The Story of the Mott Cell, COVID-19 and the Cute Little Mouse

I have worked in hematology for many years, and there are certain things that never fail to excite technologists. Working in New Hampshire, it was always exciting to sickle cells or malaria, something common to some, but not common in our patient population. I now work in Baltimore, and see sickle cells nearly every day, and we come across malaria not too infrequently, but we still share good examples and save them for training. When we see something different or unusual, we always share the finding. Cells may need to be sent to the pathologists for a pathology review, and we always check back to see the pathologist’s identification and comments. Medical Technologists by nature are a curious bunch, and we always want to see ‘cool’ things. I wrote a blog two years ago about the only patient I have ever seen with Trypanosoma (Hematology Case Study: The Race to Save a 48 Year Old Man from a Rare Disease). Last month I wrote about Blue-green cytoplasmic inclusions (COVID-19 Patients with “Green Crystals of …” STOP! Please Don’t Call Them That). So, when I saw something else ‘cool’ and different on a peripheral smear, and then saw it AGAIN, on another patient, and saw other techs here in the US and in other countries were also mentioning these, because it’s my nature, I got curious.

When I write these blogs, I often feel a little bit like the mouse in the children’s story “If You Give a Mouse a Cookie”, by Laura Joffe Numeroff. It’s about an adorable little mouse who asks for a cookie, and then decides he needs a glass of milk to go with it, and then he needs a straw, and it goes on and on, in a circle, back to the beginning. Maybe it’s that the mouse is a little ADD, but I like to believe that he’s just creative and curious. I start with an idea, and often go off on many tangents before a blog is finished and comes back to where I started.. When I started writing this, it was because I saw an interesting cell, and I started exploring, and found that others had seen them, too. Then I started looking through my textbooks for references and information, and searched for recent research or studies, and then I wanted to find out more… just like that mouse.

There are some things that we learn about in school and we may see on CAP surveys, but no matter where you work, they are still rarely seen, so are a novelty. Mott cells are one of these things. I have a collection of Hematology texts from grad school and years of teaching Hematology. Several of these don’t even mention Mott cells, but, when they do, it’s barely a sentence in a discussion of plasma cells. I happen to have a very old copy of Abbott Laboratories “The Morphology of Human Blood Cells” . The one with the red cover, from 1975. The term Mott cell does not appear in this manual, but they do show pictures and describe “Plasma cells with globular bodies (Grape, Berry or Morula cells)”, and describe these globules as “Russell bodies”.1 So some of us who have been working in the field for many years may remember Russell bodies and Morula cells, or Grape cells, even if the term Mott cell is not familiar. Regardless of what we or textbooks call them, they tend to trigger a memory because the images are so unique.

So, again, I’m a bit like that mouse and getting distracted with the background. Why am I writing this blog? In recent months I have seen cells identified as plasmacytoid lymphocytes and Mott cells in several hospitalized patients. I have heard reports of these cells in other facilities as well. So, like a good medical technologist, I got curious about Mott cells. What are they, and what is their significance? And why are we seeing more of these now?

Mott Cells are named after surgeon F.W. Mott. In the 1890’s, William Russell first observed these cells with grape like globular inclusions, but did not recognize what the inclusions were or their significance. Russell examined the cytoplasmic globular inclusions and assumed that these cells were fungi. Ten years later, Mott described cells he called morular cells. He recognized that these cells were plasma cells and the inclusions were indicative of chronic inflammation. Thus, today we refer to these cells as Mott cells, morular cells or grape cells, and the inclusions as Russell bodies.2

Hematology texts describe Mott cells as morphologic variations of plasma cells packed with globules called Russell bodies. We know that plasma cells produce immunoglobulin. When the plasma cells produce excessive amounts of immunoglobulin, and there is defective immunoglobulin secretion, it accumulates in the endoplasmic reticulum and golgi complex of the cells, forming Russell bodies. Russell bodies are eosinophilic, but in the staining process the globulin may dissolve and they therefore appear to be clear vacuoles in the cell under the microscope. Thus, a plasma cell with cytoplasm packed with these Ig inclusions is called a Mott cell.

