Since I last wrote about some testing options available for COVID-19 testing just 1 month ago, many things have changed in the regulatory requirements, and the companies offering testing options. With that in mind along with the fact that things will likely continue to changes, I’ll write to address current and future challenges facing COVID-19 laboratory testing.
What control material can be used?
How can I make specimens safe?
Supply chain issues and solutions.
False Negative results of COVID-19 tests: what to tell clinicians.
Serology Tests: Future Testing and Challenges
As the FDA said contrived specimens could be used, that means that RNA can be spiked into a clinical matrix for extraction. While this began with a requirement for genomic RNA, it has been loosened to include plasmid DNA. However, I would caution against using plasmid DNA, because when it is amplified, it can easily cause contamination and unlike RNA, DNA can persist in the environment for a long time. I once hear a story about a lab director who thought they were very careful, but in pipetting, they contaminated the lab in 3 days and it had to be cleaned up for 4 weeks.
We had some issues using in vitro transcribed RNA (of just the N-gene) and genomic RNA, because the recovery was very low. We found out that intact viral particles were better in optimization experiments using control endemic SARS strains (Zeptometrix controls, Table 1). The free RNA Ct values fell sharply (over 1000-fold) when added to Nasopharyngeal (NP) matrix or Viral Transport Media (VTM). However, much lower levels of the encapsulated viral control had consistent levels of amplification.
Therefore, we used a synthetically encapsulated SARS-CoV-2 RNA sample called Accuplex (SeraCare, Figure 1), which gave good recovery and a limit of detection down to 260 copies/ mL (5 copies/ reaction). Alternative similar material that we have not evaluated include: COVID-19 RNA synthesized inside inactivated E coli (Zeptometrix) and Armored RNA (Asuragen).
Lab Safety of Specimens
A safety recommendation of the FDA was to perform extraction of samples in a Biosafety level 2 hood. However, high-throughput extraction can’t be easily done this way. For us, we had to prepare samples in the hood then take them to the stand-alone closed system extractor. Our Micro fellow had the creative idea to do “Off-Board” lysis, which would inactivate the virus in the hood before walking it over. We later found that combining lysis with NP matrix before spiking RNA stabilized the RNA for accurate measurement. We were able to find an LOD of 14 copies/ reaction this way.
Some labs have proposed using heat inactivation (~30 minutes at 50-60C) of virus as a safety measure, but the published literature available on how that affects sensitivity is lacking currently.
Supply Chain issues
You have surely heard about all of the new companies that have come out with new testing platforms and assays for COVID-19 testing by now. However, the downside is that unless you already have their instrument, you likely won’t be able to get reagents in time to perform the assay. Even if you do have an instrument, limited resources are necessitating allocation based on high risk areas, so you are likely to receive fewer kits than you would like. Also, the reference labs are still ramping up capacity and are returning results back with long turnaround times currently (~ 1 week). This supports the strategy to bring the testing in-house, so that you can get results back quickly and have control over at least your labs reagent supply. If you have the instrumentation of another FDA approved EUA, you can start performing testing if you follow that protocol exactly- the CDC is the most widely used.
False Negative Tests of COVID-19
This is hard to assess when only one lab testing modality (PCR) is available, but clinicians report negative results in a patient with classic symptoms and a contact history with a COVID-19+ person. Given the impressive analytic sensitivity of the test (generally 1 copy of RNA in 1mL of sample), the likely explanation is that there is a specimen issue. Proper NP sampling requires sticking the swab to the very back of the nasal cavity. Furthermore, this virus may reside more in the lower respiratory track (lungs) and simply not be present in the area sampled. This is why repeat sampling could be helpful. However, the outcome should be the same whether or not you have a negative test: if you have symptoms you should self-isolate unless you require emergent care due to shortness of breath or other symptoms that can’t be managed at home. The lab is familiar with these pre-analytic limitations that can arise, but it is helpful to explain this to clinicians.
