Latest / The SHEA Podcast / COVID-19: Diagnostic Testing Part 2, 4/02

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COVID-19: Diagnostic Testing Part 2, 4/02 · The SHEA Podcast

• 0:08
  SPEAKER_02: Welcome to the Rapid Response Podcast brought to you by the Society for Healthcare Epidemiology of America, Shay, promoting the prevention of healthcare associated infections and antibiotic resistance and seeking to advance the field of healthcare epidemiology and antibiotic stewardship.
• 0:22
  SPEAKER_02: I am Dr.
• 0:22
  SPEAKER_02: David Bannock, hospital epidemiologist at the University of Connecticut School of Medicine UConn Health, and I will serve as today's podcast moderator.
• 0:30
  SPEAKER_02: The discussion on this podcast does not necessarily reflect Shay's perspective, but facilitates communication of multiple perspectives and experiences as we go through this challenging time together.
• 0:41
  SPEAKER_02: She is excited to launch the sixth episode of this podcast COVID-19 updates, What We Need to Know.
• 0:47
  SPEAKER_02: Today's episode will focus on diagnostic testing, the specifics, and microbiology of the test.
• 0:53
  SPEAKER_02: Our speakers today are Dr.
• 0:55
  SPEAKER_02: Jennifer Hanrahan from the University of Toledo and Dr.
• 0:58
  SPEAKER_02: Nicole Hubbard, clinical pathologist and medical microbiologist, and the medical director of infectious disease pathology at ProMedica Laboratories.
• 1:07
  SPEAKER_02: Thank you for joining us today.
• 1:08
  SPEAKER_02: I will now turn it over to Dr.
• 1:10
  SPEAKER_02: Hannerhan to get us started with some news and guidance updates for the week.
• 1:14
  SPEAKER_01: So before getting into the discussion about diagnostic testing, let's review a few items in the news during this last week.
• 1:21
  SPEAKER_01: We have been hearing a lot about social distancing, and news this week includes ongoing social distancing in an effort to reduce the number of daily new cases and averse deaths in the United States.
• 1:33
  SPEAKER_01: At the same time, new information is becoming available about potential for airborne spread as SARS-CoV-2, including a disturbing report about a church choir in Washington state where 45 of the 60 people who attended a rehearsal were diagnosed with COVID-19 or became ill.
• 1:52
  SPEAKER_01: An article on a preprint server from a study at University of Nebraska Medical Center described widespread contamination of personal items as well as air samples from hallways outside of patient rooms as being positive for viral RNA, raising questions about potential for airborne transmission in the healthcare setting.
• 2:12
  SPEAKER_01: Interestingly, there was no relationship between patient temperature and viral shedding in the environment.
• 2:19
  SPEAKER_01: Another paper published in Science estimates that a large percentage of undocumented infections fuel spread of coronavirus in China prior to travel restrictions being in place and suggests that undocumented infections are an important source of transmission in this outbreak.
• 2:37
  SPEAKER_01: There is updated guidance from CDC for public health recommendations to accommodate new scientific evidence evolving epidemiology, and the need to simplify risk stratification.
• 2:49
  SPEAKER_01: The new recommendations are based on growing evidence of transmission risk from infected persons without symptoms or before the onset of recognized symptoms, increased community transmission in many parts of the country, a need to communicate effectively to the general public and to simplify implementation for public health authorities, limitations to access to COVID-19 testing and increasing numbers of cases diagnosed clinically, and a continued focus on reducing transmission through social distancing of individuals in affected areas.
• 3:23
  SPEAKER_01: The changes include a change period of exposure risk from an onset of symptoms up to 48 hours before symptom onset.
• 3:32
  SPEAKER_01: Added the definition of a contact to include exposure to a laboratory confirmed case as well as a clinically compatible case in regions with widespread ongoing transmission and removed the no-risk category and replaced with unknown risk to acknowledge the fact that all persons in the United States are at some risk of COVID-19 given the increases in community spread throughout the United States.