Mott recognized that these atypical plasma cells were present in inflammation. Plasma cells are not typically seen on peripheral blood smears and constitute less than 4% of the cells in a normal bone marrow. Yet, on occasion, we can see plasma cells, including Mott cells, on peripheral blood smears in both malignant and non-malignant conditions. Mott cells are associated with stress conditions occurring in a number of conditions including chronic inflammation, autoimmune diseases, lymphomas, multiple myeloma, and Wiskott–Aldrich syndrome.3

So, why are we seeing an increased mention of Mott cells now? We seem to be seeing these on patients testing positive for SARS-CoV-2. I have seen cells on patients at my facility that resemble Mott cells. I belong to a Hematology Interest group and over the past few months I have seen several people post pictures of Mott cells, cells with Russell bodies, and plasmacytoid lymphocytes identified on peripheral blood smears of COVID-19 patients. Other techs chimed in with comments that they have also seen these cells recently. I have even seen a comment propose that these cells are indicative of COVID-19 infection.

SARS-CoV-2 definitely causes inflammatory processes and stress conditions in the body, so it makes sense that we may see these cells in COVID-19 positive patients.

Figure 1 shows a Mott cell on an image from Parkland Medical Center Laboratory, Derry, NH. A Mott cell was identified by pathologist in a male patient who tested negative for COVID-19 at the time the sample was drawn, and subsequently tested positive. Mariana Garza, a Medical Technologist working at Las Palmas Medical Center in El Paso, TX shared a case of a 59 year old diabetic male, diagnosed with COVID-19. The patient’s WBC was 31 x 103/μL. Two Mott cells were identified by pathologist on his differential. So, the curious little mouse in me researched some more.

Image 1. Mott cell. Photo courtesy Parkland Medical Center, Laboratory, Derry, NH.

Several published research papers have studied morphologic changes in peripheral blood cells in COVID-19 patients. As we now know, SARS-CoV-2 affects many organs including the hematopoietic and immune systems. A study in Germany showed that COVID-19 patients exhibited abnormalities in all cell lines; white blood cells, red blood cells and platelets. Increased WBC counts were seen in 41% of samples in their study. Differentials performed on study patients showed lymphocytopenia in 83%, and monocytopenia in 88%. Red blood cell morphology changes were noted. Platelet counts ranged from thrombocytopenia to thrombocytosis, but giant platelets were noted across the board.4

Mott cells are indicative of chronic inflammation and may have significance in association with COVID-1. In the above mentioned study, aberrant lymphocytes were noted in 81% of patients who were SARS-CoV-2 positive, and observable in 86% of the same patients after they tested negative. The paper shows plasmacytoid lymphocytes and Mott cells amongst these aberrant lymphocytes. Moreover, morphologic changes in neutrophils, such as a left shift and pseudo‐Pelger‐Huët anomaly, decreased after virus elimination but changes in lymphocytes, indicators of chronic infection, remained.4

Another study also reported reactive or plasmacytoid lymphocytes and Mott cells observed in peripheral blood.4,5 Researchers at Northwick Park Hospital, UK, presented a case study of a 59 year old male with COVID-19 with a normal WBC and thrombocytosis. His differential revealed lymphocytopenia. His differential also showed lymphoplasmacytoid lymphocytes and Mott cells. In their conclusions it is stated that “In our experience, the lymphocyte features illustrated above are common in blood films of patients presenting to hospital with clinically significant Covid‐19. The observation of plasmacytoid lymphocytes supports a provisional clinical diagnosis of this condition.”5

Can these variant plasma cells, along with other commonly seen morphological changes, be used as part of a diagnostic algorithm for SARS-Cov-2 infection? As we see more COVID-19 patients there will be more, larger studies done and more Mott cells identified. Some disorders, such as Epstein Barr Virus and Dengue Fever are characterized by distinct viral changes in cells. However, since Mott cells can be seen in many conditions, these alone could not be considered diagnostic, but the indications are that these cells, along with the entire differential and morphological patterns, could prove to be a straightforward and easy to perform supplementary diagnostic tool. More, larger studies need to be done. It was concluded in the German study, that this pattern of morphologic changes in cells could be further investigated and validated with a larger blinded study, and that this information could lead to the development of a morphologic COVID‐19 scoring system.4 In the meantime, keep an eye out for Mott cells. These should not be ignored and should be in some way noted because they may be of future diagnostic use. That’s all or now, folks! Something to dig deeper into in another blog! The mouse strikes again!

