Have virus, will travel: U.S. hospitals must be vigilant for incoming cases of MERS, H7N9 as seasonal flu hits
International travel is incredibly frequent. No community is really immune to this.’
By Gary Evans, Executive Editor
Financial Disclosure:Executive Editor Gary Evans, Consulting Editor Patrick Joseph, MD, and Kay Ball, Nurse Planner, report no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
With the approaching flu season complicated by possible introductions of an emerging coronavirus in the Middle East and a novel H7N9 flu strain in China, clinicians in U.S. hospitals may need to rely more on gumshoe epidemiology than available diagnostics.
As this issue went to press no cases of Middle East Respiratory Syndrome (MERS) coronavirus nor novel avian influenza A (H7N9) had been reported in North America. H7N9 seems to have particularly dropped off the radar, but the Centers for Disease Control and Prevention is urging vigilance in what could be a chaotic season for respiratory infections. The respective viruses both appear to need a further mutation to transmit effectively in the community, but they remain simmering with pandemic potential due to their novel nature and high mortality rates in confirmed cases. As infection preventionists are well aware, both influenza and coronaviruses have the ability to genetically reassort and mutate in ways that could make them more transmissible.
The immediate threat to hospitalized patients in the U.S. is clearly MERS, which in its present form is capable of causing a nosocomial outbreak. MERS has caused fatal and life-threatening infections in patients with underlying medical conditions and has shown the ability to spread to both patients and health care workers in hospital outbreaks in the Middle East. Though there are some distinctions, MERS is something of a pathogenic cousin to the Severe Acute Respiratory Syndrome (SARS) coronavirus that emerged dramatically in 2002-2003. An outbreak that began in China spread globally, eventually causing more than 8,000 infections and some 775 deaths. Then, like some violent squall at sea, SARS vanished as rapidly as it arose.
Only a smattering of cases occurred in the U.S., but Toronto, Canada was hit particularly hard with some 400 infections and 44 deaths in patients and health care workers. The Toronto outbreak began with a case of unrecognized SARS in an infected contact of a recent traveler to the Hong Kong epicenter. The patient was admitted to a community hospital, resulting in a large nosocomial outbreak that included a total of 128 patients, health care workers, household or social contacts, and hospital visitors.1 Indeed, hospital transmission was a primary accelerator of SARS infections during the brief pandemic, accounting for 72% of cases in Toronto and 55% of probable cases in Taiwan.2
Allison McGeer, MD, FRCPC, has now seen the grim handiwork of both viruses, having battled SARS in her own hospital and traveled recently to Saudi Arabia to consult on a MERS outbreak at Al Ahsa Hospital and several other health care facilities. (See related story, p. 103.).
"Although there are some differences, there are some really striking similarities between MERS and SARS," says McGeer, a microbiologist and infectious disease consultant at Mount Sinai Hospital in Toronto. "I am not particularly worried about introductions because we know what rules this virus lives by. But we are having that discussion here in Ontario — are we prepared to identify the first case of MERS? I think our ability to detect travel-associated cases in hospitals — which is the critical issue — is probably pretty good. If it presents in a household contact of a traveler — which is how we got into trouble with SARS — then that will be more difficult."
Since MERS first appeared in September 2012, there have been 94 laboratory-confirmed infections (as of August 19, 2013) reported in Saudi Arabia, Qatar, Jordan, the United Arab Emirates, the United Kingdom, France, Tunisia, and Italy. All the European and North African cases had a connection to the Middle East. However, France, Italy, Tunisia and the UK cases included limited local transmission among close contacts that had not travelled to the region. There have also been sixteen probable cases. Likewise, an unknown number of mild or asymptomatic cases have likely occurred, but MERS currently has a 50% mortality rate in the confirmed cases with 47 deaths among the 94 patients. Evidence of the MERS coronavirus has been found in bats and camels, but other animals may also serve as a reservoir or intermediate host. (See related story, p. 105)
Look for the epi’ link
As with SARS, infection control measures can effectively contain MERS once suspect or identified cases are placed in patient isolation, McGeer says. Compliance with infection control measures is critical because no vaccine or effective antiviral treatment is currently available for MERS. Given that and the unknown routes of transmission of MERS, the CDC essentially pulled out all stops in recommending a combination of standard, contact, and airborne precautions for patients hospitalized with known or suspected MERS. Hospitals should use airborne infection isolation rooms with health care workers donning gloves, gowns, eye protection and N95 respirators.
"Once you identify it — as the hospital in Al Ahsa did — it is completely controllable," McGeer says. "But you have to be looking for it very carefully and recognize that you will export cases to other hospitals. You have to understand that this is a regional thing as opposed to a single hospital outbreak. You have to be watching more broadly than you usually do for cases of transmission, but none of it is that difficult if you are ready to go. If you haven’t dealt with SARS, it is an interesting challenge and people could get into some trouble, though I don’t think as much trouble as we got into with SARS."