• 3:55
  SPEAKER_01: The CDC states that the person-to-person transmission most commonly happens during close exposure to a person infected with COVID-19, primarily via respiratory droplets produced when the infected person coughs or sneezes.
• 4:09
  SPEAKER_01: And that the contribution of airborne transmission is uncertain.
• 4:14
  SPEAKER_01: In other areas, guidance was published on the JAMA network website for safety recommendations for evaluation and surgery of the head and neck during the COVID-19 pandemic due to potential for high risk exposures for odolaryngologists.
• 4:28
  SPEAKER_01: And there is also guidance on surgical considerations for tracheostomy during the COVID-19 pandemic on the same website.
• 4:36
  SPEAKER_01: And these are likely to be important considerations during the next few weeks as more people require prolonged mechanical ventilation.
• 4:44
  SPEAKER_01: We are still dealing mostly with anecdotal information about treatment.
• 4:48
  SPEAKER_01: There are small studies, including some small randomized trials, but much of the information is still anecdotal.
• 4:54
  SPEAKER_01: There was a small case series of five critically ill patients with COVID-19 treated with convalescent plasma who improved following administration of convalescent plasma containing neutralizing antibodies.
• 5:06
  SPEAKER_01: Guidance for use of COVID-19 convalescent plasma as an emergency investigational new drug is available on the FDA website.
• 5:14
  SPEAKER_01: With all of this information, testing seems more important than ever.
• 5:19
  SPEAKER_01: So let's move into our discussion on testing.
• 5:22
  SPEAKER_01: Thank you for being here today, Dr.
• 5:24
  SPEAKER_01: Hubbard.
• 5:24
  SPEAKER_01: I want to ask you a few questions about testing.
• 5:28
  SPEAKER_01: Dr.
• 5:28
  SPEAKER_01: Hubbard, can you comment on why it took so long to make testing available in the United States and what are the ongoing barriers that we're experiencing?
• 5:37
  SPEAKER_00: Sure.
• 5:37
  SPEAKER_00: And I just want to say thank you for having me today to discuss this very important topic.
• 5:42
  SPEAKER_00: So I personally think that there are a multitude of reasons for the delays that we have seen in testing.
• 5:49
  SPEAKER_00: The first test kits that laboratories happen to receive from the CDC had issues with the negative controls, which prevented the ability to report those results without further testing in an effort to decrease any false positive reports.
• 6:06
  SPEAKER_00: So part of the delay is due to the labs needing to ensure the testing being provided was as accurate as possible.
• 6:13
  SPEAKER_00: Another challenge laboratories faced was upholding the strict regulations of the SDA.
• 6:19
  SPEAKER_00: So typically this involves performing numerous tests and submission of a fair number of data to the SDA to get a test approved for use.
• 6:29
  SPEAKER_00: However, after a period of time, we're finally allowed to directly act on the information we had and to release testing given COVID-19 has been a public health emergency.
• 6:40
  SPEAKER_00: Luckily, in these public health emergencies, there is a more abbreviated way to get tests approved for use by the FDA by utilizing what's called the emergency use authorization pathway.
• 6:52
  SPEAKER_00: Many diagnostic companies and testing centers have been rapidly trying to develop tests and utilize the EUA pathway, but have still found it challenging.
• 7:02
  SPEAKER_00: More rules were relaxed a few weeks ago to aid in faster adoption of testing once companies actually were able to develop a test.
• 7:11
  SPEAKER_00: So, for example, companies are allowed to sell kits to start validations prior to their EUA approval at this time.
• 7:20
  SPEAKER_00: I do want to stress that these regulations are an important part of the process for laboratory quality, but happy to hear that they are trying to work given the crisis.
• 7:30
  SPEAKER_00: As for the ongoing barriers, we still have a great demand for tests that is hard to meet given the allocation of testing kits, even what's commercially available.
• 7:42
  SPEAKER_00: But I think it's going to get better and we'll talk about that later.
• 7:45
  SPEAKER_01: Thank you.
• 7:46
  SPEAKER_01: Dr.
