Clinical laboratories are unsung heroes of COVID-19
In normal times, clinical laboratories, including pathologists, laboratory directors and clinical laboratory scientists, function in the background. We are not patient facing but provide important diagnostic tools and insights to our partner physicians and nurses. In a war analogy, we are the code breakers that support the front-line troops. Pathology is detective work, investigating the best test, understanding regulations, and figuring out the diagnosis in a timely manner. COVID-19 thrust laboratory professionals into the unknown with an immediate need to develop, implement, and scale up novel and cutting-edge testing in a trying time professionally and personally.
With great support from our partner physicians and nurses and excellent collaboration within our institution under the leadership of Dean Choi, Dr. Laura Forese, and Dr. Massimo Loda, the clinical laboratories delivered breakthrough testing and novel therapeutic options and stayed ahead of the curve. This is our story.
Call to arms
Our clinical labs first saw suspected cases at NYP/Lower Manhattan Hospital in late February. Initially, all specimens from Patients Under Investigation (PUIs) for COVID-19 needed to be sent to Centers for Disease Control and Prevention (CDC), then later to New York City Department of Health and Mental Hygiene (NYS DOHMH), when they brought up a test. Both of these options had long turnaround times and these public health labs were overwhelmed with patient specimens.
On February 29, 2020, government laboratories realized their in-house testing plans were insufficient to meet the onslaught of COVID-19. The FDA issued the guidance titled Policy for Diagnostics Testing in Laboratories Certified to Perform High Complexity Testing under CLIA prior to Emergency Use Authorization (EUA) for Coronavirus Disease-2019 during the Public Health Emergency. This allowed the emergent use of laboratory tests to detect SARS-CoV-2 after validation in a high complexity molecular laboratory, but before the tests were approved by the FDA.
This guidance immediately transformed the world for Laboratory Medicine. Clinical Laboratories are highly regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) (https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA). Clinical laboratories are used to extensive validations before the implementation of any FDA-approved test; when we develop a new test (a.k.a. a laboratory developed test, not previously approved by the FDA), we are used to a validation that takes months and is reviewed and approved by the New York State Department of Health before it can be used.
This time would be different.
Action Plan
The next day, March 1, 2020 the laboratory directors of Weill Cornell Medicine had a Zoom call with our Chair, Dr. Massimo Loda, Dr Melissa Cushing, Vice Chair of Laboratory Medicine, and Ian Hatch, Director of Laboratory Services. We developed a plan to handle testing for the surge of COVID-19 tests we were sure would come.
The plan was as follows:
- Ensure staff safety during testing.
- Start with testing equipment already on the premises to expedite implementation.
- Select reagents that were qualified by our vendors for COVID-19 testing, while ensuring that the vendors could provide reagents for the months to come.
- Choose a sensitive and specific commercial assay.
- Find negative nasopharyngeal swab specimens from the microbiology laboratory, as well as specimens positive for non-SARS-CoV-2 coronaviruses so we could assess the potential for cross reactivity (e.g., Coronaviruses HKU1, NL63, 229E, and OC43), for assay development and negative controls.
- Extend shifts in the Molecular Lab to 12 hours.
- Report test results within 24 hours.
- Identify additional equipment, disposables, PPE, personnel, or other resources needed. Stock up on as many reagents and disposables as possible in anticipation of shortages.
Submit an EUA to FDA for test approval within 15 days after beginning testing.
But our plan had obstacles. We had no source of positive control (samples with SARS-CoV-2 virus) since had no proven cases at NYP/Weill Cornell. An assay cannot be validated without the infectious organism that we are trying to prove we can detect. We added our laboratory to a list of labs waiting for a government source of virus but it would result in significant delays given the demand. We realized quickly that this would not work. Due to the quick thinking and professional networking of Dr. Lars Westblade, Director of Microbiology, we were able to source positive control material from Dr. Scott Weaver, Professor and Chair, Department of Microbiology and Immunology at the University of Texas Medical Branch in Galveston, Texas and the Director of the World Reference Center for Emerging Viruses and Arboviruses. Dr. Weaver generously supplied SARS-CoV-2 RNA to allow us to validate the test we developed in our clinical laboratory. The CDC and the NYS DOHMH had designed and manufactured new test kits for detecting SARS-CoV-2 RNA in clinical specimens, but in very limited capacity. Very few laboratories were able to get access to these reagents, and their use was limited by the need for specific instruments which were not available in our institution.
