Ebola crisis heightens awareness for lab preparedness
By Shara Rosen
In the 1980s, the recognition of HIV/AIDS as a global public health crisis stimulated the development of new avenues for rapid testing of sexually communicable diseases. Now, in 2015, the medical community is being challenged again with a need for clinical tools to manage an emerging spectrum of highly contagious tropical diseases. While recent events related to the spread of the ebola virus outside West Africa have spurred greater interest in this area of laboratory medicine, this article discusses issues that also apply to lab testing and procedures for other emerging pathogens that have been in the news, such as chikungunya virus, enterovirus D68, Marburg virus, and Middle East respiratory syndrome (MERS). As global travel becomes more commonplace, we can expect more cases of these and other emerging pathogens to appear in North America.
The tasks of diagnosing ebola and managing ebola patients are complicated by another unique challenge, because the virus has been designated as a potential biowarfare agent. As a result, samples from ebola patients require special biohazard handling. Laboratories involved in handling ebola-laden samples must juggle testing to meet patient-management imperatives while still protecting their staff and not compromising care for the rest of the patient population.
DIAGNOSIS IS THE FIRST STEP
To detect and confirm the presence of such highly infectious pathogens in symptomatic patients, the US Centers for Disease Control and Prevention (CDC) recommends that polymerase chain reaction (PCR) testing be performed in a laboratory that has the capacity and training to do the testing safely, accurately, and in compliance with local, state, and federal regulations that oversee laboratory quality and safety.
In order to facilitate the healthcare response to the epidemic by rapidly identifying patients infected with ebola, FDA has recently granted emergency use authorization (EUA) to seven ebola diagnostic tests (see Table 1). Use of these tests is restricted to laboratories that comply with the EUA requirements as stipulated by the agency.
LABS ARE PREPARED, INDUSTRY HAS YET TO SUPPLY
Because patients present with similar symptoms during the early stages of some diseases, a complete diagnosis also includes the ability to distinguish between ebola and such other emerging viruses as malaria, Marburg virus, MERS, and severe acute respiratory syndrome (SARS).
“I think that labs are in a very different place than they were 10 years ago,” says Angela M. Caliendo, MD, PhD, professor and executive vice chair of medicine at the Alpert Medical School of Brown University. “We have been through so many emerging pathogens that we now are more focused on making decisions quickly on how best to test. The frustration for labs is that there are not necessarily available tests, and that remains a substantial challenge for us.”
Kimberly E. Hanson, MD, MHS, clinical microbiology section head at ARUP Laboratories, Salt Lake City, supports this view. While it is widely believed that most tertiary care and reference labs are prepared to respond to emerging infectious diseases, she explains, for the majority of these pathogens there are no commercial FDA-approved tests. Consequently, it is up to laboratories to develop and validate their own tests—a task that may not be feasible because clinical samples are lacking for these pathogens, which are rarely seen in North America. When commercial reagents become available, many laboratories are prepared to act quickly to bring the tests in-house (see Table 2).
But difficulties resulting from a lack of clinical samples also apply to the development of commercial tests. Doug Simpson, president and CEO of Corgenix Medical Corp, Broomfield, Colo, says that the company had begun developing a set of immunoassays for ebola antigen and antibodies in 2010, but after receiving an initial grant from the National Institutes of Health (NIH), the company’s subsequent grant proposals were refused. The decision not to provide follow-on funding, he adds, was made partly because a lack of ebola samples hampered the company’s efforts to present a fully developed commercialization plan that would meet NIH funding requirements.
That is, until June 2014, when, fortunately and unfortunately, there was suddenly no lack of ebola samples, and the company was awarded a 3-year NIH grant. As of the end of November 2014, Corgenix is working with FDA to fast-track a 10-minute lateral-flow ebola antigen immunoassay, and the company’s 3-year development time frame has been compressed to just 6 months. Corgenix has already commercialized a set of CE-marked immunoassays for Lassa fever that are being used in Africa. The company’s Lassa fever and ebola tests have been developed in collaboration with the Viral Hemorrhagic Fever Consortium.
So far, Corgenix has done clinical testing of the rapid test in West Africa, and is preparing data for FDA in the hope of getting an EUA. Simpson says the test has shown good performance for symptomatic patients compared to PCR, and has no reactivity with other viruses. The goal, he adds, is that the test will be available “sooner than later,” but he would not commit to an actual launch date.
Corgenix is currently conducting a trial involving some 2,000 patient samples, with the ultimate goal of creating a screening test for asymptomatic patients. However, Simpson admits that this goal may not be achievable, because even PCR-based methods have not been proven successful when used as a screen in asymptomatic patients. In the meantime, the role of the rapid ebola antigen immunoassay is to be used as an alternative when PCR is not available or when a rapid test turnaround time is required.