Serology Tests: Future Testing and Challenges
Serology can be very helpful as a separate method from qPCR to determine if someone has been infected with SARS-CoV-2. Notice, that is in the past tense. A small (n=9) pre-print study from Nature indicates serologic conversion starts around day 8 or 10 after symptom onset, which often is not in a clinically helpful timeframe. However, these tests are cheaper and easier to perform, so could be useful for epidemiological purposes to determine who has been infected with COVID-19. Early genetic data indicates that the mutation rate is slow (4x slower mutation rate compared to seasonal flu) as one would suspect for RNA-based viruses, so the virus shouldn’t change enough to cause re-infection in someone with sufficient antibody levels.
However, several challenges in interpreting these antibody tests include:
Some conflicting data as to how quickly IgM develops relative to the onset of symptoms
What is the time-line for IgG production?
Ruling out cross reactivity with other strains of Coronavirus that cause upper respiratory infections.
-Jeff SoRelle, MD is a Chief Resident of Pathology at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and improving genetic variant interpretation.
The evolving COVID-19 pandemic has changed the world already- the way we educate, the way we conduct business, and way we socialize (or don’t). In the lab setting, there are many practices and procedures that are now being questioned. Sometimes the answer changes quickly, sometimes there is national guidance to assist with a particular issue, and sometimes your own facility or organization makes the decisions for you. As a lab safety consultant, I have received many lab safety questions about handling certain situations in these times, and I want to share some of those because others may be wondering the same thing.
Q:Should nurses or other staff come into the laboratory wearing surgical masks, even if they are taking care of COVID-19 patients?
A: Yes, it is acceptable and safe for nurses and other staff to enter the lab wearing surgical masks (unless a company policy prohibits it). Remember, if someone else wears a surgical mask, that protects you, NOT them. Even if the employee is taking care of a COVID-19 patient, science tells us that virus particles are not falling off their mask. It is generally safe for people to enter the department wearing a surgical mask.
Q:Should nurses or other staff come into the department wearing gloves?
A: No, it is generally not acceptable for others to enter (or exit) the lab wearing gloves. Door handles should be considered clean. If specimens are being delivered, the outside of the bag/container being carried is considered clean (even if a COVID-19 specimen is inside). Post signage to remind non-lab staff to remove gloves, and notify people immediately if you see them using gloves to enter or exit the lab.
Q:My lab co-worker seems to be sick. Can I tell them to go home or self-quarantine?
A: No. As an employee you do not have the right to approach a co-worker or dictate to them how to proceed. If you have concerns, escalate them to the manager. If you’re the manager, contact your employee health department. That is the department that can best determine who needs to be sent home for isolation. Remember, there are many other reasons people cough, sneeze, or have a runny nose. For instance, allergy season is in full swing. Harassing a co-worker about their health would be considered a violation of Human Resources policy.
Q:How does laboratory staff maintain an appropriate social distance from each other while working?
A: The answer to this really depends on your lab set-up and processes. Is it possible for staff in smaller labs to change work patterns in order to better maintain a distance from co-workers? Try a different receiving location so that those from outside the department can drop off specimens from a distance, like placing a cart near the lab door. Some facilities require masking of all staff, and if that is the case, then social distancing while at work may not be an issue. Be sure to limit staff in break rooms as well, and make sure areas are disinfected regularly.
Q:Should autopsies be performed during this pandemic?
A: Some pathologists have suspended autopsies at this time. While it is possible to perform autopsies on COVID-19 patients safely using the appropriate PPE, many deem the use of such PPE to be unnecessary when so many others need it.
Q:Can PPE be disinfected and re-used safely?
A: Some locations have moved to reprocessing N95 respirators, surgical masks and isolation gowns. Make sure there are appropriate quality and safety checks being performed on this equipment before it is re-used. While some methods can disinfect items used for COVID-19 patients (i.e. UV light treatment, hydrogen peroxide mist, etc.), they have not been approved for the disinfection of tuberculosis. Therefore, if PPE has been used to protect staff from TB, it should not be reprocessed with the other PPE used for COVID-19 patients.
Q:Histology and cytology slides from fresh (unfixed) samples are made in the lab space and moved to offices for reading. Can these slides from potential COVID-19 patients be safely read in clean office areas?
A: This is a valid question at all times, not just during this pandemic, and the answer depends on the process used for making the slides. It is known that xylenes or solutions containing 60% ethanol or more easily inactivate COVID-19 and other pathogens. Slides made with these chemicals can safely be transferred to office areas for reading. Fresh tissue/sample slides using other methods (i.e. methanol fixation) should be read in the lab space only. Check your reagents in your slide stains to see if they eradicate pathogens. If not, check to see if it is possible to fix the slides in stronger ethanol solutions before staining.
