulation (DIC)
  • Hemolysis

Imaging Findings

Chest Radiography

Among the 47 cases of MERS-CoV infection in Saudi Arabia, abnormalities on chest radiography were noted in all 47 cases. Abnormalities in imaging findings ranged from minimal to extensive, either unilateral or bilateral, including:

  • Increased bronchovascular markings
  • Airspace opacities
  • Patchy densities or opacities
  • Interstitial infiltrates
  • Patchy to confluent airspace consolidations
  • Nodular opacities
  • Reticular opacities
  • Reticulonodular shadowing
  • Pleural effusions
  • Total opacification of lung segments and lobes

Computed Tomography Scanning

In individuals with MERS-CoV who underwent computed tomography scanning, the most common findings were bilateral predominantly peripheral and basilar airspace changes with more extensive ground-glass opacities than consolidation.

Clinical Management and Treatment

No specific antiviral agents or vaccines for MERS-CoV infection are currently available. The WHO has issued recommendations for the management of severe respiratory infections suspected to be caused by MERS-CoV.

Treatment is supportive and based on the individuals’ clinical condition. Clinical management includes supportive management of complications and implementation of recommended infection prevention and control practices (IPCs). Individuals with MERS-CoV infection can seek healthcare to help relieve symptoms. For severe cases, current treatment includes care to support vital organ function.

Severe MERS-CoV infection can cause respiratory failure requiring mechanical ventilation and support in an ICU. In one series of 12 ICU patients, the median duration of mechanical ventilation was 16 days and median ICU length of stay was 30 days with 58% mortality at 90 days. Among these 12 critically ill individuals, 11 had extrapulmonary manifestations including shock (11 cases) and acute kidney injury (7 cases).

Clinical management of severe acute respiratory infection (SARI) in individuals with MERS-CoV is based on the WHO interim guidance protocols (2 July 2015):

Early Recognition of Individuals with SARI

  • Life-threatening manifestations of MERS-CoV infection include severe pneumonia, ARDS, sepsis and septic shock. Early recognition of these clinical syndromes allows for timely initiation of IPC’s, as well as, therapeutics.

Implementation of IPC’s (Table 2)

  • Apply STANDARD precautions routinely to all patients in all healthcare settings.
  • At triage, recognize patients with acute respiratory infection (ARI), give the patient a medical mask and place the patient in a separate area. When feasible, patients with ARI should use medical masks which will contribute to source control and diminish potential for environmental contamination.
  • Organize the space and process to permit spatial separation. Keep at least 1 - 2 meters between each patient with ARI and other individuals not wearing personal protective equipment (PPE).
  • Ensure that triage and waiting areas are adequately ventilated.
  • Encourage respiratory hygiene (i.e. covering the mouth and nose during coughing or sneezing with a tissue, sleeve or flexed elbow), followed by hand hygiene and immediate tissue disposal.
  • When caring for patients with ARI also implement DROPLET precautions. If the patient is suspected to have MERS-CoV, additionally apply CONTACT precautions.
  • For patients with suspected MERS-CoV infection that require hospitalization, place the patient in an adequately ventilated single room away from other patient care areas.
  • Do not place suspect patients in the same area or room area or room as those who are confirmed MERS-CoV cases.
  • When performing an aerosol generating procedure (i.e., aspiration or open suctioning of the respiratory tract, intubation, bronchoscopy, and cardiopulmonary resuscitation) also apply AIRBORNE precautions.
  • Though definitive evidence is lacking, non-invasive ventilation, high-flow nasal cannula, aerosolized nebulizer treatments, chest physiotherapy also have the potential to generate aerosols and facilitate transmission of respiratory viruses. When performing these treatments, also implement AIRBORNE precautions.
  • Advise visitors and family members about the risk of transmission. Instruct them on PPE use and hand hygiene. Evaluate them for symptoms of ARI before visit. Limit visitors to those essential for support. Advise that anyone who is at increased risk of severe disease does not care for the ill.
Table 2: How to Implement Infection Control Measures
When caring for ALL patients

Standard Precautions should be applied routinely in all healthcare settings for all patients. These include:

  • Hand hygiene
  • Use of PPE to avoid direct contact with patients’ blood, body fluids, secretions (including respiratory secretions) and non-intact skin
  • Prevention of needle-stick or sharps injury
  • Safe waste management
  • Cleaning and disinfection of equipment
  • Cleaning of the environment
When caring for patients with cough or other respiratory symptoms (ARI)

Droplet Precautions prevent large droplet transmission of respiratory viruses.

  • Use a medical mask if working within 1 - 2 meters of the patient.
  • Place patients in single rooms or group together (cohort) those with the same etiological diagnosis. If an etiological diagnosis is not possible, group patients with similar clinical diagnosis based on epidemiological risk factors, with a spatial separation of at least 1 meter.
  • When providing care in close contact with a patient with respiratory symptoms (e.g. coughing or sneezing), use eye protection (face-mask or goggles), because sprays of secretions may occur.
  • Limit patient movement within the institution and ensure that patients wear medical masks when outside their rooms.
When caring for patients with suspected MERS-CoV

Contact Precautions prevent direct or indirect transmission from contact with contaminated surfaces or equipment (i.e. contact with contaminated oxygen tubing/interfaces).

  • Use PPE (a medical mask, eye protection, gloves and gown) when entering room and remove it when leaving.
  • If possible, use either disposable or dedicated equipment (e.g. stethoscopes, blood pressure cuffs and thermometers).
  • If equipment needs to be shared among patients, clean and disinfect it between each patient use.
  • Ensure that healthcare workers refrain from touching their eyes, nose or mouth with potentially contaminated gloved or ungloved hands.
  • Avoid contaminating environmental surfaces that are not directly related to patient care (e.g. door handles and light switches).
  • Ensure adequate room ventilation.
  • Avoid movement of patients or transport.
  • Perform hand hygiene.
When performing an aerosol-generating procedure in patient with ARI

Airborne Precautions:

  • Ensure that healthcare workers performing aerosol-generating procedures use PPE, including gloves, long-sleeved gowns, eye protection and particulate respirators (N95 or equivalent or higher level of protection).
  • Whenever possible, use adequately ventilated single rooms when performing aerosol-generating procedures. This means negative pressure rooms with minimum of 6 to 12 air changes per hour or at least 60 liters/second/patient in facilities with natural ventilation.
  • Avoid unnecessary individuals in the room.

Collection of Specimens for Laboratory Diagnosis and Antimicrobial Therapy

  • Collect blood cultures for potential bacterial pathogens that can also cause pneumonia and sepsis, ideally before antimicrobial therapy. This must not significantly delay the start of antimicrobial therapy.
  • Collect upper respiratory tract specimens, preferably both nasopharyngeal and throat swabs, for viral testing.
  • Collect lower respiratory tract specimens, i.e., sputum (not saliva), endotracheal aspirate, and bronchoalveolar (BAL) lavage, for both bacterial and viral testing.
  • Collect serial respiratory specimens to examine early MERS-CoV replication kinetics and to confirm viral clearance. The frequency of specimen collection will depend on local circumstances, but in the initial two weeks, collect specimens at least every 2 to 4 days. Continue to collect until there are two consecutive negative results to confirm clearance of the virus.
  • Give empiric, effective antimicrobials to treat all likely pathogens, including community-acquired pneumonia or health care-associated pneumonia (if infection was acquired in health care setting) and sepsis. Give within one hour.

