MERS 4 years later: Still much to learn

Little more than 4 years after Middle East respiratory syndrome was first reported in humans, experts say there is still much to learn about the illness and the coronavirus that causes it.

Photo by Vanderbilt University Medical Center

The origin of the virus, MERS-CoV, and the reason humans became infected by it are among the key remaining mysteries. There are also questions about the virus’ suspected jump from bats to camels as a reservoir, how camels transmit the virus to humans, how deadly MERS is, and whether or not the illness has the potential to cause a global pandemic.

“We’ve learned a lot, and not very much,” William Schaffner, MD, professor of preventive medicine at Vanderbilt University and an Infectious Disease News Editorial Board member, said in an interview.

Infectious Disease News spoke with several global health experts to discover what has been learned during the past 4 years since the first cases of MERS were recorded and to explore the remaining unanswered questions about the disease and the virus that causes it.

First MERS-CoV infections in humans

MERS-CoV is a coronavirus, the same family of viruses that causes severe acute respiratory syndrome (SARS) and one of the viruses that causes the common cold. The virus attacks the lower respiratory tract, usually causing acute respiratory illness with symptoms such as fever, cough and shortness of breath, according to the CDC.

As of May 26, there have been 1,733 laboratory-confirmed cases of MERS reported to WHO since September 2012 — the majority of them a result of human-to-human transmission — with 628 associated fatalities. Cases of MERS have been reported in 27 countries, most of them occurring in Saudi Arabia. At the time of publication, there were 1,383 confirmed cases of MERS reported in Saudi Arabia and 592 deaths.

According to Susan Gerber, MD, medical epidemiologist at the CDC, the severity of symptoms caused by MERS-CoV sets it apart from the common coronaviruses most people will acquire in their lifetime.

“Human coronaviruses usually cause mild to moderate upper-respiratory tract illnesses,” Gerber told Infectious Disease News. “However, MERS-CoV is different from any other coronavirus previously found in people.”

In a large study of critically ill patients in Saudi Arabia, researchers found that patients with laboratory-confirmed MERS were more likely to be hypoxemic and require invasive mechanical ventilation, vasopressor therapy and renal replacement therapy compared with non-MERS patients with severe acute respiratory infection, or SARI. MERS patients also faced a greater risk for mortality than non-MERS patients.

“MERS is a much more severe disease than non-MERS SARI with significantly higher mortality,” study researcher Yaseen M. Arabi, MD, FCCP, FCCM, chairman of the intensive care department, medical director of respiratory services and professor at the college of medicine, King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center in Saudi Arabia, told Infectious Disease News. “This is a call to expedite the development and research for effective therapeutics and vaccine, which at present are lacking.”

There is no vaccine for MERS-CoV, in part, Schaffner said, because there is no known immune correlate.

In addition, MERS is difficult to distinguish from other forms of pneumonia, with overlapping signs and symptoms and underlying comorbidities, according to Arabi.

“As a result, physicians need to perform molecular testing for MERS in any patient who has an epidemiologic link — a resident or traveler from an endemic country with MERS, such as the Arabian Peninsula, for instance — and not to rely on clinical features to distinguish who may or may not have MERS,” he said.

MERS was initially reported by health officials in Saudi Arabia, but the first known case of the disease was later determined to have occurred in Jordan in April 2012. According to Peter K. Ben Embarek, PhD, MERS-CoV task force manager in the WHO department of food safety and zoonoses, it remains unknown if humans were infected prior to 2012.

“If not,” Ben Embarek told Infectious Disease News, “we do not know what triggered the ability of camels to infect humans from 2012.”

Indeed, one of the remaining mysteries about MERS is why humans seemed to suddenly become infected with a virus that had existed for a long time, said Schaffner.

“What was the inciting set of circumstances? In this way, it resembles SARS, which suddenly exploded, and then with equal suddenness, disappeared,” Schaffner said. “We did a lot to try to curtail it, but those animal markets are still pretty much in place, and the modes of transmission appear to be evident. I think we see something similar in MERS.”

