From Panic to Pandemic: Laboratory Emergency Response Plans

In 2018, Hurricane Florence ripped through the Carolinas causing an immense amount of destruction and taking a record amount of lives in the area. Superstorm Sandy had a devastating impact on New York and New Jersey in October 2012. In Joplin, Missouri, an EF-5 tornado cut a damaging path through town in May 2011, directly hitting the hospital. Severe storms, flooding, and even blizzards are regular events throughout large areas of the United States every year, disrupting normal life and the delivery of services, including healthcare services.

Natural disasters occur frequently, and labs must consider them in their Emergency Response plans. These disasters have consequences for hospitals and laboratories and their operations. Given the wide variety of possible disasters that can affect a laboratory, it may seem impossible to be prepared for every type of event that could occur. Some labs take a reactive approach and create individual plans for different disaster types. For example, a lab manager may decide to create a blizzard response plan after a major winter storm—a plan that is separate from any previously existing lab emergency response plan. That may not work well, and it many plans may become cumbersome for lab staff when the event occurs.

As 2020 has shown us, other types of disasters that are not normally considered can also affect laboratory operations. The COVID-19 pandemic situation has created issues like the reduction of the availability of staff, a need to quickly alter testing platforms, and even major supply acquisition issues. Clearly, pandemic issues need to be considered when looking at lab disaster responses.

The best type of laboratory emergency response plan is a single plan that will enable the laboratory to continue to provide services in a variety of disaster scenarios, including pandemics. The College of American Pathologists (CAP) requires labs to develop an emergency plan which is based on the overall facility’s Hazard Vulnerability Analysis (HVA). The HVA is a risk assessment tool that lists types of disasters that can affect the facility, and it ranks which disaster types are most likely. If you work in an independent lab, you must perform your own HVA and update it every year. In 2020, it would be prudent to quickly add “pandemic” to the list.

There is no need to panic, however. In your plan which has been designed to have an “all hazards” approach, you may find some aspects of pandemic response are already addressed. Fluctuating staffing levels should already be addressed. Be sure the plan discusses how to best utilize staff when fewer people are available. That process may include a reduction in testing or utilizing a reference lab if necessary. In some instances during the pandemic, labs were left with too many staff members once an overall reduction in lab volumes occurred. How can extra staff be used? Can they go to other departments or facilities where needs may exist? There should be a section in the response plan regarding how to handle supply issues. If it is known there is going to be a problem obtaining PPE, reagents, and other supplies, decide what procedures will occur. Stockpiling, finding alternative vendors, and changing the type of supplies purchased are some options.

Once all of the pieces of the updated lab emergency operations procedure is complete, it is important to test the plan for flaws or needed improvements. One thorough method of testing includes the use of a table-top drill or exercise. Present a step-wise disaster scenario to key lab stakeholders and discuss possible responses as the imagined situation unfolds. Be sure to discuss important aspects such as staffing, supplies, communications, and relocation of testing. If the COVID-19 pandemic has led your lab to utilize its emergency response plan, be sure to take the opportunity to review how it is working for your department. Ask lab leaders and staff members if the current plan works- what went well and what needs improvement? This current disaster can help us all to improve our current procedures and keep us ready for the next event.

Is your laboratory emergency operations plan up to date? Does your staff know how to use it or will they panic when a disaster occurs? Has the plan been tested? Now is the time to review what you have and make sure it works for pandemics as well as a wide variety of disaster scenarios.

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.

Practicing Productivity in the time of Pandemic

At this point, you are either somewhat adjusted to working from home (likely taking on new roles and responsibilities while juggling your kids, dog, and spouse), battling COVID on the front lines (caring for patients, providing us with food, or keeping the lights on), or unemployed (yet another victim among a whole host of victims during this extremely trying time). Regardless of where you fall, you have likely been on at least one video conference since January and you will likely be on many more over the next six months. As live, in person meetings of 2500 to 5000 people that we are so used to have come to a screeching halt, the world of associations such as ASCP are carefully and artfully creating virtual experiences that you can be assured will enhance and improve your life but will most definitely be in a virtual format. But the whole world is now experiencing online happy hours, teaching sessions, work meetings, telehealth visits, group therapy sessions, and kid’s birthday parties. Step back from your current situation and ask, “Have I seen MORE or LESS of my friends and peers in the last six months than in the prior year?” That answer is different for each person and carries different emotional baggage. For the constant extrovert who needs that human interaction fuel to spur them on, video conferences may not be hitting the mark. For the ever-quiet introvert who happily recharges among their books and cats and knitting, constantly being required to video chat with people for hours on end may be pushing them toward a steep cliff of insanity. For the “mover and shaker” that loves a problem a minute, thrives in crisis, and gets utter joy out of solving a problem and moving on, facing a day filled with 8 pre-scheduled video conferences or, worse, a day with an empty calendar can be demoralizing. For anyone who had a rhythm to their email usage which involved key time points to check during the day and an internal list of priorities of how to deal with emails on a rolling basis, the extreme uptick in volume of email because everyone is working remotely in the same office (“where is the water cooler chat?”) is dizzying.

It is now July 2020 and we face the uncertainly of what working from home will mean or be or even when it will end (or will we choose this as a permanent solution?). For those of us who have been and continue to report to our work place using social distancing, masks, shift rotations, and the inability to touch anything around us, how can we make this sustainable long-term, do we need to do so, and how do we know when we can end it? For the hundreds of millions of non-laboratorians who are asking, “When will there be a test so we can go back to work?”, the job of the laboratory has long been a mystery but is now suddenly thought to be a miraculous answer to a complex problem of politics, public health, and capitalism. Amidst all of the uncertainty of COVID-19 that we are facing on a continuous basis, the country was already immersed into a “fake news” war between rival political factions that already had the bulk of America either fed up with all new sources, only trusting one “news” source (the bulk of which was political agenda opinion), or simply burying heads in the sand in hopes that this was all just a bad dream. We are halfway through 2020 and the optimists are saying, “It can only get better” and the pessimists are sighing, “what comes next?”. The only people who aren’t complaining are the myriad of investors who didn’t even need a crystal ball to predict the March stock market crash, sold short, and raked in billions—which they then returned to the market buying blue chips at rock bottom (relative) prices to now be showing a 20% return. If only we could all be so lucky?

But there is a light at the end of the tunnel and the sun will come up tomorrow. Nothing lasts forever and this virus will run its course—whether we fight it tooth and nail or ignore it—to a natural conclusion which is harmony within our population. Over the next 6 months, enormous amounts of data on epidemiology, biology, virology, and treatment will emerge. We will learn from our colleagues in Africa what the impacts of early, sustained interventions can do to thwart the virus. Over the next year, vaccines will appear and be available for the population at large. The myriad of tests will have settled around a handful of reliable “winners” that have the sensitivity and specificity we need for each of the valued applications in our systems. The stock markets (and your retirement funds) will have recovered and exceeded pre-COVID-19 levels. However, one aspect of our lives will be permanently changed and that is our dependence and use of video conferencing for the special, the everyday, and the mundane. To that end, let me conclude with some of my (hard earned) lessons from both the last 6 months and the last 20 years of working in global health.