Early Supportive Therapy and Monitoring

  • Give supplemental oxygen therapy immediately to patients with SARI with signs of respiratory distress, hypoxemia (SpO2 < 90%) or shock.
  • Use conservative fluid management in patients with SARI when there is no evidence of shock.
  • Do not give high-dose systemic corticosteroids or other adjunctive therapies for viral pneumonitis or ARDS outside the context of clinical trials unless they are indicated for another reason.
  • Closely monitor patients with SARI for signs of clinical deterioration, such as rapidly progressive respiratory failure and sepsis syndrome and apply supportive care interventions immediately.
  • Understand the patients’ co-morbid condition(s) as this will impact the management of their critical illness and their prognosis. Communicate early with the patient and his/her family.

Management of Severe Respiratory Distress, Hypoxemia and ARDS

  • Recognize severe hypoxemic respiratory failure when a patient with severe respiratory distress is failing standard oxygen therapy.
  • Wherever available and with trained staff members, high-flow oxygen (up to 50 L/min) can be used in carefully selected cases of non-hypercapnic hypoxemic respiratory failure.
  • When high-flow oxygen is used, monitor the patient closely in an ICU. Because high-flow oxygen therapy has potential to generate aerosols, use with AIRBORNE precautions. If unsuccessful, do not delay endotracheal intubation.
  • Wherever available and when staff members are trained, institute mechanical ventilation early in patients with increased work of breathing or hypoxemia that persists despite standard high flow oxygen therapy.
  • In patients with SARI with non-hypercapneic hypoxemic respiratory failure, non-invasive ventilation (NIV) should be used only in selected cases and in centers with experience with NIV.
  • When NIV is used, it should be used as a short trial. Monitor the patient closely in an ICU. Because NIV has potential to generate aerosols, use with AIRBORNE precautions. If NIV is unsuccessful, do not delay endotracheal intubation. Some investigators have raised concerns regarding NIV’s potential to cause ventilator-induced lung injury by allowing the delivery of excessively large tidal volumes.
  • Wherever available and when staff members are trained, proceed with endotracheal intubation using a rapid sequence induction.
  • Initiate a lung-protective ventilation (LPV) strategy (low volume, low pressure) for patients with ARDS after intubation.
  • To reach LPV targets, allow permissive hypercapnea.
  • To reach target SpO2, use adequate PEEP (to keep alveoli aerated) for the degree of hypoxemia. PEEP-FiO2 tables are available on ventilator cards.
  • Consider deep-sedation targets if unable to control tidal volume.
  • Avoid disconnecting the patient from the ventilator. Disconnection results in loss of PEEP and lung collapse. Use in-line catheters for airway suctioning, clamp tube when disconnection is required and minimize transport.
  • In patients with moderate-severe ARDS, consider adjunctive therapeutics early, especially if failing to reach LPV targets.
  • Place the patient in the prone position. This improves oxygenation and survival with severe ARDS (PaO2/FiO2 < 150) when implemented early and for at least 16 consecutive hours a day. Care must be taken to turn the patient safely.
  • Administer neuromuscular blockade for the initial 48 hours. This improves survival in patients with severe ARDS (PaO2/FiO2 < 150) and increases time off the ventilator without causing significant weakness.
  • Use higher PEEP levels in patients with moderate and severe ARDS (PaO2/FiO2 < 200). This is associated with improved survival.
  • Use a conservative fluid management strategy for all patients with ARDS who are not in shock to shorten the duration of mechanical ventilation.

Management of Septic Shock

  • Recognize sepsis-induced shock when the patient develops hypotension (SBP < 90 mm Hg, MAP < 70 mm Hg, or a SBP decrease > 40 mm Hg compared to pre-morbid value, or less than two standard deviations below normal for age) that persists after adequate fluid challenge or has signs of tissue hypoperfusion (lactate > 4 mmol/L). Initiate early resuscitation.
  • Give early and rapid infusion of crystalloid intravenous fluids for septic shock to achieve a minimum of 30 ml/kg in adults over one hour, or 20 ml/kg over 15-20 minutes in children.
  • Overly aggressive fluid resuscitation may lead to respiratory impairment. If there is no response to fluid loading and signs of volume overload appear (i.e. jugular venous distension, crackles on auscultation, pulmonary edema on chest X-ray or hepatomegaly in children) then reduce or discontinue fluid administration. This is particularly important in resource-limited settings where mechanical ventilation is not available.
  • Do not give hypotonic or starch-based solutions for resuscitation. Starches have been associated with an increased incidence of renal dysfunction and failure.
  • Do not use fluid balance as a guide to administer or withhold further volume loading.
  • Administer vasopressors when shock persists despite fluid resuscitation. This is to maintain adequate perfusion pressure. The initial perfusion target is MAP > 65 mmHg or SBP > 90 - 100 mm Hg in adults and age appropriate targets in young children.
  • In resource-limited settings, if central venous catheters are not available, vasopressors can be given carefully through a peripheral IV placed in a large vein but closely monitor for signs of extravasation and necrosis. If extravasation occurs, stop infusion.
  • If signs of poor perfusion and cardiac dysfunction persist despite achieving MAP target with fluids and vasopressors, consider use of an inotrope, such as dobutamine.
  • Consider administration of intravenous hydrocortisone (up to 200 mg/day, 1mg/kg 6 hourly for children) or prednisolone (up to 75 mg/day) to patients with persistent shock who require escalating doses of vasopressors. Taper when shock resolves.
Table 3: Prevention of Complications
Anticipated OutcomeInterventions

Reduce days of invasive mechanical ventilation (IMV)

Weaning protocols that include daily assessment for readiness to breathe spontaneously.

Sedation protocols to titrate administration of sedation to a target level, with or without daily interruption of continuous sedative infusions
Reduce incidence of ventilator-associated pneumonia

Oral intubation is preferable to nasal intubation in adolescents and adults.

Perform regular antiseptic oral care.

Keep patient in semi-recumbent position.

Use a closed suctioning system; periodically drain and discard condensate in tubing.

Use a new ventilator circuit for each patient. Once the patient is ventilated, change circuit if it is soiled or damaged but not routinely.

Change heat moisture exchanger when it malfunctions, when soiled or every 5 - 7 days.

Reduce days of IMV.

Reduce incidence of venous thromboembolism

Use pharmacological prophylaxis (for example, heparin 5000 units subcutaneously twice daily or a low molecular-weight heparin) in adolescents and adults without contraindications. For those with contraindications, use mechanical prophylactic device such as intermittent pneumatic compression devices.

Reduce incidence of catheter-related bloodstream infection

Use a simple checklist during insertion as reminder of each step needed for sterile insertion and daily reminder to remove catheter if no longer needed.

Reduce incidence of pressure ulcersTurn patient every two hours.
Reduce incidence of stress ulcers and gastric bleedingGive early enteral nutrition (within 24 - 48 hours of admission), administer histamine-2 receptor blockers or proton-pump inhibitors.
Reduce incidence of ICU-related weakness

Early mobility.