Uncertainty remains over MERS-CoV origin, transmission mode

Although the origin of MERS-CoV remains unproven, Gerber said the virus likely came from an animal source. The source, according to Ben Embarek, was probably bats, which eventually transmitted the virus to camels.

In a recent study published in Scientific Reports, researchers from the NIH’s National Institute of Allergy and Infectious Diseases and two Colorado universities inoculated 10 Jamaican fruit bats with MERS-CoV and found that all 10 became infected, but none showed clinical signs of the disease. The ability of MERS-CoV to replicate in bats without causing clinical signs of MERS supports the hypothesis that bats are a natural reservoir of the virus, the researchers concluded.

However, proving the original source of MERS-CoV may take a lot of time and effort because isolating a particular virus from bats is difficult, Ben Embarek said. Bats also are suspected of being the natural reservoir for SARS, which caused a global pandemic in 2003. Finding the source of a virus is important for a number of reasons, according to Schaffner.

“We would like to know what the ecology is because with that knowledge, we might be able to create some interventions that would prevent the re-emergence of MERS and certainly prevent its establishment in other parts of the world if there are exportations. The more we know about the epidemiology of the disease, the more capable we are at some point of creating interventions,” he said.

MERS-CoV adapted over time and has been circulating in most of the dromedary camel populations in the Middle East and many parts of Africa for a while, Ben Embarek said, although the timeline remains cloudy.

“The jump from bats to dromedaries probably happened a very long time ago,” he said, “but researchers are unsure when this jump took place.”

The first study that linked camels to the spread of MERS-CoV was published in mBio in February 2014, almost 2 years after the first reported cases of the disease in humans. Since then, other studies have shown that close contact with camels is a risk factor for MERS-CoV infection in humans, although more information is needed to understand the exact role the animals play, experts said.

In fact, dromedary camels are the only animal found capable so far of transmitting MERS-CoV to humans, according to Ben Embarek, although the route of transmission, like so much else about the virus, remains unclear.

“We do not know exactly how the transmission occurs between dromedaries and humans, but we suspect that close contact is needed,” Ben Embarek said.

Close contact between humans and camels is common in the Middle East, which could explain why cases of MERS tend to occur in that region, Ben Embarek said. However, it also raises questions about the capacity of camels to transmit the virus to humans.

“Camels certainly play a role, but I still scratch my head concerning how much of a role they play,” Schaffner said. “One of the great mysteries is, if camels are so important, why don’t we have epidemic MERS among the camel handlers? It’s an epidemiologic paradox.”

Schaffner said he would advise travelers to areas with active MERS-CoV transmission to follow three rules: wash your hands frequently, avoid anyone with a respiratory illness, and stay away from camels. WHO recommends that anyone considered at high risk for severe MERS-CoV infection — those who are immunocompromised or have diabetes, renal failure or chronic lung disease, for example — should avoid contact with camels until more is known about the disease.“Which takes some of the fun out of going to the pyramids for some people,” Schaffner said. “But there are cases of MERS in the Middle East — well-investigated, sporadic cases — that have no immediate contact with camels. You can’t elicit that history. And there are a lot of people who have a lot of contact with camels who don’t get sick. So, the basic epidemiology of this disease is still cryptic. It’s got lots of unanswered questions.”

Stephen J. Gluckman, MD, professor of infectious diseases at the University of Pennsylvania and medical director of Penn Global Medicine, advised clinicians to consider MERS in any person with respiratory symptoms who has traveled to the Middle East or has had contact with a someone who has traveled there in the previous 2 weeks.

MERS-CoV spread in health care settings

Once infected, humans spread MERS-CoV to close contacts, especially in health care settings. According to the CDC, the incubation period is usually 5 to 6 days but can be up to 2 weeks. Like other coronaviruses, MERS-CoV is thought to spread from an infected patient’s respiratory system through coughing or sneezing, according to Gerber.

“However,” she said, “the exact ways the virus spreads are not currently well understood.”

Since the first reports of the disease, health care facilities have proven to be a major site of transmission for MERS-CoV and a dangerous setting for outbreaks.