  1. Video conferencing etiquette is a “thing”. Seriously. Tools available to the host can get you so far but nothing says, “we are all in this together” like a team on a video call that is following the rules. Mute yourself when you are not talking. Turn off your computer’s sounds or software that makes frequent sounds. Do not leave your cellphone on your desk on vibrate (computers have great microphones!). If your internet connection is bad, switch off your video. When you are listening, look directly into your webcam (then others feel you are looking directly at them and they feel more connected). Use a virtual background if possible so we do not see your kids making breakfast in the background. Brush your hair (you can totally get away with no pants and not showering but “bed head” is a dead giveaway). Sit within 3 feet of your computer. Rename yourself on the screen if possible, with your full name and organization. Do not take a video call while walking outside.
  2. Your workstation is your productivity cockpit. Make sure it has what you need. In today’s world of multitasking and conferencing, two screens are almost a must. You can use a laptop while traveling but for a home office, having two screens creates a much cleaner canvas to spread out your work, keep resources at your fingertips, take notes while conferencing, etc. Treat your digital workspace like your physical desktop. Keep only what you need on the desktop. File your files in folders you understand and can follow. If your virtual desktop is covered in hundreds of files and icons, your brain is not mentally able to process or prioritize. Use a background picture that sends you to your happy place so that, when you need a break, all windows can be closed, and you can zip to your happy place immediately.
  3. Develop a personal system for communications. Maybe you are a texter, a snapchatter, an emailer, a phone-call-aholic, an instant messenger fiend… Whatever you are comfortable with, the other dozen people you interact with are comfortable with something else. Your team lead may say, “We are using Teams!” or “We are using Basecamp!” or “We are using Sharepoint!” but, let’s face it, it may not fit your style or your work flow. The important thing is to develop a system for whatever communication type you feel most comfortable and work that system to be productive. I have seen the inboxes of people who have 85,000 unopened emails (both personally and professionally) to which I reply, “Delete them!”. If something in those emails was so important, the person will have found another way to contact you. You are never going to read them and, honestly, email just does not work for you. Pick another channel. Texting can work for many people but the organization of texts on a phone and the archiving eventually becomes a challenge such that screen captures or lots of copy/pastes must occur. Whatsapp is a good solution with its archiving function but can still present a permanence problem. Your chosen communication channel is important because it will dictate your productivity style. For example, one of my colleagues takes extensive notes on paper (extensive!) but sometimes takes extensive notes on a tablet. Their work stack (i.e., the collection of items they work through daily) is a combination of pieces of paper and digital notes, but it is disconnected from a communication system. The time required for note translation into understanding and then moving those thoughts to an email, for example, for me would be wasted time. But they remain one of the most productive people I know so this system works for them! Each person must decide what makes them most productive and what keeps them informed and connected; however, a good approach if you are feeling overwhelmed is to use a single system (digital) that moves with you. Microsoft Outlook, Gmail (and calendar), and iCloud all have cross functionality that allow seamless notetaking, email and calendar creation, and file connectivity. Outlooks category function for email can be a massive time saver for the adept user where a preliminary read through of email can allow for classification (for example, I use “Urgent”, “To do – Non-Urgent”, and “Waiting on Reply”) and then priority follow up. At the writing of this blog, I have less than 30 emails in my inbox, all are categorized, and all are calendared for completion.
  4. Go outside and breath. The single most important thing that we can achieve as a society as we emerge from the COVID-19 pandemic is an appreciation for life, freedom, and health and that is difficult to do if you stay in front of your computer for 12 hours a day. More than half a million people have died of COVID-19 and we could have been one of them. Unemployment spike from a flat 4% to more than 14% with many companies, restaurants, and small businesses never planning to reopen. The unfortunate tragedies that continue to befall our black brothers and sisters led to peaceful protests which were then corrupted by riot and ruin across many major cities. Even now, racial and ethnic disparities, especially our Navajo neighbors in the Southwest along with our black communities, cause disproportionately suffering from COVID-19. It is not a time to think, “I’ve been lucky!”. It is a time to say, “What can I do to help today?”And where the help is needed is outside, in your community. Yes, you should wear a mask if you can’t social distance. Be sure to wash your hands frequently. But get out there and be part of the change for the better!
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-Dan Milner, MD, MSc, spent 10 years at Harvard where he taught pathology, microbiology, and infectious disease. He began working in Africa in 1997 as a medical student and has built an international reputation as an expert in cerebral malaria. In his current role as Chief Medical officer of ASCP, he leads all PEPFAR activities as well as the Partners for Cancer Diagnosis and Treatment in Africa Initiative.

A Wave of Testing Advances or Just a Drop in the Bucket?

Hello again everyone and welcome back! Thanks for joining last time in my discussion of social media as an inexhaustible force in professional development. This month…something different…

Yes, indeed, this month’s piece from me to you is a well-deserved break from your regularly scheduled pandemic reading. Consider this your COVID content caesura. Whatever will we discuss without the virus at the forefront of all of our media channels? What then could possibly hold our attention, satisfy our craving for knowledge and professional development, and quench our thirst for lab-driven news?

Liquid biopsies. Obviously. Get it? Thirst? Quench? Yea? I’m sorry, let’s just jump in…

Image 1. This is totally what happens during liquid biopsies, can you guys not visually see DNA? You might need better centrifuges/brighter bulbs—talk about your 10,000 ft. diagnosis, right? (Stock image: Cancer.org)

In my recent social media scroll-binging (which is absolutely normal nowadays, don’t judge) a small story about a published article in JAMA appeared nestled gently between powerful protest content, pandemic virology, and 2020 politics. The article, which was just a small summary of a study in Science that combined liquid biopsy testing with PET-CT imaging to screen and guide interventions for a variety of cancers detected among over 10,000 recruited patients. Detected cancers included anything from solid masses to lymphoma and were found from thyroids to the ovaries. Translation: earlier, more comprehensive detection of malignant neoplasms of all sorts ….*drum-roll, please* ….BY BLOOD TEST! If you’re not impressed with this outright, then don’t fret. This kind of lab testing technology is some Penn & Teller level medical lab science, and I’m very excited about it! I could do a whole talk on this, a professional one, a TEDx one even…scroll to timestamp 4:50:00—of course I’m gonna plug the TEDx talk here. You know me.

Image 2. Remember your A-B-P’s: Always be promoting. Like the TEDx talk I gave, where I talked a bit about liquid biopsies; I don’t know if told you that I did that … (Source: TEDx)

What’s a liquid biopsy anyway?

That’s a great question, I’m glad you asked. Basically, think of it as the pinnacle of precision medicine—the gate key for all diagnoses and prognoses for an individualized treatment regimen based on the principles of known mutagens and detectable proteins and particles. Put plainly, a simple blood test that tests your blood (or other body fluid) for specific biomarkers to clue us in on the presence of an insidious malignancy. What kind of markers? Circulating tumor cells, micro-amounts of relevant RNA, vesicles, modified platelets, and other parts of cells, specific proteins—the list is growing. New concept, right? Not exactly, we’ve known about circulating tumor cells for at least 70 years now (nope, not a typo) but we haven’t been able to accurately hunt for them. We’ve had a concept of this sort of testing since the 70’s but have had a hard time implementing its clinical utility.

Image 3. A clinical lab. Somewhere. Circa 1975. To be a fly on the wall when they decided to skip gas biopsies and jump straight from solid tissue to liquid—what a concept! (Source: Univ. Texas at Austin, College of Health Sciences, historical photo of flu drug development at Memorial Sloan Kettering, NY)

Until the present day. Much like PCR, NGS, MALI-ToF, specialized mass spectrometry, and other awesome tools in our clinical arsenal, the ability is surpassing the paradigm. Whoa—philosophy check: are we moving too fast? Is this a reckless exercise? Should we do more research? No, no, and yes (obviously, always). Liquid biopsies have had pre-Wright brother success in getting airborne, so I’m recruiting all you readers out there to get excited with me and garner interest. Previous limitations might have meant we needed histological diagnosis first—I see you, everyone on the AP side… but these papers I’m showing you all today say basically three things: (1) our technology for liquid biopsy is getting better, (2) we might not need any previous test/section and could use liquid biopsy as a screening tool, (3) combined with imaging studies, this could be highly predictive and clinically useful.

The published study said what…?

Okay, let me show you the papers in the order I saw them: the JAMA article was just a primer in their Biotech Innovations magazine, a summary of an interesting development in liquid biopsies. They referenced the recent study in Science and discussed how 26 of the 10,000 women aged 65-75 were confirmed from liquid biopsy (LB) to imaging with PET-CT and, ultimately, biopsy to conclude. It said that the “blood test combined with the PET-CT had a 99.6% specificity and a 15.6% sensitivity…” with more being detected by LB at follow up. If those numbers triggered you as much as they did me, then of course you would have done what I did and followed the breadcrumbs.

Image 4. (LEFT) the three-tiered method of testing in the Detect-A Science paper and (RIGHT) the nearly 99% specificity of the CancerSEEK liquid biopsy modality in the second referenced Science article.

Que the Science study. In it, the authors presented their three-step testing process, using “Detect-A” LB for baselines. Ultimately 26 cancers in 10 organs were detected by just the blood test; this was out of a total of 96 cancers detected overall in the 10,000 participants either through liquid biopsy, current standards, or other investigative work ups. They did the math and showed that despite a sensitivity of 15.7% for the combined LB and PET-CT, the positive predictive value rose from 5.9% to 40.6% when you combined those two modalities. But the other statistics weren’t as impressive. Back to the JAMA article! The very last line said, “a newer version of the test that has a 99% sensitivity without confirmatory steps is in development…” Okay, now we’re cooking with gas—or testing with liquids—whatever: that’s the holy grail of CP testing 99% sensitivity, 99% specificity! Do tell!