Experimental Virus-Specific Therapeutics

  • At this time, there is no conclusive evidence from rigorous clinical trials in humans to recommend any virus-specific treatments for patients with suspected or confirmed MERS-CoV infection.
  • Treatment with investigational therapeutic agents should use standard research treatment protocols, employ systematic clinical and virologic data collection and occur in the context of controlled research trials and with local ethics review and approval.

Special Considerations for Pregnant Women

  • Pregnant women with MERS-CoV infection should be treated with supportive therapies as described above taking into account the physiologic adaptations of pregnancy.
  • Experimental, virus-specific treatments should be guided by individual risk-benefit analysis based on potential benefit for mother and safety to fetus, with consultation of obstetric specialist and ethics committee.
  • Emergency delivery/pregnancy termination decisions are challenging and based on many factors: gestational age, maternal condition, and fetal stability. Consultations with obstetric, pediatric and intensive care specialists are essential.

In cell culture and animal experiments, combination therapy with interferon (IFN)-alpha-2b and ribavirin appears promising. In a study in which MERS-CoV was grown in two different cell lines, high concentrations of IFN-alpha-2b or ribavirin were required to inhibit viral replication. However, when used in combination at lower concentrations, IFN-alpha-2b and ribavirin resulted in a comparable reduction in viral replication as high concentrations of either agent alone.

In a study of rhesus macaques, two groups of three monkeys were inoculated with MERS-CoV through a combination of intratracheal, intranasal, oral and ocular routes. One group was treated with subcutaneous IFN-alpha-2b plus intramuscular ribavirin beginning eight hours after inoculation and the other group was not treated. In contrast with untreated macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Treated animals had lower concentrations of serum and lung proinflammatory markers, fewer viral genome copies and fewer severe histopathologic changes in the lungs.

In a retrospective cohort study in individuals with severe MERS-CoV infection, combination therapy with ribavirin and IFN-alpha-2a, started a median of three days after diagnosis (20 patients), was associated with significantly improved survival at 14 days compared with 24 patients who received only supportive care (70% versus 29% survival), but not at 28 days (30% versus 17% survival, a nonsignificant difference). There were greater declines in hemoglobin in the ribavirin-interferon group than in the controls (4.32 versus 2.14 g/L). In other retrospective studies, combination therapy with ribavirin plus IFN-alpha-2a, IFN-alpha-2b or IFN-beta-1a has not been associated with a mortality benefit. It is difficult to interpret the results of these retrospective studies and further evaluation in randomized trials is needed before treatment recommendations can be made.

Glucocorticoids have been administered sporadically to MERS-CoV infected patients with no clear criteria for use and no clear conclusions regarding their effect. Glucocorticoids were extensively prescribed for patients with severe acute respiratory syndrome (SARS) but review of this experience suggests overall harm rather than benefit. Their use is not recommended for MERS-CoV infections.

Other experimental therapies being investigated include convalescent plasma, monoclonal antibodies, an inhibitor of the main viral protease, and entry/fusion inhibitors targeting the MERS-CoV spike protein.

A MERS-CoV neutralizing monoclonal antibody has been isolated from the memory B cells of an infected individual. The antibody, LCA60, binds to a novel site on the spike protein and neutralizes infection with MERS-CoV by interfering with the binding to the cellular receptor CD26. LCA60 protected mice transduced with adenovirus expressing human CD26 and infected with MERS-CoV in both prophylactic and postexposure settings. Monoclonal antibodies are being investigated for both prophylaxis and treatment of MERS-CoV. None are licensed for use.

Although the immunosuppressive agent mycophenolate mofetil has in vitro activity against MERS-CoV, in a study of severe infection in common marmosets, it was not effective.

Infection Prevention and Control Practices

The CDC routinely advises that all individuals help to protect themselves from respiratory illnesses by taking everyday preventive actions. These include:

  • Washing hands often with soap and water for 20 seconds and helping young children to do the same. If soap and water are not available, an alcohol-based hand sanitizer can be used.
  • The nose and mouth should be covered with a tissue upon sneezing or coughing. The tissue should then be thrown in the trash.
  • The eyes, nose and mouth should not be touched with unwashed hands.
  • Personal contact, such as kissing, or sharing cups or eating utensils, with ill individuals should be avoided.
  • All frequently touched surfaces or objects should be cleaned and disinfected frequently.

Individuals who may be at increased risk for MERS-CoV include:

  • Recent travelers from the Arabian Peninsula
  • Close contacts of an ill traveler from the Arabian Peninsula
  • Individuals recently in a healthcare facility in the Republic of Korea
  • Close contacts of a confirmed case of MERS
  • HCP not using recommended IPCs
  • Individuals with exposure to camels

Infection Control in Healthcare Settings

Transmission of the virus has occurred in healthcare settings in several countries, including from patients to healthcare providers and between patients in a healthcare setting before MERS-CoV was diagnosed. It is not always possible to identify individuals with MERS-CoV early or without testing because symptoms and other clinical features may be non-specific.

IPC’s are critical to prevent the possible spread of MERS-CoV in healthcare facilities. Facilities that provide care for individuals suspected or confirmed to be infected with MERS-CoV should take appropriate measures to decrease the risk of transmission of the virus from an infected individual to other patients, healthcare workers or visitors. Healthcare workers should be educated and trained in IPC’s should refresh these skills regularly.

The WHO and the CDC have issued recommendations for IPC’s of MERS-CoV infections in healthcare settings. An increased level of infection control precautions is recommended when caring for individuals with probable or confirmed MERS-CoV infection compared with that used for individuals with community-acquired coronaviruses or other community-acquired respiratory viruses.

The WHO recommends that standard and droplet precautions be used when caring for individuals with ARI’s. Contact precautions and eye protection should be added when caring for probable or confirmed cases of MERS-CoV infection. Airborne precautions should be used when performing aerosol-generating procedures.

The CDC recommends the use of standard, contact and airborne precautions for the management of hospitalized individuals with known or suspected MERS-CoV infection. These interim recommendations were informed by evidence-based IPCs the CDC published previously, including Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings, which includes recommendations for the related SARS-CoV, review of current evidence on MERS-CoV infection and the following considerations:

  • Current lack of a safe and effective vaccine and chemoprophylaxis
  • A possible high rate of morbidity and mortality among infected individuals
  • Incompletely defined modes of transmission of MERS-CoV

Preventing transmission of respiratory pathogens including MERS-CoV in hospital settings requires the application of infection control procedures and protocols including environmental and engineering controls, administrative controls, safer work practices and PPE.

Measures that enhance early detection and prompt triage and isolation of PUIs being evaluated for MERS-CoV are critical to ensuring effective implementation of infection control measures. Successful implementation of many, if not all, of these strategies is dependent on the presence of clear administrative policies and organizational leadership that promote and facilitate adherence to these recommendations among the various healthcare professionals within the healthcare setting, including patients, visitors and HCP.

Though these recommendations focus on the hospital setting (a setting where MERS-CoV transmission has been reported from some international locations), the recommendations for PPE, source control (i.e., placing a facemask on potentially infected individuals when outside of an airborne infection isolation room) and environmental infection control measures are applicable to any healthcare setting.