These are just some of the many questions people are asking. There are references which can help to provide some of the answers (CDC.gov, WHO.int, OSHA.gov, etc.), but if you need more lab safety information, please feel free to send me questions at email@example.com. I will provide the most current safety guidance for your issue. This is a rapidly-changing situation, and information comes from many sources, Make sure you do your best to validate what you hear, and continue to use Standard Precautions and good behaviors to keep you and your laboratory staff safe from COVID-19 and other harmful pathogens.
–Dan Scungio, MT(ASCP), SLS, CQA (ASQ) has over 25 years experience as a certified medical technologist. Today he is the Laboratory Safety Officer for Sentara Healthcare, a system of seven hospitals and over 20 laboratories and draw sites in the Tidewater area of Virginia. He is also known as Dan the Lab Safety Man, a lab safety consultant, educator, and trainer.
The patient is a 57 year old male with a history of traumatic brain injury in 2005 resulting in quadriplegia and subsequent neurogenic bladder with chronic spasms. In 2016 the patient underwent cystoprostatectomy, proctectomy, and ureteroenteric anastomosis to colon. The post-operative period was complicated by the formation of a presacral abscess consisting of MSSA and E. coli. Drain placement failed to resolve the abscess and drain studies showed the formation of a fistula to the patient’s rectal stump. The subsequent 3-year period consisted of repeat drain placements and laparotomy to drain and wash out multiple small collections of fluid seen on imaging. Bacterial cultures during this interval grew mixed gram positive and gram negative enteric bacteria, treated primarily with ertapenem. In January of 2020, the patient underwent exploratory laparotomy with debridement and drainage of pelvic abscess. Tissue cultures from the procedure grew MRSA and vancomycin was prescribed for treatment. Vancomycin was switched to daptomycin for more favorable dosing and ertapenem was added to his treatment plan. Four weeks after his operation, the patient reported pain at his drain site and the fluid in his Jackson-Pratt (JP) drain had turned green. Fluid from the JP drain was submitted for microbiological work-up.
Gram stain of the fluid from the JP drain showed neutrophils, many gram negative bacilli, and beaded gram-positive bacilli. Modified Kinyuon testing was positive for acid-fast bacilli (AFB) and cultures were ordered for mycobacteria as well as Nocardia. The gram negative bacilli was isolated and identified as Pseudomonas aeruginosa by MALDI-ToF. The beaded gram-positive bacilli were isolated on CNA agar and identified by MALDI as Mycobacterium chelonae. Concordant morphology was observed on mycobacterial culture. Nocardia culture was overgrown by P. aeruginosa.
Rapidly growing mycobacteria (RGM) include the three most common clinically relevant species: Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae.
The RGM are environmental organisms found worldwide that usually grow in subculture within one week (eg, rapidly, as compared with other mycobacteria). M. abscessus is the most commonly encountered species of this group isolated from clinical respiratory specimens, M. fortuitum is the most common from non-respiratory specimens, and M. chelonae primarily impacts immunosuppressed patients and may also cause surgical wound infections.
Postoperative infections with RGM have occurred following various procedures including cosmetic surgery procedures, augmentation mammoplasty, laser in situ keratomileusis (LASIK), and heart surgery.1-8 Infection is characterized by multiple recurrent abscesses around the surgical wound.
Diagnosis for non-pulmonary disease is made by culture of the specific pathogen from drainage material or biopsy of the affected site. The isolation of organisms from sterile, closed sites, such as bone marrow or blood or from a skin biopsy (in the setting of multiple lesions), is diagnostic of the disease. Once an isolate has been identified as a nontuberculous mycobacteria (NTM), the species should be identified. However, identification of RGM in most laboratories is either incomplete or imprecise. M. abscessus isolates are frequently identified simply as “M. chelonae/abscessus complex,” or if they are specifically identified as “M. abscessus,” they are not accurately sub-speciated.