As for molecular testing, FDA’s EUA approval for the FilmArray BioThreat-E test by BioFire Defense makes ebola diagnosis and patient monitoring more accessible. The FilmArray test is the first commercial ebola test to be authorized for emergency use on patients with signs and symptoms of ebola virus infection in conjunction with epidemiological risk factors, explains Matt Scullion, vice president of sales and marketing for the Salt Lake City-based company, a subsidiary of bioMérieux Inc, Durham, NC.
The BioFire ebola test was ready for market 4 years ago and stems from more than 10 years of development work in collaboration with the US Department of Defense for biowarfare applications, adds Simpson. The test is part of a panel for detecting 17 pathogens, which can be performed in a single run and provides results in just 1 hour (see Table 3).
“Generally, cycle threshold data can be back-related to viral titers and viral load,” explains Scullion. “BioFire currently does not have this capability available to the end user.” But the sensitivity and specificity of the test as currently formatted enables the user to see whether the patient is still shedding virus, says Scullion, and the fact that this result is available in 1 hour and near the patient is a valuable service in the management of these patients.
The BioFire FilmArray system, which has previously been cleared by FDA, is a fully automated, closed system. A patient sample with no previous sample preparation is loaded into the pouch and placed into the system. BioFire reports that “the FilmArray system is in routine use in over 300 hospitals. The rapid authorization of emergency use of the FilmArray ebola test by FDA instantly creates an extensive ebola testing network in the United States.”
But the BioFire system is only part of the lab-preparedness solution. “The problem is that an inexpensive, rapid, easy-to-perform molecular test could be needed for dozens of pathogens, but we don’t have them yet because the technology is not there yet,” says Sheldon Campbell, MD, associate professor of laboratory medicine at the Yale University School of Medicine.
THE REAL WORK BEGINS WITH PATIENT SUPPORT
With ebola patients, viral load assessment is but a small part of the patient-management process. Most ebola patients arrive at hospitals in very bad shape, according to James C. Ritchie, PhD, medical director of Emory Medical Laboratories at Emory University Hospital. In a recent webinar on ebola testing hosted by the American Association for Clinical Chemistry (AACC), Ritchie reported that the ebola patients treated at Emory “had marked electrolyte abnormalities and nutritional deficiencies, including hypokalemia, hypocalcemia, and hyponatremia.” At admission, blood gases and comprehensive chemistry panels were run. The test menu was then expanded to meet the needs of each patient (see Table 4). Ritchie emphasized that laboratory testing was critical for providing supportive care. The tests run by Emory’s team included CBC full five-part differential, coagulation INR, comprehensive metabolic panel, blood gases, and urinalysis.1
For clinical laboratories handling samples from ebola patients, the rule of thumb is that standard precautions have been highly effective at preventing transmission of blood-borne infection in the course of handling blood and other potentially infectious materials (see Table 5).
“Most laboratories have some processes in place to handle infectious specimens such as blood and body fluid,” says Peter C. Iwen, PhD, professor of pathology and microbiology and biosafety officer at the University of Nebraska Medical Center, and director of the Nebraska Public Health Laboratory. “However, protocols and the equipment and training necessary to handle highly infectious specimens are still being developed for many US hospitals.”
At Emory, testing was done on a schedule that varied from once every 6 hours to once per day, depending on patient care needs. There, as in other tertiary care hospitals, as much of the testing as possible was run in satellite labs dedicated as serious communicable disease units (SCDUs), so that critical tests for infectious patients would not have to be performed in the main lab. “This dedicated lab reduced the fear factor in handling highly infectious samples, and provided stat test results,” said Ritchie. Although a dedicated lab is not required for working with blood from patients with ebola, Ritchie emphasized, Emory set up a complete point-of-care lab “in the spirit of an abundance of caution.”
The practices employed at Emory, however, differed from the experience of Texas Health. Speaking at the AACC webinar, Beverly A. Dickson, MD, laboratory director for North Dallas Pathology Services at Texas Health Dallas, reported that Texas Health was the first US community hospital to treat an ebola patient. Since the hospital does not have an SCDU, almost all samples were run in either the core lab or the microbiology lab. Some chemistries were performed by critical care nurses in the patient’s room, using a wireless Abbott i-Stat instrument dedicated to each individual ebola patient.
Dickson emphasized that this was the first time that ebola samples had been run in a routine lab using only standard universal precautions. Prior to knowledge of the ebola diagnosis, the initial specimens were handled using only the standard universal precautions of gowns, gloves, and face shields; and all staff remained infection-free. Once the differential diagnosis indicated that ebola was highly suspect, however, more stringent requirements for personal protective equipment (PPE) were instituted during all testing in the core and microbiology labs—both as an added precaution and to assuage fear among the laboratory staff. Samples were transported to the lab utilizing special transport containers, by staff recently trained in the transport of highly infectious material. Coordination of the nurse-performed phlebotomy and batching of the ebola patients’ testing were implemented as a means of limiting exposure. Laboratory staff limited access to the lab while the samples were being tested, and afterward performed a stringent decontamination of all instrumentation. As an added precaution, closed rotors were ordered for the core lab centrifuge, to prevent a catastrophic centrifuge contamination accident.