Much ado about liquid—this was less impressive. This last line referenced a Science paper used “CancerSEEK” LB in 1,000 patients with sensitivities from 70-98%, but fantastic 99% specificity. Different panel, different cancers this time. Interesting to note, was that, applied to the specific incidence in the US population for the particular cancers detected by CancerSEEK, the sensitivity was around 55%. And, they managed to keep the cost relatively low at under $500 per test. (Sorry, if a red light just went on while you read this, CMS is probably recording now…) Well, this left me wanting. I’ve read so little about LB’s in recent years, is no one working on them? Well no, I was just busy, there’s tons of stuff out there, silly.

In just the past year alone, the American Journal of Clinical Pathology published 10 pieces on liquid biopsy cases, education, and utility for all kinds of malignancies from cytology to hemepath! AJCP—that’s us guys, it’s happening right here, right now! I told you we’ve got to do a PR run on this stuff and get it out there.

Is this the future? Are we in it now?

I’m happy to report that yes! This is indeed the future, well at least as thought of by the folks that conceptualized liquid biopsies 70 years ago. No hover-cars, or hover-boards, or hover-anything really (not without a lot of tech and work) but we’re closer to small advances in medical diagnostics!

Image 5. Maybe a better conceptual map of what liquid biopsies do. (Source: Gene Quantification)

Nature writer Catherine Alix-Panabieres put it very well when she wrote an Outlook piece this past March. On the one hand, liquid biopsies are a growing clinically useful tool in the synergy of addressing cancer in individualized medicine. On the other hand, we’ve known about this concept and have clearly been working on advancements in this testing technology for decades—it’s about time to come out of the shadow and push into widespread utility, including them in cancer algorithms, and redefining the ways in which cancer work-ups are developed in clinical trials, regulated by safety, and integrated into the toolkit of oncologic diagnostics. In my recent interview with People of Pathology Podcast show-runner, Dennis Strenk, I said we’re not quite ready to replace tissue biopsies yet—but are we close?

When do we go from pushing glass to pushing tubes?

See you next time!

References

Abbasi, J (2020) Blood Test Flags Multiple Cancers in Large Study, JAMA. 2020;323(22):2239. doi:10.1001/jama.2020.9266 → read it here

Alix-Panabieres, C (2020) The future of Liquid Biopsy, Nature 25 Mar 2020 579, S9 doi: 10.1038/d41586-020-00844-5 → read it here

Bai, Y, and Haitao, Z (2018) Liquid biopsy in tumors: opportunities and challenges, Annals of Translational Medicine, 2018 Nov; 6 (Suppl 1): S89, doi: 10.21037/atm.2018.11.31 → read it here

CAP (2020) The ‘Liquid’ Biopsy, College of American Pathologists → read it here

Cohen, J, et al. (2018) Detection and localization of surgically resectable cancers with a multi-analyte blood test, Science 23 Feb 2018; Vol. 359, Issue 6378, pp. 926-930, doi: /science.aar3247 → read it here

Lennon, AM, et al. (2020) Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention, Science doi. 10.1126/science.abb9601 → read it here


-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.

COVID-19 Patients with “Green Crystals of …” STOP! Please Don’t Call Them That

Blue-green cytoplasmic inclusions in neutrophils and monocytes are a novelty in hematology. It is rare to see these inclusions on peripheral smears, and when we do, there is excitement, but sadness too, because, when noted, they usually indicate a poor prognosis and impending death. Thus, we have heard them called “green crystals of death” or “death crystals.” I know I would not want to read a family member’s medical chart and see reference to “death crystals.” It’s an insensitive term, and one the medical community is trying to discourage. And, in fact, though it typically does indicate a poor prognosis, not all cases lead to death. In published reports, it has been shown that short term mortality in patients with these crystals is about 60%.1

These rare inclusions are refractile and irregular in shape, and are found in neutrophils, and occasionally in monocytes. Color seems to be subjective here. They call them green when inclusions in photos or cells I am looking at look very blue to me. The color perceived may depend on the type of stain (Giemsa, Wright or Wright-Giemsa) used and how fancy we get in color names and descriptions. Or, maybe I’m just color blind! Some people (like my husband) are “lumpers” and call anything blue-green, blue, or green, but don’t recognize subtleties of colors. Thus, I guess to make everyone happy, or to compromise, the blue-green description may fit them best.

Image 1. Blue-green inclusions seen in neutrophils. Photos courtesy of Alana D. Swanson. UMMC

These blue-green inclusions were originally reported in patients with hepatic injury and failure. Laboratory results include elevations in AST, ALT and LDH. More recently, there have been cases with no evidence of hepatic injury. Researchers are now finding that these crystals can occur in patients with tissue injury other than liver, and in patients with multiorgan failure. In patients with no liver injury, what is a common factor is that LDH is elevated, indicating tissue injury. Additionally, along with these crystals, lactic acid levels can be used as a predictor of survival. Higher levels of lactic acidosis at the time crystals are noted is a negative predictor of survival.2

In trying to determine the clinical significance of these crystals, they have been subject to a number of different stains to determine their content. The association with hepatic failure led researchers to hypothesize that the crystals were a bile product in circulation. Since then, the crystals have been found to be negative in bile stains. When stained with other stains, Oil Red O showed positive in neutrophils, indicating high lipid content. The inclusions did not stain positive with iron stain or myeloperoxidase. Acid fast stains showed the inclusions to be acid fast positive.3 These crystals also show an interesting similarity to sea-blue histiocytes, which further associates them with tissue injury. After analysis, it is now thought that these crystals contain lipofuscin-like deposits representing lysosomal degradation products, and may be present in multiple types of tissue injury.2

With the current pandemic, I have seen reports of these crystals in COVID-19 patients. I have heard of fellow technologists seeing these, and a recent paper described the first reported cases in patients with COVID-19. These recent incidences may lead to new information about exactly what clinical significance they hold. About one third of COVID-19 patients have elevated ALT and AST, though it is not yet clear whether the liver dysfunction is directly caused by the virus, due to sepsis, or other complications of patient comorbidities. Many COVID-19 patients have mild disease, yet some develop severe pneumonia, respiratory complications, and multiorgan failure. Mortality is increased in these severely affected patients. To better understand and manage treatment for COVID-19, physicians seek to identify biological indicators associated with adverse outcomes.1

In a New York City study, Cantu and colleagues reported on six COVID-19 patients who presented with blue-green crystals in neutrophils and/or monocytes. All six patients had an initial lymphocytopenia, and significantly elevated AST, ALT, LDH and lactic acid at the time the crystals were noted. All of the patients had comorbidities, yet only two of the six presented with acute liver disease. Interestingly, in the six cases reported on in the study, only one had blue-green inclusions reported from the original manual differential. The others were found retrospectively when correlating the cases with patients known to have elevated ALT and AST. All patients died within 20 days of initial diagnosis.1

The consensus of several papers in the last few years is that these crystals are being underreported. As seen in the above study, the crystals were originally seen in just one of the six patients. A look back revealed the other cases. With an increase in COVID-19 cases in our facilities, these blue-green crystal inclusions may be a novelty that is wearing off. We may see a rise in their presence, and need to be able to recognize and report them. This information is important to report if clinicians are to use these crystal inclusions along with acute transaminase and lactic acid elevations to predict poor patient outcomes.

Clinicians, hematologists, and laboratory technologists should be educated and have a high level of awareness of these inclusions. The University of Rochester conducted a study a few years ago that noted that, because these crystals are rare, techs may not be on the lookout for them. Once techs see them, they seem to be on the alert and more are reported. The hospital instituted an “increased awareness” campaign, which resulted in an increase in detection. This revealed cases that were not related to liver injury, including patients with metastatic cancer and sepsis. However, an important correlating factor was that all of the patients had mild to severe elevations in liver enzymes. With more awareness, we are starting to see them in patients without hepatic injury, but with other inflammation and tissue injury.4

Image 2. Blue- green crystal inclusions seen in a patient diagnosed with sepsis and multiorgan failure. Photo courtesy of Karen Cable, YRMC.