IPC recommendations for hospitalized patients with MERS-CoV include:

  • Minimize Chance for Exposures
    • Ensure facility policies and practices are in place to minimize exposures to respiratory pathogens including MERS-CoV. Measures should be implemented before patient arrival, upon arrival and throughout the duration of the affected patient’s presence in the healthcare setting.
  • Before Arrival
    • When scheduling appointments, instruct patients and persons accompanying them to call ahead or inform the HCP upon arrival if they have symptoms of any respiratory infection (e.g., cough, runny nose, fever) and to take appropriate preventive actions (e.g., wear a facemask upon entry to contain cough, follow triage procedures).
  • Upon Arrival and During the Visit
    • Take steps to ensure all patients with symptoms of a respiratory infection adhere to respiratory hygiene and cough etiquette, hand hygiene and triage procedures throughout the duration of the visit. Consider posting visual alerts (e.g., signs, posters) at the entrance and in strategic places (e.g., waiting areas, elevators, cafeterias) to provide patients and HCP with instructions (in appropriate languages) about hand hygiene, respiratory hygiene and cough etiquette. Instructions should include how to use facemasks or tissues to cover nose and mouth when coughing or sneezing, to dispose of tissues and contaminated items in waste receptacles and how and when to perform hand hygiene.
    • Provide space and encourage patients with symptoms of respiratory infections to sit as far away from others as possible. If available, facilities may wish to place these patients in a separate area while waiting for care.
    • Ensure rapid triage and isolation of PUIs who might have MERS-CoV infection
      • Identify patients at risk for having MERS-CoV infection before or immediately upon arrival to the hospital.
        • Implement triage procedures to detect PUIs at risk for having MERS-CoV infections during or before triage or registration (e.g., at the time of check-in) and ensure that all patients are asked about the presence of symptoms of a respiratory infection and history of travel to areas experiencing transmission of MERS-CoV or contact with possible MERS-CoV individuals.
        • Immediately isolate those identified as at risk for having MERS-CoV infection.
          • Implement Respiratory Hygiene and Cough Etiquette (i.e., placing a facemask over the PUIs nose and mouth) and isolate those at risk for MERS-CoV infection in an Airborne Infection Isolation Room (AIIR).
      • Provide supplies to perform hand hygiene to all patients upon arrival to the facility (e.g., at entrances of facility, waiting rooms, at patient check-in) and throughout the entire duration of the visit to the healthcare setting.
  • Ensure Adherence to Standard, Contact and Airborne Precautions
    • Standard precautions assume that every individual is potentially infected or colonized with a pathogen that could be transmitted in the healthcare setting. Elements of standard precautions that apply to patients with respiratory infections, including those caused by MERS-CoV, are summarized below. Attention should focus on training and proper putting on, removal of and disposal of any PPE. All HCP who enter the room of a patient with suspected or confirmed MERS-CoV should adhere to Standard, Contact and Airborne precautions, including the following:
    • Hand Hygiene should be performed:
      • Before and after all patient contact
      • After contact with potentially infectious material
      • Before putting on and upon removal of PPE including gloves
      • Hand hygiene in healthcare settings can be performed by washing with soap and water or using alcohol-based hand rubs. If hands are visibly soiled, soap and water should be used, not alcohol-based hand rubs.
      • Healthcare facilities should ensure that facilities and supplies for performing hand hygiene are readily available to all personnel.
  • Personal Protective Equipment (PPE)
    • Employers should select appropriate PPE and provide it to workers in accordance with OSHA’s PPE standards.
    • HCP must receive training on and demonstrate an understanding of:
      • When to use PPE
      • What PPE is necessary
      • How to properly put on, use and take off PPE
      • How to properly dispose of or disinfect and maintain PPE
      • The limitations of PPE
  • Any reusable PPE must be properly cleaned, decontaminated and maintained after and between uses.
  • Gloves
    • Put on clean, non-sterile gloves upon entry into the patient room or care area. Change gloves if they become torn or heavily contaminated.
    • Remove and discard gloves immediately upon leaving the patient room or care area.
  • Gowns
    • Put on a clean disposable gown upon entry into the patient room or area. Change the gown if it becomes soiled. Remove and discard the gown immediately upon leaving the patient room or care area.
  • Respiratory Protection
    • Use respiratory protection (i.e., a respirator) that is at least as protective as a fit-tested NIOSH-certified disposable N95 filtering facepiece respirator upon entry to the patient room or care area.
    • The respirator should be the last part of the PPE ensemble to be removed. If reusable respirators are used, they must be cleaned and disinfected according to manufacturer’s reprocessing instructions prior to re-use. If disposable respirators are used, they should be removed and discarded after leaving the patient room or care area and closing the door.
    • Respirator use must be in the context of a complete respiratory protection program in accordance with Occupational Safety and Health Administration (OSHA) Respiratory Protection standard (29 CFR 1910.134). Staff should be medically cleared and fit-tested if using respirators with tight-fitting facepieces (e.g., a NIOSH-certified disposable N95) and trained in the proper use of respirators, safe removal and disposal, and medical contraindications to respirator use.
  • Eye Protection
    • Put on eye protection (e.g., a disposable face shield) upon entry to the patient room or care area. Remove and discard eye protection immediately upon leaving the patient room or care area. Reusable eye protection (e.g., goggles) must be cleaned and disinfected according to manufacturer’s reprocessing instructions prior to re-use.
  • Using More than one Kind of PPE
    • Different types of PPE are used together to prevent multiple routes of transmission.
    • The following sequence is a general approach to putting on this PPE combination for respiratory pathogens: first gown; then respirator; then goggles or face shield; then gloves.
    • The following sequence is a general approach to removing PPE for respiratory pathogens: first gloves; then goggles or face shield; then gown; then respirator.
    • Except for the respirator, remove PPE at doorway or in anteroom. Remove respirator after leaving patient room and closing door.
    • Careful attention should be given to prevent contamination of clothing and skin during the process of removing PPE.
    • Perform hand hygiene as described above immediately before putting on and after removing all PPE.
  • Patient Placement
    • Place a patient who might be infected with MERS-CoV in an Airborne Infection Isolation Room (AIIR) that has been constructed and maintained in accordance with current guidelines.
      • AIIRs are single patient rooms at negative pressure relative to the surrounding areas, and with a minimum of 6 air changes per hour (12 air changes per hour are recommended for new construction or renovation). Air from these rooms should be exhausted directly to the outside or be filtered through a high-efficiency particulate air (HEPA) filter before recirculation. Room doors should be kept closed except when entering or leaving the room, and entry and exit should be minimized. Facilities should monitor and document the proper negative-pressure function of these rooms.
      • If an AIIR is not available, the patient should be transferred as soon as possible to a facility where an AIIR is available. Pending transfer, place a facemask on the patient and isolate him/her in an examination room with the door closed. The patient should not be placed in any room where room exhaust is recirculated without high-efficiency particulate air (HEPA) filtration.
  • Once in an AIIR, the patient’s facemask may be removed. The facemask should remain on if the patient is not in an AIIR. Limit transport and movement of the patient outside of the AIIR to medically-essential purposes. When outside of the AIIR, patients should wear a facemask to contain secretions.
  • Only essential personnel should enter the AIIR. Implement staffing policies to minimize the number of HCP who enter the room.
    • Facilities should consider caring for these patients with dedicated HCP to minimize risk of transmission and exposure to other patients and other HCP.
  • Facilities should keep a log of all individuals who care for or enter the rooms or care area of these patients.
  • Once the patient vacates a room, unprotected individuals, including HCP, should not be allowed in that room until sufficient time has elapsed for enough air changes to remove potentially infectious particles. In addition, the room should undergo appropriate cleaning and surface disinfection before unprotected individuals are allowed to reenter it.