Hanna Rennert, PhD (L), Priya Velu, MD, PhD (R)
Dr. Hanna Rennert, Dr. Priya Velu, Phyllis Ruggiero, Christina Bjurstrom and Dr. John Sipley, our leadership team from Molecular Pathology, worked together to implement the initial phase of our plan. We decided to use Altona reagents on our current equipment in our Molecular Lab due to the very positive experience we have had with performing other tests using their reagents.
The entire validation and implementation process, including staff training and test build in the laboratory information system (LIS) was completed within four days. A special nucleic acid isolation protocol to allow rapid, off-board viral inactivation and high throughput extraction was implemented, providing us with the capacity to test up to ~400 specimens per day with a turnaround time of 8 hours from receiving the samples in the laboratory.
On Wednesday March 11, 2020 we went live with the test in our laboratory with a single extended shift of 12 hours. In our first SARS-CoV-2 run in the Molecular Lab we identified the first few positive patients with a positive detection rate of ~3%. This detection rate increased to an astounding level of 60% by the end of March.
Scaling Up Testing Volumes
By mid-March, the volume of tests increased; the number of patients admitted to the hospital was shocking. It became clear that we would need to step up our game. We needed 24-hour testing on a high throughput instrument to run thousands of tests per day. This was a huge hurdle and would require more space and more personnel, two nearly impossible asks in a New York City lab.
Our microbiology and molecular labs are old and crowded. Space had been maximized for efficiency prior to COVID-19; there was no room for expansion. Expansion plans had been discussed for both labs prior to the pandemic, but space and funding had not been identified. In New York State, finding an adequate number of qualified laboratory personnel is a challenge even when we are not in the midst of a pandemic. The regulations in New York State go beyond what the federal government requires in terms of education, experience and exams. However, we were able to address both issues with out-of-the-box thinking and help from Weill Cornell Medicine, our medical school partner.
Dean Choi of Weill Cornell, Dr. Hugh Hemmings, Dean of Research, and senior leaders of NYP (notably Dr. Kate Heilpern and Dr. Laura Forese) rolled up their sleeves to understand our requirements and to mobilize the best of our institution to deliver solutions. The clinical teams were extremely supportive and helped us through the reagent shortages by prioritizing testing to patients who had the greatest need. Help came from all over the institution (the ICUs and Emergency Department to get specimens, the medical college who helped us find the space and personnel, department chairs, the facilities teams, our Laboratory Information Systems informatics team led by Bulent Oral and Sarah Russell).
Lars Westblade, PhD (L), Arryn Craney, PhD (R)
In terms of space, Dr. Hugh Hemmings was extremely helpful in identifying a new lab in the medical college. Dr. Donald D’Amico generously shared his research lab space in Ophthalmology to create a brand-new lab called the E3 Virology Lab. Its only role is to perform diagnostic SARS-CoV-2 testing. Lou Kennedy, the Capital Projects Director at Weill Cornell Medicine, and the Weill Cornell contractors miraculously designed and renovated the E3 lab within one week (!) with the advice of the Microbiology Laboratory Directors, Dr Lars Westblade and Dr Arryn Craney, Ms. Betty Panik, Manager of Microbiology, and Ms. Kathy Fauntleroy, a Supervisor in Microbiology with molecular testing expertise. Gina Imperato and Jeff Hernandez from the Department of Pathology found freezers for the lab to store specimens and helped us access other resources in the medical school. During the next few weeks, two new state-of-the-art molecular diagnostic instruments from Roche and Hologic were placed in that lab, along with a processing lab for accessioning and pipetting specimens. Two new freezers were purchased for specimen storage.