Many thanks to Nikki O’Donnell, MLT, Parkland Medical Center, Derry, NH and Mariana Garza, MT, Las Palmas Medical Center in El Paso, TX for sharing their case studies and photos.

Becky Socha MS, MLS(ASCP)CMBB

References

  1. Diggs, LAW, Sturm, D, Bell,A. The Morphology of Human Blood Cells, Third edition. Abbott Laboratories. 1975.
  2. ManasaRavath CJ, Noopur Kulkarni, et al. Mott cells- at a glance. International Journal of Contemporary Mudeical Research 2017;4(1):43-44.
  3. Bavle RM. Bizzare plasma cell – mott cell. J Oral Maxillofac Pathol. 2013;17(1):2-3.doi: 10.4103/0973-029X.110682.
  4. Luke, F, Orso, E, et al. Coronavirus disease 2019 induces multi‐lineage, morphologic changes in peripheral blood cells:eJHaem. 2020;1–8.
  5. Foldes D, Hinton R, Arami S, Bain BJ. Plasmacytoid lymphocytes in SARS-CoV-2 infection (Covid-19). Am J Hematol. 2020;1–2. https://doi.org/10.1002/ajh.
  6. Numeroff, Laura. If You Give a Mouse a Cookie, 1985.

-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.

Beggars CAN Be Choosers

There is a fine line between obtaining enough cellular material for every ancillary study in the book and risking harm to the patient. So how do we ensure that the patient remains safe, but doesn’t need to come back for a second biopsy due to insufficient material?

Hi! I’m Taryn, a Specialist in Cytotechnology at Fox Chase Cancer Center and a medical laboratory professional who thrives on patient advocacy. Welcome to my first post for Lablogatory! Each month, I’d like to share a story of how the middleman/woman cytotechnologist becomes the biggest campaigner for the patient. Typically, I’ll be posting case studies of rare tumors and how we arrived at the diagnosis, but I’ll start with how to guarantee that we have ample material to provide a comprehensive result for both the patient and clinicians.

 It’s a fight, to say the least. With personalized medicine at the forefront of our cancer center’s mission, we need ALL of the material for any and every ancillary test one can think of, from immunohistochemistry to flow cytometry to molecular diagnostics. That sounds like a lot because it is. From my experience, many clinicians feel that just because cytotechnologists can make a satisfactory adequacy statement on a Rapid On-Site Assessment (ROSE) of a Fine Needle Aspiration Biopsy (FNA), and the pathologists can make a definitive diagnosis based on cytomorphology alone, that means they have obtained sufficient material. For years, that was a valid thought. But now that we have taken various leaps from diagnostic to prognostic and now theranostic approaches, “enough” for cytomorphology is nowhere near “enough” for the patient’s clinical outlook.

As a cytotechnologist present on FNA’s, I have been called “greedy” and a “beggar” by clinicians on more than one occasion. No hard feelings, I promise. As long as the anatomical location of the biopsy does not pose more risk than reward, rest assured, I’m going for the gold medal. Starting out, I obtain one or two fine needle aspiration passes from the radiologist, pulmonologist, gastroenterologist, etc., and from each pass, I prepare one smear to be stained on-site via Diff-Quik (Modified Wright-Giemsa stain) and the mirror image smear fixed in 95% ethanol to be Papanicolaou stained later in the lab. The residual material in the needle is rinsed in Hank’s Balanced Salt Solution (A.K.A. Gatorade for cells) and later spun down into a pellet for a Formalin-Fixed Paraffin-Embedded (FFPE) Cell Block. I look at the Diff-Quik stained smears under the microscope and tell the clinician if the material I have is adequate, scant, or inadequate. This is where it gets interesting.

Clinician: “Adequate. So, we’re done? Okay.”
Cytotechnologist: “The smears are adequate, but I need more material for the Cell Block. Can I have two more passes? And a core biopsy, as requested on the presentation state.”
Clinician: “But you have enough. We already know the patient has lung cancer. You don’t need anymore. I’ll give you a core biopsy, but no more fine needles.”
Cytotechnologist: “I need at least two more needles. The core biopsy material will be saved for molecular. The ordering physician wants to know if the patient’s EGFR-mutated tumor also carries a T790M mutation to see if they are eligible for this therapy. But I also need additional needle passes for the Cell Block to prove that the immunohistochemical profile is the same as the original material. If there is a small cell carcinoma component in the metastasis, that changes things.”
Clinician: “Fine. Pathology is so greedy.”