Use Caution When Performing Aerosol-Generating Procedures

  • Some procedures performed on MERS-CoV patients may be more likely to generate higher concentrations of infectious respiratory aerosols than coughing, sneezing, talking or breathing. These procedures potentially put HCP and others at an increased risk for MERS-CoV exposure. Although not quantified, procedures that might pose such a risk include: cough-generating procedures, bronchoscopy, sputum induction, intubation and extubation cardiopulmonary resuscitation and open suctioning of airways.
  • Ideally, a combination of measures should be used to reduce exposures from these aerosol-generating procedures when performed on patients with suspected or confirmed MERS-CoV. Precautions for aerosol-generating procedures include:
    • Only performing these procedures if they are medically necessary and cannot be postponed.
    • Limiting the number of HCP present during the procedure to only those essential for patient care and support.
    • Conducting the procedures in an AIIR when feasible. Such rooms are designed to reduce the concentration of infectious aerosols and prevent their escape into adjacent areas using controlled air exchanges and directional airflow.
    • HCP should wear gloves, a gown, and either a face shield that fully covers the front and sides of the face or goggles and respiratory protection at least as protective as an N95 filtering facepiece respirator during aerosol-generating procedures.
    • Unprotected HCP should not be allowed in a room where an aerosol-generating procedure has been conducted until sufficient time has elapsed to remove potentially infectious particles.
    • Conduct environmental surface cleaning following procedures described in the section on environmental infection control below.

Duration of Infection Control Precautions

  • At this time, information is lacking to definitively determine a recommended duration for keeping patients on isolation precautions.
  • Duration of precautions should be determined on a case-by-case basis, in conjunction with local, state and federal health authorities.
  • Factors that should be considered include: presence of symptoms related to MERS-CoV, date symptoms resolved, other conditions that would require specific precautions (e.g., tuberculosis, Clostridium difficile) and available laboratory information.

Manage Visitor Access and Movement Within the Facility

  • Establish procedures for monitoring, managing and training visitors.
  • All visitors should follow respiratory hygiene and cough etiquette precautions while in the common areas of the facility.
  • Restrict visitors from entering the MERS-CoV patient’s room. Facilities can consider exceptions based on end-of-life situations or when a visitor is essential for the patient’s emotional well-being and care.
  • Visitors who have been in contact with the patient before and during hospitalization are a possible source of MERS-CoV for other patients, visitors and staff.
  • Visitors to MERS-CoV patients should be scheduled and controlled to allow for:
    • Screening visitors for symptoms of acute respiratory illness before entering the hospital.
    • Facilities should evaluate risk to the health of the visitor (e.g., visitor might have underlying illness putting them at higher risk for MERS-CoV) and ability to comply with precautions.
    • Facilities should provide instruction, before visitors enter patients’ rooms, on hand hygiene, limiting surfaces touched and use of PPE according to current facility policy while in the patient's room.
    • Facilities should maintain a record (e.g., log book) of all visitors who enter patient rooms.
    • Visitors should not be present during aerosol-generating procedures.
    • Visitors should be instructed to limit their movement within the facility.
    • Exposed visitors (e.g., contact with symptomatic MERS-CoV patient prior to admission) should be advised to report any signs and symptoms of acute illness to their healthcare provider for a period of at least 14 days after the last known exposure to the sick patient.

Implement Engineering Controls

  • Consider designing and installing engineering controls to reduce or eliminate exposures by shielding HCP and other patients from infected individuals. Examples of engineering controls include physical barriers or partitions to guide patients through triage areas, curtains between patients in shared areas,  closed suctioning systems for airway suctioning for intubated patients, as well as, appropriate air-handling systems (with appropriate directionality, filtration, exchange rate, etc.) that are installed and properly maintained.

Monitor and Manage Ill and Exposed HCP

  • HCP who care for patients with MERS-CoV should be monitored. They should immediately report any signs (e.g., fever) or symptoms (e.g., cough, shortness of breath) of acute illness to their supervisor or a facility designated person (e.g., occupational health services) for a period of 14 days after the last known contact with a MERS-CoV patient, regardless of their use of PPE.
  • HCP who develop any respiratory symptoms after an unprotected exposure (i.e., not wearing recommended PPE at the time of contact) to a patient with MERS-CoV should not report for work or should immediately stop working. These HCP should notify their supervisor, implement respiratory hygiene and cough etiquette, seek prompt medical evaluation and comply with work exclusion until they are no longer deemed infectious to others.
  • Asymptomatic HCP who have had an unprotected exposure (i.e., not wearing recommended PPE at the time of contact) to a patient with MERS-CoV, should be excluded from work for 14 days to monitor for signs and symptoms of respiratory illness and fever.
    • If necessary to ensure adequate staffing of the facility, the asymptomatic HCP could be considered for continuing patient care duties after discussion with local, state and federal public health authorities.
  • Facilities and organizations providing healthcare should:
    • Implement sick leave policies for HCP, including contract staff and part-time personnel, that are non-punitive, flexible and consistent with public health guidance (e.g., policies should ensure ill HCP who may have MERS-CoV infection stay home, unless hospital admission for isolation and treatment is recommended).
    • Ensure that all HCP are aware of the sick leave policies.
  • Provide employee health services that:
    • Ensure that HCP have ready access, including via telephone, to medical consultation and, if needed, prompt treatment.

Train and Educate Healthcare Personnel

  • Provide all HCP with job or task-specific education and training on preventing transmission of infectious agents, including refresher training.
  • HCP must be medically cleared, trained and fit tested for respiratory protection device use (e.g., N95 filtering facepiece respirators), or medically cleared and trained in the use of an alternative respiratory protection device (e.g., Powered Air-Purifying Respirator, PAPR) whenever respirators are required. OSHA has a number of respiratory training videos.
  • Ensure that HCP are educated, trained and have practiced the appropriate use of PPE prior to caring for a patient, including attention to correct use of PPE and prevention of contamination of clothing, skin and environment during the process of removing such equipment.

Implement Environmental Infection Control

  • Ensure that cleaning and disinfection procedures are followed consistently and correctly.
  • Standard cleaning and disinfection procedures (e.g., using cleaners and water to pre-clean surfaces prior to applying an EPA-registered disinfectant to frequently touched surfaces or objects for appropriate contact times as indicated on the product’s label) are appropriate for MERS-CoV in healthcare settings, including those patient care areas in which aerosol-generating procedures are performed. If there are no available EPA-registered products that have a label claim for MERS-CoV, products with label claims against human coronaviruses should be used according to label instructions. Management of laundry, food service utensils and medical waste should also be performed in accordance with routine procedures.