Susceptibility testing should be performed against a number of antibacterial agents, however, there is no established minimum inhibitory concentration (MIC) cutoff for susceptibility or resistance. M. chelonae is typically treated with Macrolide antibiotics, particularly azithromycin and clarithromycin. M. fortuitum, M. abscessus, and M. chelonae are resistant to the antituberculosis agents rifampin, ethambutol, and isoniazid, so susceptibility testing of RGM should not be performed with these.
The clinicians in our case suspected that the M. chelonae culture from the patient’s JP drain was most likely a contaminant as the same organism was never isolated from previous tissue or fluid cultures. He was continued on daptomycin, ertapenem, and ciprofloxacin was added to cover P. aeruginosa. The patient responded well with resolution of his localized symptoms at the site of the JP drain. Unfortunately, he continues to suffer from multiple, recurring presacral abscesses.
Rimmer J, Hamilton S, Gault D. Recurrent mycobacterial breast abscesses complicating reconstruction. Br J Plast Surg 2004; 57:676.
John T, Velotta E. Nontuberculous (atypical) mycobacterial keratitis after LASIK: current status and clinical implications. Cornea 2005; 24:245.
Freitas D, Alvarenga L, Sampaio J, et al. An outbreak of Mycobacterium chelonae infection after LASIK. Ophthalmology 2003; 110:276.
Sampaio JL, Junior DN, de Freitas D, et al. An outbreak of keratitis caused by Mycobacterium immunogenum. J Clin Microbiol 2006; 44:3201.
Edens C, Liebich L, Halpin AL, et al. Mycobacterium chelonae Eye Infections Associated with Humidifier Use in an Outpatient LASIK Clinic–Ohio, 2015. MMWR Morb Mortal Wkly Rep 2015; 64:1177.
Toy BR, Frank PJ. Outbreak of Mycobacterium abscessus infection after soft tissue augmentation. Dermatol Surg 2003; 29:971.
Centers for Disease Control and Prevention (CDC). Mycobacterium chelonae infections associated with face lifts–New Jersey, 2002-2003. MMWR Morb Mortal Wkly Rep 2004; 53:192.
Wallace RJ Jr, Brown BA, Onyi GO. Skin, soft tissue, and bone infections due to Mycobacterium chelonae chelonae: importance of prior corticosteroid therapy, frequency of disseminated infections, and resistance to oral antimicrobials other than clarithromycin. J Infect Dis 1992; 166:405.
Wallace RJ Jr, Brown BA, Onyi GO. Susceptibilities of Mycobacterium fortuitum biovar. fortuitum and the two subgroups of Mycobacterium chelonae to imipenem, cefmetazole, cefoxitin, and amoxicillin-clavulanic acid. Antimicrob Agents Chemother 1991; 35:773.
-Will Humphery, MD is a 1st year anatomic and clinical pathology resident at the University of Vermont Medical Center.
-Christi Wojewoda, MD, is the Director of Clinical Microbiology at the University of Vermont Medical Center and an Associate Professor at the University of Vermont.
As pathologists, patient advocacy and safety have quite unique meanings as compared to our colleagues on the wards and in the clinics. It is such a unique opportunity to affect further care and treatments, depending on how testing is used. I find the combination of patient advocacy within the clinics an opportunity for pathologists to possibly meet patients and learn from our clinical colleagues about how much the lab truly affects patient care.
At my institution, we have what is designated as “Diagnostic Management Teams” (DMT). At each DMT, our clinical pathology teams perform actions such as writing interpretations for difficult test panels or review the charts to make sure teams have changed their patients to the proper antibiotics. . In our coagulation DMT, we write the interpretations for complex esoteric coagulation studies to ensure: 1. the right tests were ordered, and if they weren’t, we recommend which are appropriate, 2. these complex tests are explained in a way that is understandable to our clinical colleagues and 3. proper patient care and safety for tests which are very critical to patients. To add a layer to this complex testing system, we also have the opportunity to attend benign hematology clinic with one of our attendings. I found this experience to be rather eye opening. Pediatrics hematology clinic is an interesting place whose patients are diagnosed with a wide variety of diseases. A vast majority of these pediatric patients have a parent who has been deemed a “bleeder” or a “clotter” at some point in their lives, or the patients themselves have exhibited such conditions. Often, the parents do not have a definitive diagnosis, and so the investigation begins. The hematologist, who also is one of the coagulation DMT attendings, will order panels which fit with clinical history not only on the patient but more often than not on their parents as well. This allows the DMT to analyze the nuances of the complex coagulation system, even down to multimer gels to figure out which type of von Willebrand disease a patient may have. Although these clinic visits may seem superficial, they give families such a comfort to know a classification of their disease, how it can be treated and if it has been passed down to the actual patient, their child. One such instance, we actually produced a family pedigree with the type of von Willebrand disease within them and then did confirmation testing. Seeing the delivery of information and subsequent relief on the patients’ faces is always a gentle reminder of how much we affect and advocate for our patients in the lab, which starts with the order or a “simple test.”