Let’s raise our level of awareness of these maybe-not-so-rare crystal inclusions. And, please be sure to call them by their preferred name, blue-green neutrophil inclusions! Let’s not talk about death crystals or crystals of death.

Many thanks to my colleague Alana D. Swanson, MLS(ASCP)CM , University of Maryland Medical Center and Karen Cable, Hematology Section Lead, Yavapai Regional Medical Center, Arizona, for the photos used in this blog. 

References

  1. Cantu, M, Towne, W, Emmons, F et al. Clinical Significance of blue-green neutrophil and monocyte cytoplasmic inclusions in SARS-CoV-2 positive critically ill patients. Br J Haematol. May 26, 2020.
  2. Hodgkins, SR, Jones, J. A Case of Blue-Green neutrophil inclusions. ASCLS Today. 2019;32:431.
  3. Hodgson, T.O., Ruskova, A., Shugg, C.J., McCallum, V.J. and Morison, I.M. Green neutrophil and monocyte inclusions – time to acknowledge and report. Br J Haematol, 2015;170: 229-235.
  4. Patel,N, Hoffman,CM, Goldman,BJ et al. Green Inclusions in Neutrophils and Monocytes are an Indicator of Acute Liver Injury and High Mortality. Acta Haematol. 2017;138:85-90

-Becky Socha, MS, MLS(ASCP)CM BB CM graduated from Merrimack College in N. Andover, Massachusetts with a BS in Medical Technology and completed her MS in Clinical Laboratory Sciences at the University of Massachusetts, Lowell. She has worked as a Medical Technologist for over 30 years. She’s worked in all areas of the clinical laboratory, but has a special interest in Hematology and Blood Banking. When she’s not busy being a mad scientist, she can be found outside riding her bicycle.

A Resident’s Perspective of SARS-CoV-2 Testing Using the Double Diamond Model of Design Process

During the 2019-2020 residency interview season, I “courted” – no better way to describe those interactions over lunch–several potential co-residents, who were eager to know why I came to University of Chicago (NorthShore) for my residency. My answers and those of my fellow residents would help the candidates determine how high they should rank our program, so I enthusiastically recalled things I liked when I interviewed at NorthShore about a year earlier. I had also recently completed my first microbiology rotation in residency and I had enjoyed seeing all of those factors work synergistically to improve patient health outcomes through improved testing. So passionately, I shared how I fell in love with the physical structure of the department which has almost all the labs and offices one floor, the automation of the labs-especially the core and microbiology labs, the capability and regular expansion of its molecular laboratory, the people and of course, “the feel” about NorthShore.

With these experiences, I looked forward to my second microbiology in March 2020, where I would learn more about the diagnostics of various microorganisms–E. coli: Gram negative short stubby/broad shouldered rods vs. Pseudomonas aeruginosa, Gram negative long slender rods, etc. (Un)fortunately, March came, but the novel coronavirus (SARS-CoV-2) had other plans for my learning. Cases of Coronavirus disease 19 (COVID-19), caused SARS-CoV-2[1] were increasing rapidly in the US, so laboratories, including ours had rapidly implement testing. Rather than have morning rounds and other educational activities where the differential diagnoses of several clinically relevant microorganisms were discussed, we had virtual and in-person meetings discussing what to do about one virus. These continued and by the middle of March, we had become the only non-government lab in Illinois and second in the Midwest that had developed a clinical PCR test for SARS-CoV-2. I was excited to be part of that success, but more so, about learning how we achieved that as a team.

Our approach could be summarized using the Double diamond or 4D model of design process which consists of four phases: Discover, Define, Develop and Deliver (Figure 1).

Figure 1. Double diamond or 4D model of design process which consists of four phases: Discover, Define, Develop and Deliver. Plan Do Study Act (PDSA) is an iterative model of quality improvement embedded in the 4D design process.
  1. In the discover phase, a phase of divergent thought [2] and exploration, we identified from events in China and other parts of the world as well as some other states in the US that the community we care for could potentially be affected by the COVID-19 outbreak.
  2. The next phase- define- is a convergent phase where the problem to be solved, as well as the resources available and resources needed to solve it are delineated [2]. As we transitioned from the discovery to define phases-and recalling the 2009 H1N1 influenza outbreak about 10 years ago- it became evident that an epidemic of a relatively fatal respiratory virus which we knew very little about was heading our way. As clinical laboratory professionals, our objective was to help identify members of the community who had been infected through testing so appropriate steps could be taken to sequester and care for them. Among our available resources was our molecular laboratory, but like most laboratories outside the Centers for Disease Control and Prevention, CDC we lacked the reagents, primers and authorization to run the test.
  3. Develop is the next phase in the process and this is a divergent phase where the team explores and refines potential solution to the issues and selects one[2]. This is often followed by the convergent deliver phase where one of the solutions from the develop phase is implemented. Feedbacks which are used for projects are also received during this phase[2]. But, the outbreak continued to evolve rapidly [3] with briskly increasing positivity rates[4] and some of the solutions we considered would require some time to be implemented and/or have long turnaround times. For instance, since we had a roust molecular laboratory, one option was to develop our assays and test in-house, while another was to send the samples to outside labs where they could be run. Running the tests in-house would have a shorter turnaround time and would be more efficient, which is extremely important considering the severity of COVID-19.
  4. Deliver is the last phase of the process.  We decided to develop a SARS-CoV-2 RT-PCR test at our institution, but we also knew we needed to put logistics and protocols in-place to deliver our solution.  For example, COVID-19 presents with flu-like symptoms but flu is common between December and March[5-7] so it would be impractical to expect to test all patients with flu-like symptoms – at least with the limited resources we had. In any case, it was clear that we would not have an ideal amount of time or information to develop and implement the perfect solution. As such, the revolving and fluid nature of the develop and deliver phases of our response is best depicted using the Plan Do Study Act (PDSA), an iterative model of quality improvement. As shown in Fig. 1, we developed and validated our assay, as well as developed an initial protocol for screening patients and logistics for patient-centered delivery in the “Do” step. Importantly, we also reviewed the effectiveness of these operations, and made necessary changes corresponding in the “Study” and “Act” steps respectively.

The prompt decision to implement in-house COVID-19 testing at NorthShore has proven to be the right one. To date we have tested 75,000 specimens and nearly 20,000 tests have been positive. Success which was possible because of the factors which made me come to NorthShore, amongst others. The LEAN, bright and capacious design of the department limits the innate barriers of hierarchical organizational structure; encouraging seamless horizontal and vertical intradepartmental consultation and collaboration as COVID-19 led us into uncharted territory. Also, having a molecular lab that regularly expands its capability made the decision to test in-house relatively easy. In addition, having an automated microbiology lab made it easier for staff to be flexible and deal with the various demands of testing for a new bug in a pandemic. And of course, the people at NorthShore who are ready to volunteer, take up new roles or change shifts to accommodate the demands of a rapidly evolving pandemic, stay in constant communications and provide feedback, and who make everything else at NorthShore work!

References

  1. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200130-sitrep-10-ncov.pdf?sfvrsn=d0b2e480_2
  2. Council, Design. “Eleven lessons: Managing design in eleven global companies-desk research report.” Design Council (2007).
  3. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/summary.html
  4. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200324-sitrep-64-covid-19.pdf?sfvrsn=723b221e_2
  5. https://www.who.int/news-room/q-a-detail/q-a-coronaviruses#:~:text=symptoms
  6. https://www.cdc.gov/flu/symptoms/symptoms.htm
  7. https://www.cdc.gov/flu/about/season/flu-season.htm
  8. Christoff, Patricia. “Running PDSA cycles.” Current problems in pediatric and adolescent health care 48.8 (2018): 198-201.

Adesola Akinyemi, M.D., MPH, is a first year anatomic and clinical pathology resident at University of Chicago (NorthShore). He is interested in most areas of pathology including surgical pathology, cytopathology and neuropathology -and is enjoying it all. He is also passionate about health outcomes improvement through systems thinking and design, and other aspects of healthcare management. Twitter: @AkinyemiDesola

-Erin McElvania, PhD, D(ABMM), is the Director of Clinical Microbiology NorthShore University Health System in Evanston, Illinois. Follow Dr. McElvania on twitter @E-McElvania. 