Establish Reporting within Hospitals and to Public Health Authorities

  • Implement mechanisms and policies that promptly alert key facility staff including infection control, healthcare epidemiology, hospital leadership, occupational health, clinical laboratory and frontline staff about suspected or known MERS-CoV patients.
  • Communicate and collaborate with public health authorities.
    • Promptly notify public health authorities of suspected or known patients with MERS-CoV.
    • Facilities should designate specific persons within the healthcare facility who are responsible for communication with public health officials and dissemination of information to HCP.

Interim Home Care and Isolation or Quarantine of Individuals Not Requiring Hospitalization for MERS-CoV

The CDC recommends that ill individuals who are being evaluated for MERS-CoV infection and do not require hospitalization may be cared for and isolated in their home. HCP should contact their state or local health department to determine whether home isolation or additional measures are indicated because recommendations might be modified as more data becomes available. Isolation is defined as the separation or restriction of activities of an ill individual with a contagious disease from those who are well. Additional information on home care and isolation guidance is available on the CDC's website.

This interim guidance is for staff at local and state health departments, IPC professionals, healthcare providers and healthcare workers who are coordinating the home care and isolation or quarantine of individuals who are confirmed to have or being evaluated for MERS-CoV infection. The interim guidance is based on what is currently known about viral respiratory infections and MERS-CoV.

Individuals who are confirmed to have or being evaluated for MERS-CoV infection and do not require hospitalization for medical reasons may be cared for and isolated in a residential setting after a healthcare professional determines that the setting is suitable. Providers should contact their state or local health department to discuss home isolation, home quarantine or other measures for close contacts, especially for individuals who test positive for MERS-CoV and to discuss criteria for discontinuing any such measures.

Assess the Suitability of the Residential Setting for Home Care

  • In consultation with state or local health department staff, a healthcare professional should:
    • Assess whether the residential setting is suitable and appropriate for home care
    • Assess whether the patient is capable of adhering to precautions that will be recommended as part of home care or isolation (respiratory hygiene, hand hygiene, etc.)
    • Contact their local or state health department to notify them that the residential setting has been determined to be suitable for home care and that hospital discharge is planned.

Provide Guidance for Precautions to Implement during Home Care

  • A healthcare professional should:
    • Provide CDC’s interim guidance for Preventing MERS-CoV from Spreading to Others in Homes and Communities (http://www.cdc.gov/coronavirus/mers/hcp/home-care-patient.html) to the individual confirmed to have or is being evaluated for MERS-CoV infection and to the caregiver and household members.
    • Contact their state or local health department to discuss criteria for discontinuing any such measures.

Preventing MERS-CoV from Spreading to Others in Homes and Communities

The following interim guidance from the CDC may help prevent MERS-CoV from spreading among individuals in homes and in communities. The interim guidance is based on what is currently known about other viral respiratory infections and MERS-CoV. The CDC will update this interim guidance as additional information becomes available.

This interim guidance is for:

  • Individuals who can receive care at home and do not need to be hospitalized for medical reasons.
  • Individuals being evaluated by a healthcare provider for MERS-CoV infection.
  • Caregivers and household members of an individual confirmed to have or are being evaluated for MERS-CoV infection.
  • Other people who have had close contact with an individual confirmed to have or are being evaluated for MERS-CoV infection.

Prevention Steps for Individuals Confirmed to Have or are Being Evaluated for MERS-CoV Infection

If an individual is confirmed to have or is being evaluated for MERS-CoV infection, they should follow the prevention steps below until a healthcare provider or local or state health department says they can return to normal activities. The individual should be instructed to:

  • Stay home
    • Restrict activities outside the home except for getting medical care.
    • Not go to work, school or public areas and do not use public transportation or taxis.
  • Separate themselves from other people in the home. As much as possible, they should:
    • Stay in a different room from other people in the home.
    • Use a separate bathroom, if available.
  • Call ahead before visiting their healthcare provider.
  • Wear a facemask.
    • A facemask should be worn when the individual is in the same room with other people and when visiting a healthcare provider.
    • If the individual cannot wear a facemask, other individuals in the same household or others who come in contact with the individual should wear one while they are in the same room.
  • Cover their nose and mouth when they sneeze or cough.
    • The mouth and nose should be covered with a tissue when the individual coughs or sneezes.
    • If not possible, the individual can cough or sneeze into their sleeve.
    • Used tissues should be thrown in a lined trash can.
    • The individual should immediately wash their hands with soap and water.
  • Wash hands.
    • The individual should be instructed to wash their hands often and thoroughly with soap and water.
    • An alcohol-based hand sanitizer can be used if soap and water are not available and if their hands are not visibly dirty.
    • Their eyes, nose and mouth should not be touched with unwashed hands.
  • Avoid sharing household items.
    • The individual should not share dishes, drinking glasses, cups, eating utensils, towels, bedding or other items with other individuals in the home.
    • These items should be washed thoroughly with soap and water after use.
  • Symptoms should be monitored.
    • Prompt medical attention should be sought if the illness worsens (e.g., difficulty breathing).
    • Before a medical appointment, telephone the healthcare providers office and inform them that you have or are being evaluated for MERS-CoV infection. This will help the healthcare provider’s office take steps to implement ICPs.

Prevention steps for caregivers and household members of an individual confirmed to have or are being evaluated for MERS-CoV infection should include:

  • Understanding and assisting the individual to follow the healthcare provider's instructions for medication and care. They should also be able to help the individual with basic needs in the home and provide support for getting groceries, prescriptions and other personal needs.
  • Allowing only people in the home who are essential to providing care for the individual.
    • Other household members should stay in another home or place of residence. If this is not possible, they should stay in another room or be separated from the individual as much as possible. A separate bathroom should be used, if available.
    • Visitors should be restricted who do not have an essential need to be in the home.
    • Elderly people and those who have compromised immune systems or certain health conditions should be kept away from the individual. This also includes people with chronic heart, lung or kidney conditions and diabetes.
  • Shared spaces in the home should have good air flow, such as by an air conditioner or an opened window, weather permitting.
  • Hands should be washed often and thoroughly with soap and water.  An alcohol-based hand sanitizer can be used if soap and water are not available and if the hands are not visibly dirty. Touching the eyes, nose and mouth with unwashed hands should be avoided.
  • A disposable facemask, gown and gloves should be worn when in contact with the individual’s blood, body fluids and/or secretions, such as sweat, saliva, sputum, nasal mucus, vomit, urine or diarrhea.
    • Disposable facemasks, gowns and gloves should be thrown out after use and should never be reused.
    • Hands should be washed immediately after removal of the facemask, gown and gloves.
  • Sharing household items should be avoided. Do not share dishes, drinking glasses, cups, eating utensils, towels, bedding or other items with an individual who is confirmed to have, or being evaluated for, MERS-CoV infection. These items should be washed thoroughly after the individual uses them.
  • All “high-touch” surfaces should be cleaned, such as counters, tabletops, doorknobs, bathroom fixtures, toilets, phones, keyboards, tablets and bedside tables, every day. Any surfaces that may have blood, body fluids and/or secretions or excretions on them should be cleaned thoroughly whenever necessary.
    • Read label of cleaning products and follow recommendations provided on product labels. Labels contain instructions for safe and effective use of the cleaning product including precautions that should be taken when using the product, such as wearing gloves or aprons and ensuring good ventilation during use of the product.
    • A diluted bleach solution or a household disinfectant with a label that says “EPA-approved” should be used. To make a bleach solution at home, add 1 tablespoon of bleach to 1 quart (4 cups) of water. For a larger supply, add ¼ cup of bleach to 1 gallon (16 cups) of water.