-Melissa Hogan, MD is Chief Resident in her fourth year in anatomic and clinical pathology at Vanderbilt University Medical Center and will be starting her Cytopathology fellowship at VUMC in 2020. She is currently Chair-Elect of ASCP Resident Council. She is passionate about patient care and medical education.
When I was approached about writing an essay about our rural lab, I was initially stymied. There’s a universality about the work we do; tech work is pretty much the same wherever you go. A differential is a differential in the biggest cities and smallest towns. The thing that makes us unique is that we’re 50 miles from a city with a full-service hospital and many of our patients are elderly and don’t drive, so we try to cobble together as much care as we can give them in a clinic setting.
Our clinical laboratory is a small independent lab in Cairo, IL, midway between Memphis and St. Louis. We are attached to a regional system of rural clinics that provides care for the residents of the poorest counties in Illinois. We are the only high-complexity FQHC lab in the country, and we’re extremely proud of the work we do with our limited financial and geographical resources.
Our part in battling the COVID-19 pandemic feels a little odd compared to the work of hospital labs. We see our job as keeping our patients out of the overburdened hospitals for as long as possible. We screen everyone who presents with a fever for flu and strep. That includes the prisoners from the two local prisons, the nursing home patients in all the small towns scattered around rural southern Illinois, the teachers, daycare and home health workers. The criteria for a C-19 test is still very stringent in Illinois and most of our patients don’t yet meet it. We generally send them home with free samples of over-the-counter palliative meds, instructions about avoiding other people, and what new symptoms they should watch for.
Even so, we’re running low on basic supplies: PPE, swabs, disinfectant, etc. Like everyone else, we’re having trouble finding more. Yesterday I took a couple of hours to open every cabinet and paw through every box, hunting for overlooked supplies. There was a stash of sixty N95 masks in a closet and forty painter’s masks left over from when the lab was built. The box claims the masks “have N95 properties”…whatever that means. Hopefully we won’t have to find out. I distributed the N95 masks to the clinics that were running low and traded a box of disposable lab coats to our local clinic for 3 hazmat suits for our lab staff. I sent a few dozen more nasopharyngeal swabs to the prison with instructions to use them sparingly. We’re currently backordered until mid-April for more.
All the techs I know (locally and all around the country) are pretty fatalistic about this. We expect to be infected. We’re hoping it’ll be later rather than sooner and we’re trying to protect our more medically fragile and/or elderly colleagues. As you probably know, the average age of MTs in this country is about my age…56. A new virus brings attention to the medical lab profession, and that causes a brief uptick in new interest in our field, but we’re chronically understaffed and techs are retiring faster than we can train new ones to replace them.
In the meantime, of course, we continue to test and treat our regular patients. Mostly poor, mostly elderly, for the diabetes, hypertension, cardiovascular diseases and cancers that are the meat and potatoes of rural health. The concession they’ve made to social distancing is that less of them hug me, although a fair number say “If it’s my time, it’s my time” and hug me anyway. Many of our patients don’t drive, and they arrive one by one on the transit vans designed to seat 12 that pick them up from home. I wonder if the van driver disinfects between patients. I wonder if the patients know he ought to. I assume they hug him, too, so it probably doesn’t matter. This coronavirus crisis will eventually wind down, but the ongoing needs of medically underserved rural communities will continue unabated. Our hope is that this pandemic shines a big light on the many challenges of providing quality care to geographically large, sparsely populated rural communities.
-Evelyn Rubinas is a Medical Technologist at Community Health and Emergency Services, Inc. (CHESI) in Cairo, IL. She is a graduate of Southern Illinois University and the University of Arizona and has been a laboratory generalist for over two decades. She lives in Cairo, IL with her wife and a small menagerie of rescue animals.