Some hard-earned wisdom gained from that trouble was to "think epidemiologically," McGeer adds. "The first thing about detecting cases is that at presentation in the hospital emergency department you really need to be able to detect the epi’ risk," she says. "Thinking epidemiologically when you first see people is something that has taken all of us a while to learn because it is not the traditional clinical approach to things."
Hospital outbreaks of both SARS and MERS underscore the epidemiological consequences of patient movement, and the cost of failed communication between facilities.
"It is not just the patients who have disease," she says. "Who are the other patients in the ICU who were exposed and are no longer there? Have exposed patients in your hospital gotten sick and then turned up in another hospital? Now of course unless you are on top of it and telling that other hospital — they have no idea there is an epi’ link. Not a clue."
An immediate challenge for American IPs and clinicians will be discerning between a panoply of severe respiratory infections with similar symptoms that may include fever and pneumonia requiring hospitalization. The CDC has developed a checklist for frontline workers that include using "source control" measures like putting a face mask on suspect cases until they can be placed in an isolation room. (See related story)
"The clinicians are really going to be the first line of defense for a case of MERS, H7N9 or seasonal flu," says Terri Rebmann, PhD, RN, CIC, associate professor in the Institute for Biosecurity at Saint Louis (MO) University. "They are going to have to be really thorough in their history taking, ask the right questions and then follow up with prompt reporting to the health department."
While flu tests may help guide decision making, the rapid tests lack sensitivity and can result in false negatives, she says. "The CDC instructs clinicians to interpret negative lab result findings with caution, and to base treatment decisions on signs and symptoms as well as lab test results," Rebmann notes.
Epidemiologically, travel history is the immediate triage point between suspect MERS cases and those with seasonal flu or some other serious respiratory infection.
"It is a small world today and people are within 12 hours of most places on the globe," says William Schaffner, MD, chairman of preventive medicine at Vanderbilt University Medical Center in Nashville. "International travel is incredibly frequent. There is no community that is really immune to this."
The CDC advises considering MERS if a patient with severe respiratory symptoms has been to the Middle East in the last 14 days. Similarly, patients with severe respiratory infections should be considered for novel H7N9 flu if they have travelled to China in the last 10 days.
"We’re back to doing things as in the SARS era with travel histories," Schaffner says. "Certainly we did that then and we will be doing this going forward here at Vanderbilt — reminding all of our providers that when they see patients with respiratory illness ask them the simple question: Have you been traveling out of country, and if so where?’ That’s very simple. It’s easy to do and costs no money — you just have to remind your practitioners to do that."
Widening the net
Concerned that some MERS introductions could be missed, the CDC recently revised its guidance for the coronavirus.3 In the previous guidance the CDC did not recommend MERS testing for people whose illness could be explained by another etiology. The new guidance states that, in patients who meet certain clinical and epidemiologic criteria, testing for MERS and other respiratory pathogens can be done simultaneously. Moreover, positive results for another respiratory pathogen should not necessarily preclude testing for MERS, the CDC said.
"We just want to make it clear that it is not essential to rule out other causes of a severe acute respiratory infection," says Susan Gerber, MD, a medical epidemiologist in the CDC Respiratory Virus Program. "Clinicians may order testing for MERS coronavirus while also investigating other causes. A lot of symptoms for severe respiratory infections overlap and that’s why testing is so important. Severe influenza infection and community-acquired pneumonias may also be due to streptococcal infections or legionella. Many of these symptoms and clinical presentations [are similar to] the MERS coronavirus."
Hospitals that have a suspect case of MERS should contact their state and local health department for testing. Lab tests using polymerase chain reaction for MERS-CoV detection have been distributed to state health departments by the CDC. The CDC has not changed the case definition of a confirmed MERS case, but the criteria for laboratory confirmation were recently clarified. The CDC has also revised its definition of a "probable case" so that identification of another etiology does not exclude someone from being classified as a probable case of MERS.
"The way I read this is that MERS is a continuing and potentially growing problem," Schaffner says. "They want to increase their capacity to pick up cases that are imported into the United States. In effect, they’re widening the net. "
At the risk of putting too fine a point on it, the CDC guidelines suggest that a hypothetical patient positive for seasonal flu could still be worked up for MERS if he had traveled to the Middle East in the prior two weeks.
"If it were a sufficiently serious illness, that’s correct," Schaffner says. "If you have a rapid [positive] test for flu but that patient has just come back from Yemen, you would think seriously of getting another specimen and getting it off to CDC for MERS testing."
The new CDC guidance also clarifies recommendations for investigating unexplained clusters of severe acute respiratory illness when there is no apparent link to a MERS case. Clusters of patients with severe acute respiratory illness should be evaluated for common respiratory pathogens and reported to local and state health departments. If the illness remains unexplained, testing for MERS should be considered in consultation with state and local health departments, the CDC recommends.