“One of the things we do know is that there is clear person-to-person transmission that can be hazardous in the health care environment,” Schaffner said. “Hospitals are clearly a hazardous place if you have patients who have MERS and who are admitted.”

Recent studies have shown that better infection control practices are needed to help contain the spread of MERS-CoV in health care settings. An investigation of MERS cases reported in health care facilities in the United Arab Emirates from Jan. 1, 2013, to May 9, 2014, found that the virus spread in health care facilities often before the disease was diagnosed, underscoring the need for infection control measures at points of entry and increased awareness of the virus, researchers said.

Another study showed that the virus remained viable on a majority of touchable surfaces inside the hospital rooms of recovered MERS patients in South Korea, which has experienced the largest outbreak of the disease outside of the Middle East. The virus also was found in the air ventilation system located on the ceiling of isolation rooms, and previous findings suggest possible airborne transmission of the virus. Further, data recently published by the CDC indicated a 2014 outbreak of MERS in Saudi Arabia was propelled by overcrowding, poor infection control and inconsistent separation of suspected cases.

“The biggest risk right from the beginning has been for health care workers,” Gluckman said in an interview.

A study recently presented at the American Thoracic Society International Conference in San Francisco showed that health care workers accounted for 10% of critically ill MERS patients admitted to the ICUs of 14 hospitals in four cities in Saudi Arabia between September 2012 and September 2015.

According to Schaffner, it could be difficult to limit the spread of MERS-CoV in these settings because there is a tendency among health care workers — particularly physicians — to cut corners. SARS was interrupted through a series of rigorous infection control procedures, though not without some dramatic measures, he added.

“In order to get that implemented in Canada, where a lot of transmission occurred, they actually had to put a monitor outside the door of every SARS patient to make sure that every health care worker rigorously complied with putting on all the personal protective equipment in the appropriate way and then taking it off,” he said.

Schaffner said that kind of rigorous infection control was not always in place during MERS outbreaks in the Middle East and South Korea, and half-measures are not enough to limit the spread of the virus.

“You’ve got to not only have all the equipment and training in place, you have to ensure that it is done 24/7,” he said.

Challenges of gauging mortality

Although WHO says about 36% of MERS patients have died, the exact mortality rate may be unknown, Ben Embarek said, adding that a high fatality rate among MERS patients is generally due to the fact that people with underlying health conditions are more susceptible to a severe or fatal form of the disease.

“Young and healthy adults will generally have a milder form of the disease and recover more easily,” he said. “Some also may have no or very mild symptoms.”

These patients may contribute to an overestimation of the true mortality rate of MERS because surveillance activities often miss those who are infected but have symptoms that are either mild or nonexistent, Ben Embarek said.

“This is a bit of the same picture we would see with seasonal influenza,” he said. “MERS has a broad range of symptoms and outcomes.”

Patients with milder symptoms could appear to have a cold, in which case they would not be evaluated for MERS, Gluckman said. In this way, the situation is comparable to the early days of another disease that was poorly understood.

“This was certainly the case with Legionnaire’s disease when it was first described,” Gluckman said. “The initial mortality rate turned out to be quite a bit higher than what was subsequently learned after we realized it could cause milder disease. So this may be just partially a statistical [issue] that it’s only the sicker patients who are diagnosed.”

Potential for a global pandemic?

Last year, nearly 200 people were infected with MERS-CoV in South Korea after the virus was introduced by a single infected patient with a history of travel to several Middle East countries, WHO reported. There also have been travel-related cases — and in some instances, secondary transmission of MERS-CoV — in the United Kingdom, France and Tunisia, according to Gerber. Saudi Arabia continues to confirm new cases of the disease.

“The potential for travel-related cases to cause outbreaks remains,” Gerber said.

Despite this potential, the world has not seen a MERS pandemic, and the number of annual cases has declined since a peak in 2014, according to WHO tallies.

Since 2012, there have been unrealized fears that the annual Muslim pilgrimage to Saudi Arabia for the hajj could trigger a global pandemic of MERS by drawing millions of visitors to the area with the most documented cases of the disease.