Okay, so we have definitely progressed into a new era. Many newly trained clinicians understand the need for ample material, but this conversation still occurs on a daily basis. Don’t get me wrong, the veteran clinicians (from my snippet) are remarkable. They can find a needle in a haystack, hit a moving target time and time again, and provide me with a perfect tumor-rich sample. But alas, in trying to educate and advocate, I admit- I do come off as a beggar. The key in our ROSE role is to not back down though. Cytotechnologists remain strong in their convictions, fighting for the patient, so that not only do we have enough cellular material for all of the necessary ancillary studies the first time around, but that hopefully the first time around is the ONLY time around.

We’ll chat soon!


Taryn Waraksa, MS, SCT(ASCP)CM, CT(IAC), has worked as a cytotechnologist at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, since earning her master’s degree from Thomas Jefferson University in 2014. She is an ASCP board-certified Specialist in Cytotechnology with an additional certification by the International Academy of Cytology (IAC). She is also a 2020 ASCP 40 Under Forty Honoree.

False Negatives in COVID-19 Testing

I left for vacation at the beginning of June thinking “once I get back, all of this COVID stuff will be quieted down.” …Well that wasn’t quite the case and testing for novel Coronavirus has continued to be very important. In fact, this last weekend I was tested by occupational health. It came back negative, but I’m am very enthusiastic to get alternative specimen types validated; those Nasopharyngeal swabs are quite…uncomfortable. Luckily, my test was processed at our institution which gets results back in 24-48 hours. However, with the resurgence around the country, turnaround times are backing up to 7-8 days. One solution has been the widely used IDNOW point of care platform. However, there has been significant concern over false negatives produced by this platform. One reason the sensitivity is different is because this platform performs isothermal amplification of nucleic acid. This method amplifies RNA at a stable temperature instead of cycling the temperature as in real-time PCR.

Colleagues at my institution reflexed any negative IDNOW samples to the m2000 Real-Time PCR assay for SARS-CoV-2 for one month. Within that time, over 500 samples were tested and the IDNOW was found to have missed 21% of positive cases (prevalence rate of 5%)2. One the positive side, it had a 98% negative predictive value, which helped rule out COVID19 infection. However, as prevalence rates are increasing, a high negative predictive value isn’t as important as sensitivity.

One study drew much attention when it claimed the IDNOW had a sensitivity of 52% in a New York City academic institution (Basu)4. However, this seems to be an outlier compared to other studies of this platform: one large multi-center study found positive percent agreement (equivalent of sensitivity when a gold standard test hasn’t been established) of 74%1. The highest PPA of 88%3 for the IDNOW was found in a study that indicated it can be completed in 17 minutes, whereas another quick instrument (but not point of care instrument: Xpert Xpress, 45min) had a PPA of 98%2.

Myself and other colleagues looked more closely at the clinical characteristics of false negative test results on the IDNOW. Overall, we found 82% PPA, and 8 patients with false negative tests. Interestingly, a majority of these patients were tested over 2 weeks after their initial onset of symptoms. The virus is known to be at its highest levels at the beginning of symptom onset. So the test may not be limited, but it should be used in the correct clinical context (< 2weeks from symptom onset). After that time, other RT-PCR based tests are more appropriate.

As clinical laboratorians, we often hear: “the right test for the right patient at the right time.” Now with so many platforms available for use in different contexts, we should help guide clinicians to Choose Wisely.

References

  1. Harrington A et al. Comparison of Abbott ID Now and Abbott m2000 methods for the detection of SARS-CoV-2 from nasopharyngeal and nasal swabs from symptomatic patients. JCM 2020. PMID: PMID: 32327448
  2. McDonald et al. Diagnostic Performance of a Rapid Point of Care Test for SARS-CoV-2 in an Urban ED Setting. Academ. Emerg. Med. 2020. PMID: 32492760
  3. Zhen W et al. Clinical Evaluation of Three Sample-To-Answer Platforms for the Detection of SARS-CoV-2. JCM 2020. PMID: 32332061
  4. Basu A et al. Performance of the rapid Nucleic Acid Amplification by Abbott ID NOW COVID-19 in nasopharyngeal swabs transported in viral media and dry nasal swabs, in a New York City academic institution. BioRxiv 2020.