Laundry should be washed thoroughly.

  • Immediately remove and wash clothes or bedding that have blood, body fluids and/or secretions or excretions on them.
  • Wear disposable gloves while handling soiled items.
  • Hands should be washed immediately after removing gloves.
  • Directions on labels of laundry or clothing items and detergent should be read and followed. In general, wash and dry with the warmest temperatures recommended on the clothing label.
  • All used gloves, gowns, facemasks and other contaminated items should be placed in a lined container before disposal with other household waste. Hands should be washed immediately after handling these items.
  • The individual’s symptoms should be monitored. If symptoms worsen, the healthcare provider should be telephoned and informed that the individual has or is being evaluated for MERS-CoV infection. This will help the healthcare provider’s office take steps to implement ICPs.
  • Caregivers and household members who do not follow precautions when in close contact with an individual who is confirmed to have or is being evaluated for MERS-CoV infection, are considered “close contacts” and should monitor their health.

Prevention Steps for Close Contacts

If an individual has had close contact with someone who is confirmed to have or is being evaluated for MERS-CoV infection they should:

  • Monitor their health starting from the first day of exposure to the infected individual or PUI and continue for 14 days after they were last exposed to the individual. They should watch for the following signs and symptoms:
    • Fever - monitor temperature twice a day
    • Coughing
    • Shortness of breath
    • Other early symptoms: chills, body aches, sore throat, headache, diarrhea, nausea/vomiting, runny nose.
  • Should symptoms develop the prevention steps for caregivers and household members as described above should be followed. The healthcare provider should be telephoned and informed about the possible exposure to MERS-CoV. This will help the healthcare provider’s office take steps to implement ICPs.
  • If the close contact does not have any symptoms, he/she can continue with their daily activities, such as going to work, school or other public areas.

A person is not considered to be at risk for MERS-CoV infection if they have not had close contact with someone who is confirmed to have or is being evaluated for MERS-CoV infection. The CDC advises all individuals to follow prevention steps to help reduce their risk of getting infected with respiratory viruses, like MERS-CoV.

Avoiding Camels

As a general precaution, the WHO recommends that members of the general public adhere to general hygiene measures when visiting farms, markets, barns or other places where camels and other animals are present. These general hygiene measures include:

  • Regular hand washing before and after touching animals
  • Avoiding contact with sick animals
  • Following food hygiene practices
  • Unless wearing a face mask and protective clothing, individuals should avoid contact with any camel that has tested positive for MERS-CoV until subsequent tests have confirmed that the animal is free of the virus

The consumption of raw or undercooked animal products, including milk and meat, carries a high risk of infection from a variety of organisms that might cause disease in humans. Animal products that are processed appropriately through cooking or pasteurization are safe for consumption but should also be handled with care to avoid cross contamination with uncooked foods. Camel meat and camel milk are nutritious products that can continue to be consumed after pasteurization, cooking or other heat treatments.

Until more is understood about MERS-CoV, the WHO recommends that individuals at high risk such as immunocompromised individuals and those with diabetes, chronic lung disease or preexisting renal failure take precautions when visiting farms, barn areas, camel pens or market environments where camels are present. These measures should include:

  • Avoiding contact with camels
  • Practicing good hand hygiene
  • Avoiding drinking raw camel milk or camel urine
  • Avoiding eating meat that has not been cooked thoroughly
  • Avoiding eating food that may be contaminated with animal secretions or products unless they are properly washed, peeled or cooked

Specific recommendations for camel farm and slaughterhouse workers can be found on the WHO's website.

Travel Recommendations

Detailed information for travelers to Mecca, Saudi Arabia, for Hajj and/or Umrah can be found on the WHO's website. The WHO does not recommend either special screening for MERS-CoV at points of entry or the application of any travel or trade restrictions. However, the WHO recommends that countries outside the affected regions maintain a high level of vigilance, especially countries with large numbers of travelers or guest workers returning from the Middle East.

The Ministry of Health of Saudi Arabia recommended that, in 2014, the following individuals postpone their plans to travel to Mecca, Saudi Arabia, for Hajj and/or Umrah due to the outbreak of MERS-CoV infection:

  • Older individuals (greater than 65 years of age)
  • Individuals with chronic diseases (e.g., heart disease, kidney disease, respiratory disease, nervous system disorders, diabetes)
  • Individuals with immunodeficiency (congenital or acquired)
  • Patients with malignancy
  • Patients with a terminal illness
  • Pregnant women
  • Children

No cases of MERS-CoV infection were detected during Hajj in 2012 or 2013.

In May 2014, the CDC's travel notice was upgraded to a Level 2 Alert, which includes enhanced precautions for travelers to countries in or near the Arabian Peninsula who plan to work in healthcare settings. Such individuals should review the CDC's recommendations for infection control for confirmed or suspected MERS individuals before they depart, practice these precautions while in the area and monitor their health closely during and after their travel.

The CDC recommends that all United States travelers to countries in or near the Arabian Peninsula protect themselves from respiratory diseases, including MERS-CoV, by washing their hands often and avoiding contact with individuals who are ill. If travelers to the region have onset of fever with cough or shortness of breath during their trip or within 14 days of returning to the United States, they should seek medical care. They should call ahead to their healthcare professional and mention their recent travel so that appropriate IPC’s can be taken in the healthcare setting. More detailed travel recommendations related to MERS are available on the CDC's website.

Reporting Patients under Investigation (PUIs)

The CDC requests that healthcare providers immediately report to their state or local health department any individual being evaluated for MERS-CoV infection if they meet the criteria for a PUI. State and local health departments are then requested to immediately report PUIs for MERS-CoV infection to the CDC. The World Health Organization (WHO) has developed a questionnaire to be used for the initial investigation of cases. It can be found on the WHO's website.

There are now two options to submit a completed MERS PUI short form to the CDC:

  1. Online: Health departments can now fill out the PUI short form online which automatically enters it into a secure database and submits the information to the CDC. To begin completing PUI short forms online, state health departments should contact the CDC MERS Team at the DomesticMERS@cdc.gov to obtain a unique state-specific password and follow the directions.
  2. By FAX or email: Alternately, health departments may download, print and send the completed investigation short form below by FAX to the CDC at 770-488-7107 or attach the short form to an email to eocreport@cdc.gov (subject line: MERS Patient Form).

The WHO recommends that probable and confirmed cases be reported within 24 hours of classification through the Regional Contact Point for International Health Regulations at the appropriate WHO Regional Office.

Vaccine Development

There is no licensed vaccine for MERS-CoV, although one manufacturer has developed an experimental candidate MERS-CoV vaccine based on the major surface spike protein using recombinant nanoparticle technology. Other candidate vaccines that are being studied include a full-length infectious cDNA clone of the MERS-CoV genome in a bacterial artificial chromosome, a recombinant modified vaccine Ankara (MVA) vaccine expressing full-length MERS-CoV spike protein and vaccines encoding the full-length MERS-CoV S protein and the S1 extracellular domain of S protein using adenovirus vectors.