In keeping with the Texas Health experience, the professionals interviewed for this article agree that high-consequence pathogens such as ebola require different handling. As ever, the goal of a clinical laboratory is to provide patient care while also maintaining the safety of lab personnel. But North American laboratories have had limited experience handling specimens potentially contaminated with such a highly contagious pathogen, so an abundance of caution is in play.
Caliendo suggests that laboratories are taking greater precautions for ebola than for typical infectious diseases. “With seasonal influenza, for example, we have an understanding of how the virus is contracted and what infection control policies need to be followed to prevent putting laboratory personal at risk of infection,” she says. “The virus can be handled safely on the bench, although some labs may do testing in a biosafety hood.”
But for ebola, “many laboratories are doing more than the CDC recommendations, because we really do not have a great grasp of how significant the risk is in the developed-world laboratory context,” says Campbell. “We haven’t had very much experience with hemorrhagic fever virus samples in our laboratories, so we really don’t know the magnitude of the risk. Many laboratories are doing more than the CDC recommendations out of an abundance of caution.”
A LEARNING EXPERIENCE
“CDC staff continue to discuss our protocol with us, as they want to use what we did and what we learned to pass on to the general lab community,” says Dickson. “The most important thing—the biggest takeaway message of all—is the great need to limit test utilization altogether when dealing with these highly infectious diseases. Eliminating all testing that is not necessary, and using only the specific panels needed for treatment of the critically ill patient, protects the nurses by reducing the need for phlebotomy, and also provides the greatest protection to lab staff.”
“I think that in general, we all took universal precaution procedures for granted, and this is a good opportunity for us to reinforce with our staff what the CDC really means by universal precautions—which for us is generally different from our usual practices,” says Ritchie. By way of example, he adds, “we should have nonpenetrating lab coats that should be worn only in the lab, technologists should be wearing a face shield at all times, and those types of things.”
“We have become somewhat complacent about these procedures,” says Ritchie. “Face shields are somewhat awkward to work with, and working behind a shield of some sort is cumbersome. Everyone is always in a hurry, and we sometimes underestimate the risk in which we sometimes work. I think this might be a teaching tool to raise awareness about lab safety.”
“The average clinical lab in the US and Canada deals with unknowns on a daily basis,” says Michael G. Schmidt, PhD, vice chairman of microbiology and immunology at the Medical University of South Carolina. “Laboratory-acquired infections are defined and managed as an acknowledged risk. Because of the skill and continued reinforcement of these well-established protocols, laboratory-acquired infections are the exception rather than the rule.”
Nevertheless, experts agree that when it comes to handling highly infectious pathogens, preparation is priceless. Spokesperson Kristen Nordlund reports that CDC is working with laboratories across the country to increase the preparedness of hospital-based laboratories to handle specimens from highly infectious patients.2 (For more information, see the companion article, “CDC Recommendations for Routine Testing of High-Risk Specimens.”)
Efforts to improve lab preparedness never have an end, says Ritchie. “We have to be prepared for the next ebola,” he says. “This could have been Marburg, MERS, or another highly contagious pathogen. The important aspect is that you never know. Lab staff are not always aware that a sample is from a very contagious patient.”
[reference id=”40403″]Sidebar: Resources on Handling High-Risk Pathogens[/reference]
The concern today is from the threat of the ebola virus, but no one can predict what highly infectious pathogen might emerge tomorrow. Medical facilities need to focus their efforts on preparing for any highly infectious pathogen that might arise. Today’s global community makes this a top priority.
A CDC communication reminds us that the ebola epidemic is one of the worst viral hemorrhagic fever outbreaks in history and that the human toll has been horrific. However, the epidemic has revealed a number of areas in which we can improve our laboratories, not only during times of emergency response, but in our everyday practices. Laboratories will be better prepared for any future emerging infections if they take advantage of current opportunities to accomplish the following:
- Make laboratories a safer environment in which to work by better understanding risk assessment and risk mitigation;
- Establish better collaboration among clinical laboratories, public health laboratories, industry, and federal agencies charged with oversight of laboratory quality and safety;
- Improve the safety of laboratory equipment by encouraging manufacturers to identify potential exposure risks and design safety controls.
The battle against an ebola threat in the United States has very little to do with what we do here, says Campbell. “We are unlikely to have ebola spread here. The most important efforts to protect the US are to improve what is happening in Africa.”
Shara Rosen is a contributing writer for CLP. For more information, contact CLP chief editor Steve Halasey via [email protected].
1. Iwen PC, et al. Safety considerations in the laboratory testing of specimens suspected or known to contain ebola virus. Am J Clin Pathol. 2015;(143):4–5. [epub ahead of print]
2. Centers for Disease Control and Prevention. Detailed hospital response for ebola preparedness. Available at: www.cdc.gov/vhf/ebola/pdf/hospital-checklist-ebola-preparedness.pdf. Accessed December 2, 2014.