I’ll get straight to the point this time: there’s a legitimate crisis happening in our world that is highlighting a multitude of things. Just to name a of few: the complex intersection of state-sponsored healthcare as a human right, the availability of resources to clinical personnel, the logistics and implications of public health measures to the average person, our global connectivity, and lack of damn tests!
And that’s our stop. Please take a minute to locate your exits, as they may be behind you, and get ready to talk about this SUPER CRITICAL aspect of the COVID-19 pandemic. What are clinical tests?
I know, this “viral” topic right now will be shared and spread to a vast array of audiences. So, I’m going to try something new here. The last four years of posts on this blog have been aimed somewhere between laboratory professionals and working clinicians. I open a rare window into our clinical world from time to time, but this pandemic is something affecting everyone. Today, we’ve got a major problem about what’s being said in the media and who understands which parts of it…so, as I discuss some major points below, I will take short pauses to highlight clinically relevant information as well as put things in plain, simple terms for all of us to get up to speed together.
(If you are one of my clinical colleagues, from the bench to the bedside, your notes will be in BLUE. If you are not in the healthcare world, or just want some simple clarification, your notes are going to be GREEN. Let’s run an example so you can see what I mean…)
Last month I talked about the background and biology of the SARS-CoV-2 virus as a novel, emerging pathogen and potential pandemic and discussed how we must contextualize these epidemics with proper understanding of data and statistics. Numbers are important and if we’re going to combat a super bug, we’ve got to know what it is, how it acts, where it came from, and what’s happening in the field. A subsequent and fantastic post right after mine by Dr. SoRelle at UTSW, discussed how to validate a COVID-19 test in your laboratory. Basically, he presented a snapshot of the current climate of academic hospital labs now depending on LDTs to respond to the pandemic and discussed where to read more, what limitations testing might have, and how to address things like designing/purchasing primers, cross-reactivity, detection capabilities, and EUAs under the new FDA guidance.
But back to business, this month we’re talking about testing, and if you just google search “COVID-19” in the states, you’re met with a myriad of failure stories…
“As US fumbles COVID-19 testing, WHO warns social distancing not enough” (source)
“Limited access to COVID-19 tests frustrates patients, health professionals” (source)
“What went wrong with coronavirus testing in the US” (source)
“Why coronavirus testing in the US is so delayed” (source)
“America’s shamefully slow coronavirus testing threatens all of us” (source)
I’ll stop torturing you. You’re forced to watch and/or read enough news as it is nowadays (you’re social distancing, right? …right?) I mean, even Norway took a jab and called us “underdeveloped” citing our poorly developed healthcare delivery system—ouch. So, what’s the big problem with testing? What stark revelation exists between all these different news sources and highlights our “laboratory failures” in America? Well, luckily nearly all of these lab-fail stories aren’t aimed at our labs at all, they’re aimed at governmental decisions and red tape traps. But that’s hard to get to in a sea of clickbait. So instead of giving you more rabbit-hole lab talk, let’s talk about two main tenets of this narrative that everyone should be aware of: what laws affect lab tests and what does it mean to create a new lab test? After we clear the air for those two key points, we’ll come back around and tell you what COVID-19 looks like in the medical laboratory.
The Law of the Lab
There are SO MANY regulations and accrediting bodies that govern the way labs operate, deliver results, and function in clinical settings. Let’s name some! Various federal, state, and local laws ensure the highest calibers of safety and accountability for clinical and research laboratories; laws from OHSA, the FDA, recommendations from the CDC and local health departments; regulations for mechanical, noise, chemical, exposure, pathogen/infectious safety, pollution, radiation, blah blah blah! Trust me, there are a ton. What feels ever present to us laboratorians are the accrediting and inspection agencies that grant us authority to continue performing our clinically vital roles. Joint Commission, FDA, and other inspections make sure hospitals are up to snuff. Laws that govern what labs can do what tests fall under CLIA. They help us define high complexity to waived (not complex) testing. There’s a massive difference in a clinical office’s medical assistant obtaining a point of care (POCT) glycated hemoglobin (Hgb A1c) than a medical laboratory scientist conducting a hemoglobin electrophoresis study, and that difference highlights specialized training, laboratory ability, safety and quality requirements.