• 7:46
  SPEAKER_01: Hubbard, are these tests complicated to perform?
• 7:49
  SPEAKER_01: And are there any specific pitfalls that healthcare workers should be aware of with PCR-based testing?
• 7:56
  SPEAKER_00: Sure.
• 7:56
  SPEAKER_00: So to address whether or not the tests are complicated.
• 7:59
  SPEAKER_00: So the initial testing options that came out did require more specialized equipment, that you have to manually extract the RNA or have very specific instruments to extract it, following amplification and detection, which wasn't a process available at all diagnostic laboratories in the United States.
• 8:20
  SPEAKER_00: Instead, these other labs typically use platforms that do not require specific RNA extraction steps separately, and instead, many of their assays rely on a more simplistic system.
• 8:33
  SPEAKER_00: So recently, Dr.
• 8:34
  SPEAKER_00: Michael Minna was quoted by Time magazine stating most microbiology laboratory testing is like a microwave dinner.
• 8:42
  SPEAKER_00: It comes as one kit, you push the button and you get your result.
• 8:46
  SPEAKER_00: Nobody can screw it up.
• 8:48
  SPEAKER_00: The CDC test kit for COVID-19 was more like a blue apron.
• 8:53
  SPEAKER_00: So it comes with a box of ingredients that you can go to the store and buy, and it's packaged, but it requires a recipe.
• 9:00
  SPEAKER_00: And this allows for individuals that are really unfamiliar with the testing terminology to understand the concepts between these platforms.
• 9:08
  SPEAKER_00: One is more complex and it does require equipment and expertise to perform.
• 9:13
  SPEAKER_00: That's not widely available in every laboratory in the country, while the other is designed for easier sample to result use.
• 9:22
  SPEAKER_00: This doesn't highlight that each of these still do require extensive validations or show that the microwave dinners really have their own issues if not done properly.
• 9:32
  SPEAKER_00: The overall goal of the statement was to highlight these differences so that people could understand why everybody cannot adopt the CDC test kit.
• 9:41
  SPEAKER_00: However, at the end of the day, testing for a novel virus such as COVID-19 is still complex to implement, regardless of which equipment option you use.
• 9:51
  SPEAKER_00: And there's a lot of behind-the-scenes work that has to be performed prior to offering either type of test.
• 9:59
  SPEAKER_01: I think that that gives us a clearer picture of what the potential problems are.
• 10:04
  SPEAKER_01: Are there any pitfalls we should be aware of with PCR-based testing?
• 10:08
  SPEAKER_00: Yeah, there's several pitfalls.
• 10:11
  SPEAKER_00: And really, I'd like to first state that the pitfalls related to PCR-based testing are not specific for COVID-19, so they really affect any PCR assay that we use in the laboratory.
• 10:23
  SPEAKER_00: So first and foremost, I would like to stress the importance of specimen collection.
• 10:29
  SPEAKER_00: So our test results are really only as good as the specimen that we're provided in the laboratory.
• 10:35
  SPEAKER_00: We commonly say to joke around in the laboratory that garbage in and you know garbage out.
• 10:41
  SPEAKER_00: If we start with a really bad specimen, that result is going to be impacted.
• 10:46
  SPEAKER_00: So in order for each hospital to ensure that you are getting the best results, you really need to focus and educate on proper specimen collection, especially for nasopharyngeal swabs.
• 10:57
  SPEAKER_00: Again, it's not a new issue related to COVID-19 testing, but all testing that requires an NP collection really is subject to issues with understanding how to appropriately collect a swab.
• 11:10
  SPEAKER_00: Another pitfall to PCR assays that people should be aware of is that each test has a defined limit of detection of the virus.
• 11:19
  SPEAKER_00: So basically, this means that there is a defined limit to which the test can actually detect the virus or a viral load in which it can determine its presence.
• 11:29
  SPEAKER_00: And this is going to vary greatly by genetic targets of the test, the test methodology, among other factors.
• 11:37
  SPEAKER_00: So one test may actually outperform others.