In one study, immunogens based on full-length S DNA and S1 subunit protein administered in a prime-boost regimen elicited robust serum neutralizing activity against several MERS-CoV strains in mice and rhesus macaques. Immunization of rhesus macaques reduced the severity of MERS-CoV-induced pneumonia, as assessed by computed tomography.

Surveillance Systems

The CDC’s Role in MERS-CoV

The CDC responds quickly whenever there is a potential public health problem. The CDC continues to closely monitor the MERS-CoV situation globally. The CDC works collaboratively with the WHO and other partners to better understand the virus, its mode(s) of transmission, the source and risks to the public’s health. The potential for MERS-CoV to spread further and cause more cases in the United States and globally is recognized. In preparation for this, the CDC has:

  • Improved data collection concerning MERS-CoV cases
  • Increased laboratory testing capacity to detect MERS-CoV cases in all states
  • Developed guidance and tools for health departments to conduct public health investigations when MERS-CoV cases are suspected or confirmed
  • Provided recommendations for healthcare infection control and other measures to prevent disease spread
  • Provided guidance for flight crews, Emergency Medical Service (EMS) units at airports and United States Customs and Border Protection (CPB) officers about reporting ill travelers to the CDC
  • Disseminated up-to-date information to the general public, international travelers and public health partners
  • Used Advanced Molecular Detection (AMD) methods to sequence the complete virus genome on specimens from cases to help evaluate and further describe the characteristics of MERS-CoV

The WHO Response

The WHO is working with clinicians and scientists in affected countries and internationally to gather and share scientific evidence to better understand the virus and the disease it causes and to determine outbreak response priorities, treatment strategies and clinical management approaches. The WHO is also working with countries to develop public health prevention strategies to combat the virus.

Together with affected countries and international technical partners and networks, the WHO is coordinating the global health response to MERS-CoV, including:

  • Provision of updated information on the situation
  • Conducting risk assessments and joint investigations with national authorities
  • Convening scientific meetings
  • Developing guidance and training for health authorities and technical health agencies on interim surveillance recommendations, laboratory testing of cases, IPC’s and clinical management

The Director-General has convened an Emergency Committee under the International Health Regulations (2005) to advise her as to whether this event constitutes a Public Health Emergency of International Concern (PHEIC) and on the public health measures that should be taken. The Committee has met a number of times since the disease was first identified. The WHO encourages all Member States to enhance their surveillance for severe acute respiratory infections (SARI) and to carefully review any unusual patterns of SARI or pneumonia cases.

Countries, whether or not MERS-CoV cases have been reported in them, should maintain a high level of vigilance, especially those with large numbers of travelers or migrant workers returning from the Middle East. Surveillance should continue to be enhanced in these countries according to WHO guidelines, along with infection prevention and control procedures in healthcare facilities. The WHO continues to request that Member States report to WHO all confirmed and probable cases of infection with MERS-CoV together with information about their exposure, testing and clinical course to guide the most effective international preparedness and response.

Outcomes

As of July 10, 2015, 489 of 1,368 individuals (36%) with laboratory-confirmed MERS-CoV infection reported to the WHO have died. Because individuals with mild symptoms are less likely to be evaluated than individuals with severe disease, those with MERS-CoV and mild disease might be underrepresented in published reports and reports from the WHO. The reported case-fatality rate might therefore be an underestimate. This hypothesis is supported by an analysis pointing out that 14 of 19 (74%) individuals with infection detected through routine surveillance died compared with 5 of 24 (21%) of secondary cases.

In a study of 47 individuals with MERS-CoV infection in Saudi Arabia, case-fatality rates rose with increasing age, from 39% in those younger than 50 years of age, to 48% in those younger than 60 years of age, to 75% in those aged 60 years or older. A separate analysis has shown similar findings.

Summary and Recommendations

Middle East respiratory syndrome (MERS) is a viral respiratory disease caused by a novel coronavirus (MERS-CoV) that was first identified in Saudi Arabia in 2012.
Coronaviruses are a large family of viruses that can cause diseases ranging from the common cold to Severe Acute Respiratory Syndrome (SARS).
Many additional cases and clusters of MERS-CoV infections have been detected subsequently in the Arabian Peninsula, particularly in Saudi Arabia. Cases have also been reported from other regions, including North Africa, Europe, Asia and North America. In countries outside of the Arabian Peninsula, individuals developed illness after returning from the Arabian Peninsula or through close contact with infected individuals. The number of cases in the Arabian Peninsula increased dramatically in March and April 2014 then declined sharply in ensuing months. However, cases continue to be detected. A large outbreak occurred in the Republic of Korea in May and June 2015. The index case was an individual who had traveled to the Arabian Peninsula.
MERS-CoV is closely related to coronaviruses found in bats, suggesting that bats might be a reservoir of MERS-CoV. Although the majority of human cases of MERS-CoV have been attributed to human-to-human transmission, camels are likely to be a major reservoir host for MERS-CoV and an animal source of MERS-CoV infection in humans. However, the exact role of camels in transmission of the virus and the exact route(s) of transmission are unknown.

The presence of case clusters strongly suggests that human-to-human transmission occurs. The virus does not seem to pass easily from human-to-human unless there is close contact, such as occurs when providing unprotected care to an infected individual.

Typical MERS-CoV symptoms include fever, cough and shortness of breath. Pneumonia is common, but not always present. Gastrointestinal symptoms, including diarrhea, have also been reported.

Individuals with an acute respiratory infection who have an epidemiologic link to MERS-CoV or who have had an unusual or unexpected clinical course (especially sudden deterioration despite appropriate treatment) should be tested for MERS-CoV. Certain other individuals may also require evaluation for MERS-CoV infection.

rRT-PCR testing applied to respiratory secretions is the diagnostic assay of choice. Ideally, lower respiratory tract, upper respiratory tract and serum samples should be obtained. Lower respiratory tract specimens should be a priority for collection and testing. To increase the likelihood of detecting MERS-CoV, collection of multiple specimens from different sites should be collected at different times.

There is currently no treatment recommended for coronavirus infections except for supportive care as needed.

An increased level of IPCs is recommended when caring for individuals with probable or confirmed MERS-CoV infection compared with that used for individuals with community-acquired coronaviruses or other community-acquired respiratory viruses. The CDC recommends the use of standard, droplet, contact and airborne precautions for the management of hospitalized individuals with known or suspected MERS-CoV infection.

About 3 - 4 out of every 10 individuals reported with MERS-CoV infection have died. Most of the individuals who have died had an underlying medical condition. Approximately 36% of reported individuals with MERS-CoV have died.Some infected individuals had mild symptoms (such as cold-like symptoms) or no symptoms at all. They recovered.

There is no licensed vaccine for MERS-CoV.

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This course is applicable for the following professions:

Advanced Registered Nurse Practitioner (ARNP), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Registered Nurse (RN), Respiratory Therapist (RT)

Topics:

CPD: Practice Effectively, Infection Control/Disease, Medical Surgical


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