-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 Laboratory’s Role in Inclusion

“Where do we go from here…chaos or community?” is the question Dr. Martin Luther King, Jr. asked in 1967 before the civil rights riots in the hot summer of 1968.  The query was directed to the nation as it sought to address the racism and pain deeply felt in the daily lives of its African-American citizens.  Over 50 years later, that very same question is asked again as the nation is roiled with civil demonstrations, daily videos of racist behavior, and the seemingly senseless killings of African-American men and women. 

As American culture and the nation evolves, uncomfortable conversations are beginning to occur in healthcare and across the country.  Laboratory administrators and managers may want to reflect on the culture of their laboratory to ensure all voices are heard and that they are creating and supporting an inclusive work environment.

Diversity, inclusivity, and equity are goals healthcare organizations seek to incorporate into their culture to foster a healthy workplace environment and be reflective of the communities they serve.  As with most industries, the laboratory has found itself challenged to improve cross-cultural intelligence and eliminate implicit and unconscious bias.  The scientific community would like to believe it operates and makes decisions based solely on objectivity and facts.  However, everyone is human and prone to perceptions influenced by preconceived beliefs and life experiences. 

In the laboratory, questions involving race relations are pondered and discussed by workers of all creeds and colors.  Historically, laboratorians have viewed themselves as scientists focused strictly on the pursuit of facts, hard data, and helping patients.  However, one would err in thinking the lives of minority lab workers were encased in impenetrable bubbles of logic and reason. Instead, early on in their career (correction—their lives), many minority workers learned to compartmentalize and hide feelings of unfairness and helplessness in their effort to “fit in” and not make others feel uncomfortable.

Laboratory administrators should let employees know that their office is a “safe place” if an employee feels he or she needs to discuss issues affecting how they feel about their work environment. Many employees of color working in predominately white environments may avoid conversations involving race out of fear as being labeled as “one of those.”  However, avoiding difficult conversations does not make the problems go away; in fact, the lack of addressing an issue often creates a more significant problem later on, or the employee simply quits.  One thing managers should be prepared to hear if they are successful in creating a safe space and the employee chooses to talk, harsh truths.

Lab managers can be proactive and ask if the employee has encountered any barriers or obstacles to their success in the healthcare organization.  Minority employees frequently experience microaggressions, favoritism, and racial discrimination.  Discussing feelings may provide a release for the employee, allow the manager to begin to understand, and offer the opportunity for the manager to reflect on their behavior. 

 The diversity of today’s protest marchers provides evidence of the progress America has made toward vanquishing the problems of racism and discrimination.  All colors, creeds, and ethnicities are together expressing their desire to defeat the scourge of racial injustice.  Laboratories are a part of the social community, and minority employees are often reluctant to share anxiety and experiences they feel are race-based.  Lab managers should be reflective and reach out to their employees to let them know their office is a “safe place” to discuss issues openly, including those with racial overtones.  It is only through open and honest dialogue that we can avoid chaos and become the community we seek.

Darryl Elzie, PsyD, MHA, MT(ASCP), CQA(ASQ), has been an ASCP Medical Technologist for over 30 years and has been performing CAP inspections for 15+ years. Dr. Elzie provides laboratory quality oversight for four hospitals, one ambulatory care center, and supports laboratory quality initiatives throughout the Sentara Healthcare system.

Microbiology Case Study: Skin and Soft Tissue Infection Caused by an Unusual Bacterium

Case History

A 20 year old female with no significant past medical history presented with a painful pruritic rash on the bilateral inner thighs that had been persistent for one month. Prior to presentation, she had been treated with oral and topical antihistamines, topical steroids, valacyclovir, and partial courses of doxycycline and cephalexin without improvement. Physical examination was notable for diffuse erythema and dermal edema of the bilateral medial thighs with superimposed exophytic papules with dark, necrotic cores, the largest of which measured 1 cm in diameter (Image 1). Punch biopsy of the lesions was taken and sent for histology. A sample from necrotic tissue was sent to microbiology laboratory for gram stain and cultures.