Accreditations and recommendations can come from many professional societies like the CAP, ASCP, AABB, AACC, ASM, ASH, and many subspecialized groups. Laboratorian trigger warning: I’m a certified CAP inspector. No; you don’t have to put away your desktop coffee…for now. But I’ve certainly—along with all of you—been wholly immersed in the endless accreditation and regulation protocols we follow. We know exactly why these regulations exist and we should talk more about them, since they define our role as such a critical one.
Feeling Validated Yet?
Some of you lost a breath when I said CAP inspector. The rest of you may now spit out your coffee and run for the hills because I’m talking about VALIDATIONS. Rotating MLS students sometimes do their capstones or theses on validating a test or instrument, but we do them because that’s just a part of our job! So what goes into validating a test? The short answer: a whole lot. The long answer: a whole lot more! Let’s take PCR testing for example, it’s topical because we’re talking about COVID-19 testing and that’s the prime modality so let’s explore that validation.
So, you want to add a qPCR to your lab’s test menu, eh? You first have to decide quantitative or qualitative. If its quantitative you’re in for a treat—yay statistical variant analysis! You have to prove applicability, practical application, specificity, sensitivity, efficiency, correlatable translation into useful clinical data. Detecting a number or degree of mutations? Make sure its accurate and precise (and repeatable). Buying commercial kits or making your own in-house assay? What about a qualitative test, just a simple yes or no. Easier right? Not really, you need to prove most of the same data and statistical soundness depending on methodology used, instrumentation, nature of variation, etc. AND: it all must be documented, proven, up to regulatory standards, and you better have a database FULL of data that proves your test works. Now, I have good news and bad news.
The good news: this is pretty routine, and pretty easy to follow even for simple new tests your incorporating from commercial vendors with ready-to-validate test kits. The bad news: COVID-19 is not this type of test. Say what you will about the US’s decision to NOT utilize the WHO testing model available weeks ago, the CDC responded in kind here by providing a two-control kit that SLOWLY started to break out. Using this as a model, many labs in academic hospital pulled the trigger on their LDT work. (LDT = laboratory developed tests) I’ve already revealed myself as a CAP inspector (pshh, not even my final form!) and I can tell you that there are hundreds of citations for how to validate already existing tests, compare tests across different instruments, compare them across the same instrument, prove your statistical ability to ensure quality results, and even how to make your own test from scratch! Talk about extra work!
Running COVID-19 testing alongside B. burgdorferi: Corona…with Lyme?
Now we’ve come to the heart of the current discussion. Dr. SoRelle talked about validating a COVID-19 assay last month, so I’m letting him take point on that—read his piece, its great! What we’re talking about today is what exactly regulations and validations have to do with COVID-19 testing. Remember the regulations that say how laboratories run tests and operate clinically? Okay, well there are issues with this narrative. You’ll see plenty of news stories about the regulatory red tape that has hindered lab professionals from providing COVID testing. This makes it sound like because of “rules” we just can’t give them out to everyone, or we can’t set up testing for whatever regulatory reason. This is not the case. This is how the relationship between those aforementioned regulatory bodies work. The FDA makes sure labs operate up to federal standards and, and specifically, enforce regulations outlined in CLIA. While the FDA would like to call tests/results products of analyzers/devices to fall in their prevue, the interpretation and translation of that clinical data is not a print out but a MEDICAL SPECIALTY—hi, I’m pathologist #2465827, part of the FDA regional lab result response team—nope. Lab developed tests (LDTs) are not FDA products, but CLIA certified processes that only CLIA certified laboratories can perform. No CLIA no LDT—it’s as simple as that. You now understand that a lot goes into a single test, and that not every lab can perform high-complexity testing, thus, not every lab is CLIA certified to do LDTs… which means no COVID testing for them.