• 11:40
  SPEAKER_00: A negative test result for a test means that the SARS-CoV-2 RNA was not present in the specimen above that limit of detection.
• 11:51
  SPEAKER_00: Additionally, development of genetic mutations in viruses may affect detection by the specific assays.
• 11:57
  SPEAKER_00: Most of the tests look for a certain part of the genetic sequence, amplify it, and then use some technology to detect the presence of it.
• 12:06
  SPEAKER_00: So if all of a sudden a virus mutates and it alters that specific part of a genetic sequence, there is a potential that it would no longer be detected by that specific assay.
• 12:17
  SPEAKER_00: Ultimately, all of our PCR tests, included COVID-19 testing, need to be interpreted in conjunction with the clinical picture.
• 12:25
  SPEAKER_00: Many results will have statements that specifically state these limitations.
• 12:30
  SPEAKER_00: And also, fact sheets are available for the EUA assays that contain a statement stating a negative result does not rule out COVID-19 and should not be used as the sole basis for treatment of patient or patient management decisions.
• 12:46
  SPEAKER_00: A negative result does not exclude the possibility of COVID-19.
• 12:50
  SPEAKER_00: And they go on to further describe what you need to do if you're still concerned about the patients having COVID-19.
• 12:58
  SPEAKER_01: Thanks for that information.
• 13:00
  SPEAKER_01: That makes it sound quite a bit more complicated than what we think of when we look at a test result.
• 13:05
  SPEAKER_01: Given all that, what do you think the overall sensitivity and specificity is expected to be?
• 13:12
  SPEAKER_01: Do you have any idea?
• 13:14
  SPEAKER_00: So this is one of the questions that I get quite frequently, but I also think it's one of the hardest to address currently.
• 13:20
  SPEAKER_00: And while I cannot put exact numbers to answer, I can respond in generalization.
• 13:25
  SPEAKER_00: So I'll start with specificity just because I think it's easier to address.
• 13:30
  SPEAKER_00: In the validation process for any assay, we look for cross-reactivity among other viruses.
• 13:36
  SPEAKER_00: And specifically, you target other viruses or pathogens that you would expect to see in that particular body site.
• 13:44
  SPEAKER_00: Sometimes this isn't done by directly testing the organism, but by analyzing the genetic sequence of one pathogen and determining if cross-reaction is expected.
• 13:56
  SPEAKER_00: With the data I have seen and reviewed in terms of cross-reaction, I think that the false positives are going to be minimal.
• 14:03
  SPEAKER_00: In other words, the specificity is very high.
• 14:06
  SPEAKER_00: Conversely, I think unfortunately we have less data on the true clinical sensitivity like we typically do for our other lab tests.
• 14:15
  SPEAKER_00: There are reports from other countries that do show lower detection in samples such as nasal swabs, but with very few results included.
• 14:24
  SPEAKER_00: And these studies really weren't designed looking for true clinical sensitivity, just comparing different types of specimens.
• 14:31
  SPEAKER_00: Past literature for other viruses, such as influenza, definitely shows superiority of nasopharyngeal swabs as compared to nasal swabs for detection of the virus.
• 14:41
  SPEAKER_00: So again, I think focusing on specimen collection needs to be stressed to improve that clinical sensitivity of any of the available assays being used.
• 14:51
  SPEAKER_00: Another confounding factor to the sensitivity question are technical considerations of the assays.
• 14:57
  SPEAKER_00: The U.S.
• 14:58
  SPEAKER_00: did not adopt the same test as other countries, and each diagnostic company will have its own specific performance characteristics based on their exact methodology, their genetic targets of the assay, and what limit of detection is expected with their platform.
• 15:15
  SPEAKER_00: Without having more studies that directly compare each of these different tests, which is common practice in our well-known diagnostic tests, such as our influenza PCRs, the answer to this question is really challenging to create a direct answer for.
• 15:30
  SPEAKER_00: Anecdotally, we know that the tests have not had 100% sensitivity.