Laboratory diagnosis

Gram stain showed gram positive cocci in clusters. After 32 hours of incubation, tissue cultures grew white, β-hemolytic colonies which were catalase positive, coagulase negative, and pyrrolidonylarylamidase (PYR) positive. The organism was identified as Staphylococcus lugdunensis by MALDI-TOFmass spectrometry. Histology revealed eosinophilic inclusions consistent with molluscum bodies as well as inflammatory infiltrate (Image 2). Brown and Hopps stain on tissue showed Gram-positive cocci is small clusters (Image 3). A diagnosis of molluscum contagiosum superinfected with Staphylococcus lugdunensis was made based on laboratory and histologic findings.

Image 1. Lesions on left medial thigh (left) and right medial thigh (right).
Image 2. Molluscum bodies
Image 3. Brown and Hopps stain on tissue showing gram positive cocci

Discussion

S. lugdunensis is a coagulase-negative staphylococcus first isolated in 1988 that was initially thought to be a commensal skin organism but has been shown to cause skin and soft tissue infections (SSTIs), bacteremia, endocarditis, prosthetic joint infections, and osteomyelitis,2 with a virulence more similar to S. aureus than to that of other coagulase-negative staphylococci. SSTIs are one of the more common manifestations of S. lugdunensis infection; one analysis of 229 S. lugdunensis clinical isolates demonstrated that 55.4% were associated with SSTIs.3 The spectrum of S. lugdunensis-related SSTIs includes folliculitis, pustulosis, cellulitis, abscesses, and rarer secondary infection of molluscum contagiosum and hidradenitis suppurativa.5 Molluscum superinfection itself is a rare phenomenon, and when it occurs, the superinfecting agent is most often S. aureus.1 Our case suggests that S. lugdunensis should also be considered as a potential causative agent of molluscum superinfection. There is growing recognition that S. lugdunensis is a virulent pathogen that should not be disregarded as a contaminant if found on culture. Importantly, when compared with S. aureus, S. lugdunensis has a more limited resistance profile; methicillin resistance is still uncommon, and 74.6% of isolates in one recent study were penicillin susceptible.4 Awareness of this more favorable resistance profile can facilitate selection of narrower-spectrum antibiotic therapies for S. lugdunensis infections.

In our case, patient received one dose of vancomycin and metronidazole in the emergency department and was then started on cefazolin for cellulitis. After wound culture identified S. lugdunensis, the patient was discharged on cefadroxil 1g twice daily for 10 days. On follow up, the rash had resolved.

References

  1. Berger EM, Orlow SJ, Patel RR, Schaffer JV. Experience With Molluscum Contagiosum and Associated Inflammatory Reactions in a Pediatric Dermatology Practice: The Bump That Rashes. Arch Dermatol. 2012;148(11):1257–1264. doi:10.1001/archdermatol.2012.2414
  2. Douiri N, Hansmann Y, Lefebvre N, Riegel P, Martin M, Baldeyrou M, Christmann D, Prevost G, Argemi X. Staphylococcus lugdunensis: a virulent pathogen causing bone and joint infections. Clinical Microbiology and Infection, 2016;22(8):747-748. doi:10.1016/j.cmi.2016.05.031
  3. Herchline TE, Ayers LW. Occurrence of Staphylococcus lugdunensis in consecutive clinical cultures and relationship of isolation to infection. J Clin Microbiol. 1991;29(3):419–421.
  4. Taha L, Stegger M, Söderquist B. Staphylococcus lugdunensis: antimicrobial susceptibility and optimal treatment options. Eur J Clin Microbiol Infect Dis. 2019;38(8):1449–1455. doi:10.1007/s10096-019-03571-6
  5. Zaaroura H, Geffen Y, Bergman R, Avitan‐Hersh E. Clinical and microbiological properties of Staphylococcus lugdunensis skin infections. J Dermatol, 2018;45: 994-999. doi:10.1111/1346-8138.14496

-Ansa Mehreen, MD. 1st year AP/CP resident at University of Chicago hospital program based at Evanston Hospital. Her academic interests include gastrointestinal pathology.

-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. 

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.