Pathology and Histology Services Being Developed at the Biamba Marie Mutombo Hospital (HBMM), Kinshasa, Democratic Republic of the Congo (DRC)

Dikembe Mutombo Foundation

The Dikembe Mutombo Foundation (DMF) was created by NBA Legend Dikembe Mutombo in in 1997 with a mission to improve the health, education, and quality of life for the people in his homeland, the Democratic Republic of the Congo (formerly Zaire).

It took 10 years of intense work and many challenges but in December 2007, the Biamba Marie Mutombo Hospital named in memory of Dikembe’s mother opened its doors to patients in the capital city of Kinshasa, DRC. Dikembe personally contributed more than $23 million to build and equip the hospital. The total cost of the new hospital was $29 million.

The hospital currently has close to 170 beds with an ultimate future capacity of 300 beds. It is a modern facility with state-of-the-art equipment including a new donated CT scanner (the first in the DRC.) This general hospital has the following traditional services: primary care, internal medicine, pediatrics, surgery, OB-GYN, surgical subspecialties such as neurosurgery, orthopedics, urology, and ENT. The goal for the hospital is to provide quality care and to train a cadre of health professionals who in turn will continue to build capacity in the health institutions of the country. Hospital management espouses the following values: respect for the dignity of the patients, professionalism, continuous quality improvement, transparency, and accountability. Currently, the hospital is the most modern, if not the best in the country and to date it has treated close to 500,000 patients.

In 2017, Dikembe Mutombo was honored by the Harvard University Medical School for his ongoing humanitarian efforts and dedication to health care during the Global Health Catalyst Cancer Summit in Boston. The three-day summit, hosted by Dana-Farber Cancer Institute, Brigham and Women’s Hospital (BWH) and Harvard Medical School, brought together African ambassadors, ministers of health, celebrity cancer advocates and global health stakeholders to discuss cancer and examine its global effects on society.

Background

In 2016, the Dikembe Mutombo Foundation successfully implemented a Women’s Oncology Institute at the Biamba Marie Mutombo Hospital (BMMH) in the capital city of Kinshasa. Using classic bedside and surgical teaching methodology, aided by low-cost telecommunications technology, and wise infrastructure investments, the Friends of Africa, Inc. (led by Dr. Groesbeck Parham) has been able to successfully build effective, Congolese-led programs for the early detection and treatment of female cancers at BMMH, thereby providing public access to these critical life-saving services for the first time ever in the DRC. Widespread access to such services is known to result in significant alterations in cancer death rates.

Several months ago, the hospital purchased a new ultrasound machine from GE Healthcare to aid in evaluating breast and abdomino-pelvic abnormalities for the female cancer patients.

Cervical Cancer Early Detection and Treatment Clinic

·     A new Cervical Cancer Early Detection and Treatment Clinic was opened at BMMH in July 2016, under the leadership of the Congolese healthcare providers that were trained in Zambia by Dr Groesbeck Parham.

·     During opening week 8,800 women requested cervical cancer screening services and 3,000 were accommodated

·     To date (July 2016-November 2017), the clinic has screened over 15,000 women for cervical cancer, the largest number ever reported in the DRC.

·     Almost 1,000 women (1 out of every 14 screened) were found to have cervical pre-cancer, all of whom were treated on the same day (the largest number ever reported in the DRC), using modern outpatient techniques.

Through intensive, quarterly, hands-on training demonstrations held at BMMH, a team of board-certified U.S. gynecologic oncologists from the University of North Carolina, Chapel Hill, successfully trained a local cadre of Congolese gynecologists to safely and effectively treat women diagnosed with invasive cervical cancer using oncologic surgical procedures. This novel form of competency-based surgical training was developed in Zambia and is specifically designed to rapidly build surgical proficiency in resource-constrained settings, based on the principles of “Deliberate Practice”, intense replication, and mental narration of a limited repertoire of surgical procedures. 

Using an approach tailored specifically for training surgeons in resource-constrained environments, a team of U.S., board-certified breast surgical oncologists from the University of Arkansas (led by Dr. Ronda Henry-Tillman) successfully trained local Congolese general surgeons to safely and effectively perform surgical procedures that are fundamental to the modern treatment of breast cancer. The training approach was identical to the one used to train gynecologists to perform cervical cancer surgery. To date 81 patients with breast cancer have been treated with surgery by the newly trained team of Congolese general surgeons, under the tutelage of U.S. breast surgical oncologists. All surgeries have taken place in the newly formed Breast Cancer Surgical Unit at BMMH.

In summary, the following has been accomplished:

  1. Developed a local Congolese workforce that has the capacity to provide modern, high quality cervical and breast cancer early detection, diagnostic and treatment services, and to train others
  2. Established two new female cancer (cervix and breast) specialty clinics at BMMH
  3. Established two new female cancer (cervix and breast) surgical units at BMMH
  4.  Leveraged web-based videoconferencing (Skype, Zoom) technology to facilitate continued education and develop an international women’s oncology community of practice, made up of Congolese, Zambians and Americans.
  5. Implemented a women’s oncology data collection system
  6. Designed culturally appropriate health promotion messages
  7. Initiated a cervical cancer prevention outreach program

 Women’s Oncology Care for Africa, known as WOCA. They are the visiting breast and cervical cancer team from the U.S.

Dr. Michael Hicks (L), gynecologic oncologist consultant from Detroit, Michigan, and Dr. Alex Mutombo Baleka (R) from Kinshasa, DRC, performing the first radical hysterectomy ever at BMMH in Kinshasa on a woman recently diagnosed with invasive cervical cancer during a cervical cancer screening program sponsored by the Dikembe Mutombo Foundation and supported by UNFPA.

Pathology and Histology

Histology is the next step that the HBMM hospital is working on establishing. This will provide a needed tool for a more complete diagnostic picture for better patient care. Presently, the hospital is working with 2 different Pathologists to help establish the diagnostic part of the Pathology lab. This is where I have come in to help the Pathologist develop their histology lab needs at BHMM. On my first trip over the hospital selected a team of medical techs to be the core of the histology lab. July 2019, I spent 3 weeks giving formal histology lab classes, organized our equipment and lab area, and started some initial hands-on training on basic histology procedures. On Feb 27th, 2020, I return to the DRC for my second trip to the HBMM hospital. The trip started on the 27th of Feb. in San Jose, Costa Rica. I spent parts of 2 days in Atlanta at the Mutombo Foundation picking up 2 donated microtomes and a double headed microscope to take over for the lab. My first task was to review my previous classroom teachings and spent more time on performing laboratory techniques. With the equipment we now have in the lab we were able to do some valuable training. We worked on tissue embedding, microtome sectioning, floatation bath pickup of the thin cut specimen tissues, and general good laboratory practices with the Pathology Lab. (photos)  Additionally, I was able to spend time visiting and training other histology groups in Kinshasa. I spend one day giving classes at the University of Kinshasa, in the Pathology Dept., to a hand full of Histologists from 4 different labs within the city of Kinshasa. My focus of visiting and presenting classes to those outside of the HBMM hospital was to educate the local labs more about basic histology, to help them to start networking to help each other, and for me to find out the available histological resources within the community. All this will not only help our present histology setup at the HBMM, but it will help the others develop better lab uniformity and quality to help each lab’s patients. We are still short a few things at the HBMM to get histology up and running. We would like to have the lab operational on our next trip to Kinshasa. We had projected the opening of Histology for July – Aug. 2020.  However, due to the COVID-19 pandemic and travel restrictions this timeline may not be met. We are still hoping for the histology\pathology lab opening at HBMM in 2020.

I would like to thank Dr. Dan Milner and Ms. Alpa Pandya from ASCP for their instrumental help in making this lab project possible. This is not the first time they have assisted me overseas and I hope it is not our last program to jointly help.  Additionally, I would like to thank Susan Johnson, Executive Director at DMF in Atlanta, GA, for her tireless support. She made sure everything came together for me. This included the obtaining (twice) a visa for me for the DRC.  This visa was not an easy task, especially for someone living in Costa Rica without a DRC Embassy in all Central America. Last, but of course not the least by any means, I would like to thank the Mutombos for their generosity and compassion for helping the medically underserved people of the Congo.