“The hajj provides one of the elements for a possible rapid spread, namely a large congregation of people in close contact with each other who then travel back to their countries of origin,” Ben Embarek said. “However, MERS is not easily transmissible between humans during casual contacts in the community.”

MERS remains a new disease with the potential to become a serious epidemic, even if the news media and public in general has lost interest, according to Ben Embarek. Indeed, the fact that there has yet to be a MERS pandemic is the only reason fears have lessened, Gluckman said.

“I think the possibility is still there,” he said. “It does seem to be fairly contagious.”

While the fact that MERS has not spread more internationally remains somewhat of a mystery, heightened awareness of any respiratory illnesses in travelers may play a role in limiting its spread, Schaffner said.

“In the Middle East, despite its turmoil, there are still many tourists, businesspeople and combatants, and all things considered, there has not been much exportation of MERS to other parts of the world,” he said. “I think the world is alert to influenza-like illness, serious illness, particularly involving the respiratory tract in travelers, so those people would get queried and have diagnostic studies done. People are looking for influenza transmitted internationally of novel types, so people would also be looking for MERS.”

While it will take time to learn everything about MERS, it is never too early to be asking questions about what we already know, Schaffner said.

“Our capacity to investigate epidemiologically and in the laboratory is so much better than it was 25 or 30 years ago that we get a lot of information,” he said. “But it’s perhaps unreasonable to expect that all the questions will have been answered.”

In fact, although there is much left to learn, MERS is understood better than another disease causing headlines around the globe, according to Gluckman.

“We know more about MERS than Zika,” he said.

According to Ben Embarek, a number of studies have been recommended by WHO and its partners in an effort to close some of the knowledge gaps pertaining to MERS. They also are promoting research into vaccines, the management and treatment of cases, and transmission patterns among dromedaries, which may help reduce the number of primary MERS cases.

“Research is being conducted, but not at the pace and in the coordinated way one could hope for,” Ben Embarek said. “We will ultimately have most of these answers. This is still a relatively rare disease with many unknowns.” – by Gerard Gallagher

• References:
• Alagaili AN, et al. mBio. 2014;doi:10.1128/mBio.00884-14.
• Arabi YM, et al. Abstract A6891. Presented at: American Thoracic Society International Conference. May 13-18, 2016; San Francisco.
• Arabi YM, et al. Abstract A6892. Presented at: American Thoracic Society International Conference. May 13-18, 2016; San Francisco.
• Azhar EI. mBio. 2014;doi:10.1128/mBio.01450-14.
• Balkhy HH, et al. MMWR Morb Mortal Wkly Rep. 2016;doi:10.15585/mmwr.mm6506a5.
• CDC. Middle East respiratory syndrome (MERS) — symptoms & complications. 2015: http://www.cdc.gov/coronavirus/mers/about/symptoms.html. Accessed May 12, 2016.
• Hastings DL, et al. Emerg Infect Dis. 2016;doi:10.3201/eid2205.151797.
• Hunter JC, et al. Emerg Infect Dis. 2016;doi:10.3201/eid2204.151615.
• Jeong HW, et al. Abstract 1978a. Presented at: IDWeek; Oct. 7-11, 2015; San Diego.
• Munster VJ, et al. Sci Rep. 2015;doi:10.1038/srep21878.

• For more information:
• Yaseen M. Arabi, MD, FCCP, FCCM, can be reached at yaseenarabi@yahoo.com.
• Peter K. Ben Embarek, PhD, can be reached at benembarekp@who.int.
• Susan Gerber, MD, can be reached at media@cdc.gov.
• Stephen J. Gluckman, MD, can be reached at Stephen.Gluckman@uphs.upenn.edu.
• William Schaffner, MD, can be reached at William.Schaffner@vanderbilt.edu.

Disclosures: Arabi, Ben Embarek, Gerber, Gluckman and Schaffner report no relevant financial disclosures. Please see the full studies for a list of all other authors’ relevant financial disclosures.