Okay, the other half of the narrative says that because of a lack of supplies from industry vendors, commercial kits were unavailable either from them or the CDC and if they got them, their reagents were not good. Frustrated, scorned immunology/chemistry lab specialists decide, “we’ll show them…we’ll make our own test! *evil laugh*” A bit dramatic, because it is dramatic. That’s not how LDTs work. How, then, do we get to LDTs? That answer is simple: regardless of politics, resources, or any other social concerns, medical laboratorians and clinical pathologists are part of the essential healthcare team that strives to care for the sick and hopes to prevent unnecessary infection or illness. We’re in this together and if one system can’t provide tests for the whole country, hundreds of thousands of hospitals will rise to the occasion and share partial LDTs or create their own. Just like with any other test, labs know full well how to get this done and work together to do it.
But what about the stories that say some tests take 8 hours vs others that take 4 days to turn around results? How come some kits came with 2 swabs, and some with 3? Why did other countries like South Korea do a lot better than us in testing their population? Did we wait too long to set up LDTs? Can’t I just go to my doctor and get tested now? Okay, okay, I hear you. This is where it gets heavy, especially in the media. The takeaway can be a simple comparison: look back to the Zika epidemic. Zika is an Arbovirus/Flavivirus that we knew about for roughly 60 years. As such, we had time to understand it and create tests quickly that measured exposed patients’ antibody response to acute or resolved infections. Even simpler, Zika is part of a family of mosquito-borne illnesses that we generally understand pretty well. SARS-CoV-2 is not like Zika. The word “novel” is used because it’s just that: brand spankin’ new. And, even though it’s a cousin of its predecessor in the old SARS epidemic, we’ve been racing the clock to create accurate and reliable testing. That’s why there’s so much variability happening across commercial industry to academic hospital laboratories.
I love to make puns but let me be clear: this is a serious global pandemic, as defined by the CDC and WHO and we must understand this fully and appropriately. We’re still in the dark about a lot of data, mostly because of missing numbers. What we do know continues to inform our daily-changing climate of public health awareness in the US. The following images speak for themselves and I’ve collected them as a resource and snapshot for you to look through, just to get your SARS-CoV-2 bearings.
What can I say? It’s hard to write a conclusion about something that’s changing every day. I’ve been doing my best editing to keep this as up to date as it could possibly be for publication, but there are a million more resources sitting in the queue that I wish I could walk you all through. But I think, at the end of the day, what we need to remember is one simple thing: we’ve been here before and we’ll be here again. Public health epidemics and our responsiveness is one of the more serious aspects of laboratory medicine and pathology, not to mention healthcare at large. I said it last month that we’re lucky that this isn’t an influenza-type virus, because that would look a lot different. There are still some highly serious infectious etiologies out there more lethal than COVID-19, but this pandemic is bringing to light a lot of public health awareness and an opportunity to examine our population’s medical/health literacy, our policy priorities, our strength and resolve, as well as our ability to adapt.
In the coming days, weeks, months you’re going to most likely hear about municipal infrastructures cutting back on things in order to prevent the spread of the virus. Listen to these warnings and heed the advice of the medical community. If you think you’re being a hero by braving the storm, you’re no better than a mosquito that carries malaria with no symptoms itself. Wash your hands, practice appropriate social distancing, continue your daily life with your necessary trips out being mindful of what those of us in healthcare live with on a daily basis. Practice compassion as well, just because we’re social distancing to “flatten the curve” doesn’t mean its time for martial law and cleaning supply hoarding. I know these are serious times, but humor and compassion can be infectious too.
Thank you for reading.
Please remember to follow the most updated, verified, and trusted sources on this starting with the CDC and your local public health organizations.
Wash your hands. Change your clothes. Minimize exposures. Take time to reflect and keep as close to your normal routine as possible while remembering things will get better.
If you have specific questions, comments, or concerns leave them in the comments below. Feel free to contact me anytime, and follow my social media (@CEKanakisMD on Twitter) for more/updated material.
Take care, see you next time!
-Constantine E. Kanakis MD, MSc, MLS (ASCP)CM is a new first year resident physician in the Pathology and Laboratory Medicine Department at Loyola University Medical Center in Chicago with interests in hematopathology, transfusion medicine, bioethics, public health, and graphic medicine. His posts focus on the broader issues important to the practice of clinical laboratory medicine and their applications to global/public health, outreach/education, and advancing medical science. He is actively involved in public health and education, advocating for visibility and advancement of pathology and lab medicine. Watch his TEDx talk entitled “Unrecognizable Medicine” and follow him on Twitter @CEKanakisMD.