Each trip I have done overseas that I have provided teaching, basic or IHC lab setups, or fine-tuning of histology labs have all been different, but always rewarding. Just to note, many any of these trips I have done with the support of ASCP. I hope this article stimulates others to go out and help others. We all have something to offer. Please share your knowledge with others who many do not have the opportunities that you have been given. Do not let borders or languages be a deterrent. Remember, everything is possible if approached correctly.

The grounds at Biamba Marie Mutombo Hospital, Kinshasa, DRC.
A portion of one histology class.
Teaching in the lab at HBBM.

-David J. Davis BS, HT(ASCP)QIHC is a certified Histologist and has his qualification in immunohistochemistry with ASCP.  He has been a histologist for the past 38+ years. He has worked in various capacities in 26 countries around the world. Since 1992 he’s been teaching and assisting the international community in histology. He’s retired, but definitely not finished working.

The Social Medium is the Message

Hello again everyone and welcome back to Lablogatory!

If you read my post last time, I talked about preserving integrity and delivery of our professional duty as laboratorians in the face of both overwhelming pandemic demands as well as working to  advocate for our field as more people realize each day what goes into every single lab result around the world. A run on sentence and a heavy discussion—and it was just in time to celebrate Lab Week 2020!

This time let’s expand on the second topic a bit. Advocacy in our profession and spotlighting our critical roles as pathologists and medical laboratory scientists. As much as you or I might agree that this is proof positive, just from looking at the regular old news media this year, it’s not so easy. But something that’s been quietly creeping higher and higher on the Lab-Med radar this past year or so is now growing faster than it ever has before: Social Media.

The medium you disseminate information on also translates a message about the author/speaker. For me, I was not only staying the course about data-driven testing science regarding COVID, but I took every ad-lib and opportunity to praise the medical laboratory profession. I praised laboratorians for their hard work, and took a minute to say clearly and plainly, that they are indisputably healthcare heroes in this season of notability. In doing so, I found myself addressing a more pressing pandemic: The Path and MLS pipeline problem. We have a serious issue with finding new medical laboratory scientists and medical students to go into our field. The main cause and culprit? Our essential clinical invisibility. As we are much less patient facing than our other colleagues, it’s difficult to expose younger students considering various careers in healthcare to our specialty. Cue Twitter, Facebook, Instagram, LinkedIn, and even TikTok.

Image 1. Throwback to the 2019 ASCP Annual Meeting in Phoenix, AZ. Dr. Kamran Mirza (left), myself, and Dr. Adam Booth (right) are all part of the growing community of pathologists/trainees plugged into the social network to advocate, collaborate, and spotlight our profession. Follow them both on twitter at: @KMirza and @ALBoothMD, they are champions of using social media as an educational connection.

I’ve talked about this before. And, of course, I’m biased: I’m on the official ASCP Social Media Communications Committee and was highly active in previous iterations including the #SoMeTeam as well as ASCP Social Media Ambassadors programs. Anyone who reads my pieces here knows I’m not social media shy—heck, I weaponized my online presence for residency interview season, networking around the clock to get my name and my work out there for programs to notice. Spoilers: it worked really, really well.

(If you’re one of those senior medical students who is preparing to practice the age-old tradition of wiping the internet clean of your presence, consider a 180 turnaround from that plan—at least if you’re applying to pathology…)

So what worked so well for me? Well, first some background. You know I’m on two ASCP committees, CCPD and Social Media. I’ve already told you I’ve been working the social media angles for a while now, at ASCP meetings, sharing content, etc. And I had a super busy, and super rewarding, residency interview season. With rotations and interviews at some amazing places, I was able to both learn a lot about what it is I really want to do and meet folks to talk about it with. All that being said, sometimes things just fall into place. Specifically, a global pandemic happened. …too soon?

I’m not going to rehash the early days of the pandemic for you, or talk about how I became involved on the ground floor of a lot of outreach and education efforts: that was sooo last month, I did that already (read it all here). But what I will talk about is the butterfly effect that each media engagement set into place for me.

Image 2. When everyone’s talking, the loudest microphone gets the audience. When no one’s making sense, the best content wins. Many of the talks and interviews since the very first ones with my friend and colleague Dr. Ajufo set up a cascade of content to answer some serious concerns during these strange times.

In effect, the order of events for me these last few months looked like this:

  • Writing pieces for Lablogatory¸ some based in scientific analysis of testing, some to address public health concerns and education.
  • Making small viral online tid-bits aimed at educating lay people about overall health, avoiding exposure, and what testing means.
  • Social media connection to join the #PathCast lecture series, of which my video has garnered approximately 20,000 individual views and was seen in almost 50 countries.
  • Invitations from CDC-funded training agencies to explain testing considerations, virology details in translational science, and discuss how those most vulnerable to social determinants of health are most inequitably affected by pandemic conditions.
  • Informal features where I was invited to discuss those intersectional tenets of medicine, public health, and socioeconomics with lay persons in a virtual group setting.
  • An interview with Lifehacker magazine’s Vitals section, to answer reddit-style ask-me-anything questions regarding COVID testing online live with open to the public availability.
  • Inclusion in Lifehacker magazine’s online podcast, where I was featured alongside other experts to discuss the effect of the pandemic on many aspects of life from health to finances.
  • An interview with The Endless Files Podcast¸ where I was invited as a content expert to discuss the connections between laboratory data, public health, public policy, and discuss the political climate surrounding coronavirus concerns all over the sociopolitical spectrum.
  • An interview with People of Pathology Podcast which gave me the chance to talk about my individual career path and transition from education about testing to advocacy and representation for our amazing profession.
  • The nomination and selection by my medical school faculty and peers to deliver the student charge at my formal, virtual, medical graduation.
  • …more are on the way!

Why am I listing these things? Is it my misplaced Greek hubris? Maybe. But before I fly too close to the sun, I’m trying to prove a point. That what started out as creating content on social media for health and wellness during a pandemic essentially became a snowball by summer. I was addressing pressingly relevant information during the obvious opportunity to step up and educate. But something else was happening; something I didn’t realize until recently. And whatever it was, I wasn’t getting there alone.

**All of this was made possible by social media recommendations and connections from friends and colleagues!**

PathCast? I was recommended by a pathologist friend on ASCP’s CCPD committee with me. The CDC-funded training? A former grad student friend of mine when I studied at Rush. Lifehacker? Made possible in a public call for content by our favorite medical lab scientist and Lablogatory editor, Kelly Swails. The Endless Files? Reached out to an old political science professor and friend at Loyola. People of Pathology? Social media connections with friends and CLS colleagues in Canada—you want to make things happen? Don’t go at it alone!

Don’t know how to get started in all this social media frenzy? Don’t fret. Basically, here’s a four-step process: make accounts on one or all of your favorite platforms, follow everyone you want to learn more from, share other’s content or your own frequently, and (most importantly) promote others before yourself! There are countless webinars and talks on how to use social media to leverage advocacy and education, just look at some of the greatest pathology teachers on Twitter: @KMirza, @CArnold_GI, @MArnold_PedPath, @RodneyRhode, @HermelinMD, @KreuterMD, @JMGardnerMD, and many, many more. But there’s more than just twitter! Many super talented folks team up to produce lectures, webinars, and even podcasts (check out the brand-spankin’-new PathPod here!)

Just dive in!

Image 3. Virtual graduation, social media outreach. 2-for-1 sale. In my on-screen graduation quote during the conferment of degrees, part of it read “don’t let me be the last pathologist you were friends with…” and during my student address, I implored my classmates and anyone else watching to consider creative, new ways to solve clinical problems. Maybe with new tools, new skills, and a new understanding of interdisciplinary collaboration. I also reminded people that our digital presence can indicate our professional message, as champions of truth in science.

In conclusion, social media is the new (old) heavy hitter in the medical world. Younger med students are getting access to more specialty information than they ever have before, informing and guiding their career choices. Specialists of all kinds share and reshare excellent diamonds of content that galvanize medical discourse everywhere from Twitter to TikTok. What does this do? It closes the gap between professionals across disciplines, shines new spotlights on fields that traditionally got stamped with basement autopsy stereotypes, and creates digestible and understandable bridges for lay people to access our jargon-filled discourse. It only goes up from here.

Post-script: if you haven’t noticed the racially charged, horrible situations adding to the tumultuousness of 2020, there’s another lesson in this. Social media again proves a most-valuable and all-powerful tool to mobilize, demonstrate, collaborate, and unify thoughts, ideas, and causes. I doubt we will ever be free of tragic moments in history, but when we come together as one collective we can use our various platforms to honor heroes, shame wrong doers, celebrate positive change, and highlight systemic failings that might hold us back from true progress, justice, and peace. That includes the medical world, as all things cross at the intersections of human life and human rights.