• 15:35
  SPEAKER_00: Even this morning, I was answering questions for a fellow pathology colleague where in their hospital they were dealing with potential false negatives and how it had impacted some of their isolation requirements.
• 15:47
  SPEAKER_00: I think we have to analyze the results in the clinical context until we can truly answer the clinical sensitivity question better.
• 15:56
  SPEAKER_01: Yeah, so that makes it really difficult, especially since we're now learning that there is, in fact, asymptomatic transmission.
• 16:03
  SPEAKER_01: That means that even with a negative test, we really can't say with 100% certainty that someone is negative.
• 16:09
  SPEAKER_01: Dr.
• 16:10
  SPEAKER_01: Hubbard, one of the potential bits of good news has been regarding two tests that have much shorter turnaround times.
• 16:16
  SPEAKER_01: Can you comment on these tests?
• 16:19
  SPEAKER_00: Yes, there have been two tests recently with test results or turnaround time expected within approximately an hour or less.
• 16:29
  SPEAKER_00: I think that these are great tests to consider, but maybe utilized very differently in different systems depending on their needs and alternate access to testing.
• 16:41
  SPEAKER_00: One option is to utilize these tests on patients to help remove from isolation and conserve PPE, but again, this has its own limitations when we don't truly understand the sensitivity of the test.
• 16:54
  SPEAKER_00: Other options people are considering with these are to utilize in symptomatic healthcare workers.
• 17:00
  SPEAKER_00: Again, maybe needing to repeat at least once to help us better understand which workers need to stay at home and quarantine versus which may be able to come back to work earlier.
• 17:12
  SPEAKER_00: I've also heard people discuss using these in emergency medicine for quick results for patients so that when they return home, they may understand their true need to quarantine if their result is positive.
• 17:24
  SPEAKER_00: I believe that it's going to really depend on each healthcare system defining how they can use these to improve all aspects of healthcare right now.
• 17:36
  SPEAKER_01: I think you've given us really a lot of things to think about.
• 17:39
  SPEAKER_01: Dr.
• 17:40
  SPEAKER_01: Hubbard, do you think there are any other types of tests, such as serological tests, that are needed to help define the outbreak?
• 17:47
  SPEAKER_00: I think that serological tests are going to be important moving forward as we understand more and more about the immune response that is mounted in patients when antibodies are becoming positive in patients, how we can use these in healthcare workers to understand who we can send to the front line.
• 18:10
  SPEAKER_00: But I think we still have a lot to learn on the actual protective immunity of the antibodies and which tests are going to be best to do that, whether it's going to be lateral flow kits that are out there versus the tests that some of the reference laboratories are working on that are more complex immunology assays.
• 18:33
  SPEAKER_00: But I definitely do think that there's going to be a need for them moving forward.
• 18:38
  SPEAKER_01: Thank you, Dr.
• 18:39
  SPEAKER_01: Hubbard.
• 18:40
  SPEAKER_01: You have been a wealth of information.
• 18:42
  SPEAKER_01: I really appreciate your time.
• 18:43
  SPEAKER_01: I know that you're extremely busy right now.
• 18:45
  SPEAKER_01: So thank you for joining us today.
• 18:48
  SPEAKER_02: Thank you.
• 18:49
  SPEAKER_02: Thank you very much to Dr.
• 18:51
  SPEAKER_02: Hanrahan and Dr.
• 18:52
  SPEAKER_02: Hubbard for sharing your perspectives and experiences and a sincere thank you from Shay to all healthcare personnel for all you're doing to respond to COVID-19.
• 19:00
  SPEAKER_02: This podcast can be accessed on Shay's online education center, Learning CE, under the Rapid Response Program.
• 19:06
  SPEAKER_02: You will also find additional resources such as the recorded webinars, healthcare facility outbreak preparedness, and the first Shay COVID 19 town hall.
• 19:15
  SPEAKER_02: This concludes this episode of the Rapid Response Podcast.
• 19:18
  SPEAKER_02: Thank you for tuning in.