"This is an illness that has the potential to spread from person to person [in the community] so if there is a cluster of serious respiratory illness that immediately doesn’t have an answer as to etiology, MERS ought to be considered," Schaffner says. "This is another way to think of how possible introductions may present themselves."
Though testing for MERS if a patient has another etiology for severe respiratory infection may be exercising an abundance of caution, in general the CDC guidelines fall within reasonable epidemiological parameters, says Stanley Perlman, MD, PhD, a microbiology professor who studies coronavirus pathogenesis at the University of Iowa in Iowa City.
"As an infectious disease physician I would have done this anyway," he says. "If I had somebody in my clinic who was sick and just traveled to Saudi Arabia I would certainly be thinking in the back of my mind they could have MERS. But if it’s the middle of December and somebody from Saudi Arabia is positive for a flu culture I would probably think they had the flu."
On the other hand, if a patient came back from the Middle East and had a positive culture for a rhinovirus, MERS testing would be considered, Perlman says. "What they are saying makes some sense, it just can’t be crazy."
Indeed, at some point in all of this it may be useful to invoke "Occam’s razor," a principle of parsimony and logic that essentially says if you have competing hypotheses, the one with the fewest assumptions is likely correct.
"Most of us — if we had a cluster of patients with severe respiratory disease and we didn’t know what was going on — would do widespread testing," Perlman says. "The caveat here is that most people who have gotten sick [with MERS] had underlying diseases. If I have a group of people who just came back from scuba diving in San Diego — perfectly healthy otherwise and 25 years old — it is unlikely they have MERS even if one of them also traveled to Saudi Arabia."
A more realistic concern for MERS exposures and subsequent U.S. introductions by thousands of returning travelers is the Hajj pilgrimage to Saudi Arabia in mid-October. (See related story, this page.)
"That could be a major concern — some of the elderly pilgrims may be immune compromised," Perlman says. "[MERS] could cause immediate infections with the possibility for dissemination. "
Overall, in the absence of another mutation, MERS appears to lack the staying power needed for true pandemic potential — the ability to spread in the community between people with competent immune systems. Researchers recently compared MERS to SARS using the classic epidemiological measure of reproductive ratio, the expected number of secondary infections from a single case. The reproductive ratio reaches a tipping point for further transmission at 1 or above, indicating secondary infections can sustain an outbreak. Researchers looked at 55 of the 64 laboratory-confirmed cases of MERS as of June 21, 2013. Under their most "pessimistic scenario," they estimated a MERS reproductive ration of .69, noting that pre-pandemic SARS was at .80. With recent implementation of effective contact tracing and isolation procedures in the affected regions, they concluded that MERS does not yet have pandemic potential.4
"The only thing that is worrying people in Saudi Arabia if cases continue to be acquired—is if MERS achieves a reproductive ratio above 1 in the community," McGeer says. "If it’s above 1 in the community then we’re in trouble because as an endemic disease, MERS would be a very difficult problem. You couldn’t tell who was coming in [with it]. But as long as it is just travel related I’m quite optimistic that we have enough global experience with these viruses to contain it."
Perlman made the same point in a recent editorial, though warning of the potential for MERS mutation.5
"Basically if the virus spreads to fewer people than it initially infected then it is going to go away," he says. "[But] with these coronaviruses you have to be wary about being too optimistic because they do mutate so easily."
For example, a mutated coronavirus that has been previously seen in Europe is currently infecting swine in the U.S., he notes.
"There is a huge outbreak now in North America of this porcine epidemic diarrhea (PED) coronavirus," Perlman says. "It probably came from Europe and it probably mutated with something else to allow this virus to cause severe infections in pigs. The point is that MERS has the potential to do that. During the SARS epidemic, we realized [the virus] changed during the course of the epidemic. So it could still mutate, but the good news is that we are now many months in with this virus and that really has not happened."
1.Varia M, Wilson S, Sarwal S, McGeer A, et al. Hospital Outbreak Investigation Team. Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada. CMAJ. 2003;19:28592.
2. McDonald LC, Simor AE, Su I-J, et al. SARS in healthcare facilities, Toronto and Taiwan. Emerg Infect Dis [serial on the Internet] 2004 May. Available from: http://wwwnc.cdc.gov/eid/article/10/5/03-0791.htm
3.Centers for Disease Control and Prevention. Notice to Healthcare Providers and Public Health Officials: Updated Guidance for the Evaluation of Severe Respiratory Illness Associated with Middle East Respiratory Syndrome Coronavirus (MERS-CoV). August 12, 2013. http://emergency HAN.cdc.gov/ /han00352.asp
4.Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: Estimation of pandemic risk. Lancet Early Online Publication, 5 July 2013 doi:10.1016/S0140-6736(13)61492-0
5.Perlman S, McCray PB JR. Person-to-Person Spread of the MERS Coronavirus — An Evolving Picture. N Engl J Med 2013; 369:466-467