Thank you for reading! Stay safe, stay well, and continue to practice safe, compassion-informed social distancing. The pandemic isn’t over, and neither is our work.

Until 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.

COVID-19 Testing Explained

By this point I believe we are all tired of reading and talking about COVID. However based on reading comments on social media, it’s quite clear that there are a lot of misconceptions about COVID testing. For starters COVID-19 is the disease caused by the SARS-CoV-2 virus. So all of the tests we are using to assist in the diagnosis of COVID-19 are really looking for signs that the person was infected with SARS-CoV-2. There are also 3 main categories of tests for SARS-CoV-2 based on the target of the assay: RNA, antigen, and antibody.

Diagnosis of COVID-19 should be based on clinical symptoms, risk of exposure, test results and timeline. The diagnostic tests based on detection of SARS-CoV-2 RNA are the most commonly used and reliable for diagnosis of COVID-19.1 All of these assays are based on amplifying the viral RNA to detect the presence of the RNA. Most assays use some form of PCR to amplify the virus, however because the virus is RNA-based it has to be converted to cDNA with reverse transcriptase PCR before amplification and detection. TMA or transcription-mediated amplification is another chemistry that can be used to amplify the RNA to a detectable level. Both PCR and TMA based assays are very sensitive at detecting the virus especially within the first week after symptoms develop.1,2 Due to the RNA-based nature of the SARS-CoV-2 genome, the mutation rate is anticipated to be high. Most of the RNA-based assays have adopted a strategy to target 2 different areas of the viral genome to prevent missing the presence of the virus due to a mutation in the primer binding site.

A SARS-CoV-2 antigen test received EUA in early May. The test is designed with immunofluorescence-based lateral flow. This type of test is designed to detect SARS-CoV-2 proteins present on the outside of the virus. In general, this class of test is cheaper and faster than RNA-based testing however it is less sensitive (80% clinical sensitivity).3 The clinical specificity of antigen assays is shown to be 100%,3 therefore a positive result is reliable. These tests can be used for screening; however patients with negative results may still need to proceed to testing by an RNA-based method. Antigen based tests is typically more sensitive during the same timeframe when PCR testing is more sensitive, ie earlier in the course of disease.

SARS-CoV-2 antibody tests are the last class of tests. Seroconversion appears to occur within 7-14 days of symptom onset2 or 15-20 days post exposure to the virus.4 There are many different tests to choose from to determine if the patient has previously been exposed to SARS-CoV-2. The assays range from lateral flow cassettes to high throughput chemiluminescent based assays. Some of the SARS-CoV-2 antibody assays detect IgG, IgM, IgA or some combination of the 3 including total antibody without differentiating between the three. The latest studies have shown that some patients develop IgM first, some with IgG, and others had both IgG and IgM develop at the same time.5 Therefore differentiating IgG from IgM is not providing a timeline for acute infection as we have seen in response to other viruses. Although sensitivity and specificity vary widely between manufacturers total antibody detection appears to be more sensitive than IgG or IgM detection alone.4 The FDA recently pulled numerous assays off of the market due to poor performance.

It is important to note that even with the most sensitive and specific antibody test, these tests cannot determine if a patient has protective immunity. Unfortunately we don’t know enough about immunity with regards to COVID yet. Early studies are promising, showing that some level of antibody will likely provide protection from future exposure. We don’t know if there is a threshold of antibody that needs to be present before a patient is immune, will the immunity only decrease the severity and not prevent reinfection, and how long the antibodies are maintained after exposure. These will be important questions to answer before the clinical utility of antibody testing can be realized. Right now the test is useful to determine is a patient was previously exposed to SARS-CoV-2 and is helpful to address epidemiological questions with regards to prevalence of COVID-19 in the community. The antibody test should not be used for diagnosis of current infection due to the delay to seroconvert after exposure.

References

  1. Sethuraman, N., Jeremiah, S. S., & Ryo, A. (2020). Interpreting Diagnostic Tests for SARS-CoV-2. JAMA. doi:10.1001/jama.2020.8259
  2. Wolfel, R., Corman, V. M., Guggemos, W., Seilmaier, M., Zange, S., Muller, M. A., . . . Wendtner, C. (2020). Virological assessment of hospitalized patients with COVID-2019. Nature, 581(7809), 465-469. doi:10.1038/s41586-020-2196-x
  3. Quidel Sofia®2 SARS Antigen FIA. https://www.quidel.com/sites/default/files/product/documents/EF1438900EN00_0.pdf 5/29/2020.
  4. Lou, B., Li, T. D., Zheng, S. F., Su, Y. Y., Li, Z. Y., Liu, W., . . . Chen, Y. (2020). Serology characteristics of SARS-CoV-2 infection since exposure and post symptom onset. Eur Respir J. doi:10.1183/13993003.00763-2020
  5. Long, Q. X., Liu, B. Z., Deng, H. J., Wu, G. C., Deng, K., Chen, Y. K., . . . Huang, A. L. (2020). Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. doi:10.1038/s41591-020-0897-1

-Tabetha Sundin, PhD, HCLD (ABB), MB (ASCP)CM,  has over 10 years of laboratory experience in clinical molecular diagnostics including oncology, genetics, and infectious diseases. She is the Scientific Director of Molecular Diagnostics and Serology at Sentara Healthcare. Dr. Sundin holds appointments as Adjunct Associate Professor at Old Dominion University and Assistant Professor at Eastern Virginia Medical School and is involved with numerous efforts to support the molecular diagnostics field. 

Clinical Laboratory Scientists are Imperative to Patient Education

Medical Laboratory Professionals work behind the screens of the medical industry. The contributions produced by this diligent, dynamic, accuracy-driven teams, provide approximately 70% of diagnostic information. This information is imperative for proper diagnosis and treatment. Due to the nature of laboratory work, laboratory personnels are not visible at the forefront of delivering patient care. Therefore, much of society is unaware of the efforts conducted within other parts of the medical industry.

In November of 2018, I had an experience with an elderly couple that will always remain at the forefront of my mind. I was an evening shift Blood Bank Technical Supervisor at a Trauma Level I hospital housing with more than 1000 beds. The Blood Bank served in/out transfusion-dependent patients, as well as being a transplant institution conducting cardiac, liver, and lung transplants. To say we were busy is an understatement.

We had an outpatient order for an older woman who was accompanied by her husband. Her husband, being her advocate, was known to express his concern regarding an issue concerning his wife. The patient’s two units of blood were delayed and the patient’s husband proceeded to call the blood bank to inquire about the delay. The medical laboratory assistant informing him the order was being worked on was not enough, so he proceeded to hound the nurse. The nurse then proceeded to ask to speak to the supervisor.

Before speaking to the nurse, I got the status of the order and asked the technologist approximately how much longer the wait would be. She explained intital testing had revealed an antibody, and so she followed protocol and informed the nurse there would be a delay in blood products.Completing the workup and finding appropriate blood for the patient is what caused the delay. She was at the last portion of crossmatching the blood, and after my review of the workup, it should be 15 minutes.

I informed the nurse it would be 15 minutes, and she pleaded with me to explain the delay to the patient and her husband. After receiving confirmation from my manager to proceed, I hand-delivered the blood to the outpatient room.

“Perception is reality,” so it is imperative to be aware of all verbal and nonverbal communication when interacting with patients. Therefore, accompanied by the nurse, I entered the room and introduced myself and my position. I explained in layman’s term an ABO Type, antibody screen, and finding suitable blood when an antibody has developed. When I was through, they had an exceptional understanding of concept and turnaround time. The patient and husband were appreciative of my explanation and grateful for my staff. The patient’s husband then asked me about my education and what it entailed for me to hold my position. He was highly impressed and never knew all the science and math courses required to become a medical laboratory scientist. He said it was an opportunity he was going to pass along to his granddaughter, who was interested in science.

The following day, the patient’s husband called and apologized to the staff member he initially spoke with and praised the work we do for all patients. This experience highlighted the importance of training laboratory management when interacting with patients. It is more common for the pathologist or medical director to reach out to patients but there are times, especially on the off-shifts, where a laboratory supervisor or manager may be the best option available.

Being an advocate for the medical laboratory science profession is a means of educating the society of a vital career which impacts all lives. Medical laboratory lrofessionals may be behind the scenes, but to administer treatment, essential laboratory results are required; without the laboratory – you’re guessing.

-Tiffany Channer, MPH, MLS(ASCP)CM honed her skill and knowledge of Blood Banking at Memorial Sloan Kettering Cancer Center in New York, NY, where she completed her 9 year tenure at Memorial Sloan as Blood Bank Educational Lead Medical Technologist III/ Safety Officer. She’s currently working as a Quality Assurance Specialist / Educational Supervisor at Memorial Sloan Kettering Cancer Center. Tiffany was a Top Five 40 under Forty Honoree in 2015 for her dedication and advocacy to education and laboratory medicine.

Overview of Laboratory Tests for Cytomegalovirus

Introduction

Cytomegalovirus (CMV) is considered the most important pathogen in transplant recipient patients as it can cause significant morbidity and mortality. Anti-CMV treatments have proven to be effective but are not without adverse side effects. Thus, there is a strong need for sensitive and reliable tests to diagnose and monitor active CMV infection. Several testing methodologies are available in today’s clinical laboratories to evaluate a patient’s CMV status: viral culture, serology, histopathology, pp65 antigenemia, and quantitative PCR. In this post, we will review the advantages and limitations of these tests.

Viral culture

Viral culture is performed most commonly by the shell vial assay (also known as rapid culture), in which a cell line (usually human fibroblast cells) is inoculated with patient sample by centrifugation. The virus is then detected by either direct or indirect fluorescent monoclonal antibody, providing results within 1-3 days. The centrifugation step greatly improves turnaround time when compared to traditional tube cell culture technique, which may take 2-3 weeks before a result can be reported as negative.

Culturing CMV has been largely replaced by newer methodologies like quantitative PCR and CMV antigenemia. This is due to relatively weaker sensitivity for diagnosing CMV infection compared to newer tests, as well as slower turnaround time. Viral cultures of urine, oral secretions, and stool are not recommended due to poor specificity; however, for diagnosis of congenital CMV, viral culture of urine or saliva samples is an acceptable alternative if PCR is not available.

Serology

CMV serostatus is an important metric to evaluate prior to patients receiving a hematopoietic or solid organ transplant. Serologic testing is done primarily via enzyme immunoassays and indirect immunofluorescence assays. These tests check for presence of anti-CMV immunoglobulin (Ig)M and IgG to provide evidence of recent or past infection. Outside of establishing serostatus (primarily in organ donors and recipients), serologic testing for CMV is not recommended in diagnosing or monitoring active CMV infection.

CMV IgM antibodies can be detected within the first two weeks of symptom development and can be present for another 4-6 months. IgG antibodies can be detected 2-3 weeks after symptoms develop, and remain present lifelong. These antibody measurements are particularly useful in determining risk of CMV acquisition in seronegative patients (negative for IgM and IgG) at time of transplantation. IgG titers can also be measured every 2-4 weeks to assess for CMV reactivation in seropositive patients. Since CMV IgG persistently remains in circulation, testing for it has a higher specificity compared to IgM, and thus is the preferred immunoglobulin to test for in establishing serostatus. Serologic tests can be falsely positive if patients have recently received IVIG or blood products, so testing on pretransfusion samples are preferred if possible.

Histopathology

Under the microscope, cells infected with CMV can express certain viral cytopathic effects. These infected cells classically show cytoplasmic and nuclear inclusions (owl eye nuclei) with cytoplasmic and nuclear enlargement. Additionally, immunohistochemistry (IHC) can stain antibodies specifically for CMV proteins to highlight infected cells, making histologic examination quicker and improving diagnostic sensitivity.

Histopathology can be useful in identifying tissue-invasive disease, such as CMV colitis or pneumonitis. Cases in which PCR testing is negative does not necessarily exclude tissue-invasive disease; thus, the diagnosis of tissue-invasive disease relies on histologic examination (with or without IHC) or possibly viral culture. On the other hand, a negative histologic result does not exclude tissue-invasive disease, possibly due to inadequate sampling, and shows the potential for weak diagnostic sensitivity.

pp65 antigenemia

CMV antigenemia testing uses indirect immunofluorescence to identify pp65 antigen, a CMV-specific matrix protein, in peripheral blood polymorphonuclear leukocytes. Whole blood specimens are lysed and then the leukocytes are cytocentrifuged onto a glass slide. Monoclonal antibodies to pp65 are applied, followed by a secondary FITC-labeled antibody. The slide is then read using a fluorescence microscope for homogenous yellow-green polylobate nuclear staining, indicating presence of CMV antigen-positive leukocytes. Studies have suggested that a higher number of positive cells correlates with an increased risk of developing active disease. The sensitivity of antigenemia testing is higher than that of viral culture and offers a turnaround time within several hours.

This test has been utilized since the 1980s, but has seen less use recently due to the increasing popularity of quantitative PCR. Antigenemia testing is labor intensive, and requires experienced and trained personnel to interpret the results (which can be somewhat subjective). This test also must be performed on whole blood specimens within 6-8 hours of collection due to decreasing sensitivity over time, which limits transportability of specimens. Additionally, It is not recommended to be run on patients with absolute neutrophil counts below 1000/mm3, due to decreased sensitivity. Despite these limitations, CMV antigenemia testing is still considered a viable choice for diagnosing and monitoring CMV infection, especially when viral load testing is not available.

Quantitative PCR

Quantitative real-team polymerase chain reaction (PCR) is the most commonly used method to monitor patients at risk for CMV disease and response to therapy, as well as for diagnosing active CMV infection. The advantages of using a quantitative PCR assay include increased sensitivity over antigenemia testing, quick turnaround time, flexibility of using whole blood or plasma specimens for up to 3-4 days at room temperature, and the availability of an international reference standard published by the World Health Organization (WHO).

Several assays from Roche, Abbott, and Qiagen are available and FDA-approved. The targets of these assays vary, with some targeting polymerase and other targeting CMV major immediate early gene. These assays are all calibrated with the WHO international standard, which was developed in 2010 to help standardize viral load values among different labs when results are reported in international units/mL. The goal of this international standard is to decrease the interlaboratory variability of viral load, and determine the appropriate cut-offs for determining clinical CMV disease. There is still improvement to be made in this area, as variability still exists between labs.

Conclusion

There are several tests to determine the CMV status of patients. Some of these tests are suited for particular goals, such as serology for determining serostatus prior to organ transplantation, or histology and IHC to diagnose tissue-specific CMV disease. For diagnosis and monitoring of general CMV disease, the test of choice in most laboratories is quantitative PCR, which offers automated, quick and sensitive results. Antigenemia, while dated and labor intensive, is still an acceptable alternative when PCR is neither available nor cost-effective for smaller labs. Both of these testing methods are preferred over viral culture, which has poorer diagnostic sensitivity and relatively longer turnaround time.

Despite the numerous advantages quantitative PCR has, there is still variability in viral load counts among laboratories. This is due to varying DNA extraction techniques, gene targets used by PCR, and specimen types used. There is still a lot of work to be done in standardizing testing in regards to not just CMV, but also other viral pathogens like Epstein-Barr virus, BK virus, adenovirus and HHV6. Updated standards and increased use of standardized assays will hopefully decrease this variability between labs to improve testing results and in turn, improve patient care.

References

  1. https://www.uptodate.com/contents/overview-of-diagnostic-tests-for-cytomegalovirus-infection#H104411749
  2. https://www.uptodate.com/contents/congenital-cytomegalovirus-infection-clinical-features-and-diagnosis?topicRef=8305&source=related_link#H9542666
  3. Kotton CN, Kumar D, Caliendo AM, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013;96(4):333-60.
  4. Hayden RT, Sun Y, Tang L, et al. Progress in Quantitative Viral Load Testing: Variability and Impact of the WHO Quantitative International Standards. J Clin Microbiol. 2017;55(2):423-430.
  5. Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018;102(6):900-931.

-David Joseph, MD is a 2nd year anatomic and clinical pathology resident at Houston Methodist Hospital in Houston, TX. He is planning on pursuing a fellowship in forensic pathology after completing residency. His interests outside of work include photography, playing bass guitar and video games, making (and eating) homemade ice cream, and biking.