To staff the new laboratory, we needed a creative solution. On March 7th, Governor Cuomo had declared a disaster emergency in New York State, along with this declaration, Governor Cuomo signed an Executive Order which among many other things, suspended the New York State licensure requirement for individuals performing testing for COVID-19. We appreciated the helpfulness of Ms. Beverly Rauch, the Director of the Clinical Laboratory Program at New York State Department of Health for her help on this issue. This opened the door for us to use research faculty, graduate students and research staff at Weill Cornell Medicine with research experience in molecular testing to perform clinical SARS-CoV-2 testing. With help from Ms. Kathleen Crowley, Manager of Transfusion Medicine and Cellular Therapy, we created a new process for qualifying Weill Cornell Medicine employees as laboratory technologists in the SARS-CoV-2 testing lab. Jeff Catalano from the Clinical Genomics laboratory contributed his operational expertise and helped us staff the new lab 24 hours per day. This made all the difference in March. We were able to staff the new lab around the clock and perform all SARS-CoV-2 tests within 24 hours (usually within 6-8 hours). Soon after rapid testing from Cepheid became available, the microbiology laboratory rapidly validated this test changing our turnaround times from 8 hours to <1 hour for urgent tests. As the landscape of testing has changed throughout the COVID-19 surge the microbiology laboratory has continued to validate and clinically implement SARS-CoV-2 molecular tests, including 2 additional rapid assays, both from BioFire Diagnostics, and also validate the testing of pooled specimens on the high-throughput testing platforms; for a total of 6 independent assays (some of which required an EUA request to the FDA)! Often these validations have been performed within an extremely short period of time from days (2 days is the record!) to a week.
Finally, the microbiology laboratory has had to deal with unexpected consequences of COVID-19, including a surge in blood cultures, despite the fact that patients with COVID-19 typically do not have bacteremia. This surge led to the depletion of automated blood culture capability. The laboratory was swift to generate and analyze data that showed we could reduce our blood culture incubation time from 5 to 4 days without loss of pathogen detection and thus free up space in the automated blood culture incubators. In addition, the microbiology laboratory has struggled for key reagents not related to COVID-19 testing, including microbiology culture media and reagents for bacterial and fungal growth and identification. However, through it all the team has rallied to provide elegant and quick workarounds without causing any disruption to the clinical service. The flexibility, commitment and empathy to and for patient care exhibited by the microbiology laboratory staff has been truly inspirational.
From Diagnostic to Antibody Testing
Sabrina Racine-Brzostek, MD, PhD (L), He Sarina Yang, PhD (R)
Just as the diagnostic testing was coming under control, in late March, the serology (antibody) testing became a new pressure point. Around the nation, there was a clamor for antibody testing and discussion of “immunity passports” and other similar concepts. Health care workers in our institution wanted to know if they had been exposed to the virus. The laboratory directors from the Central Laboratory, Dr. Zhen Zhao, Dr Sarina Yang and Dr. Sabrina Racine, Central Lab Administrative Director, Sandra Aranibar-Atristain, and Jim Yee, Medical Technologist, stepped up to the plate.
The central laboratory team rapidly evaluated a number of serological testing platforms and performed a comprehensive validation of the SARS-CoV-2 IgM/IgG antibody test on the ET Healthcare Pylon 3D analyzer. Supported by its robust analytical performance, we were one of the first laboratories in the US to implement COVID-19 serology testing. On 3/23/2020, we began offering this test for COVID-19 convalescent plasma donors and subsequently to healthcare providers and patients.
Zhen Zhao, PhD
At the end of March, there was tremendous skepticism about the quality of serology assays. We had little experience with our new assay. The laboratory of Dr. John Moore in the Department of Microbiology and Immunology of Weill Cornell Medicine helped us immensely to confirm the sensitivity and specificity of our Pylon test. Dr. Moore and his lab showed excellent correlation between our Pylon test and ELISA and neutralizing antibody assays, he and his team had developed in-house against SARS-CoV-2 antigens. Additionally, they have also been able to analyze samples for IgA against SARS-CoV-2. The Central Lab is now able to offer thousands of tests per day, easily keeping up with clinical need, on high throughput instruments from Siemens and Roche. By the end of July 2020, we had performed over 40,000 SARS-CoV-2 serology tests.
Therapeutic Clinical Trial Involvement
Robert DeSimone, MD (L), Melissa Cushing, MD (R)
The Transfusion Medicine Service partnered with the Division of Infectious Disease to join an international randomized clinical trial (CONCOR-1) to assess the efficacy of COVID-19 convalescent plasma (CCP). Dr. Robert DeSimone, Chief of Transfusion Medicine, partnered with Dr. Grant Ellsworth and Dr. Tim Wilkins from Infectious Diseases to create a recruitment and qualification process for CCP donors. Dr. Melissa Cushing, Vice Chair of Laboratory Medicine and Director of Transfusion Medicine and Cellular Therapy, partnered with Dr. Marshall Glesby to implement the trial at the Weill Cornell, Brooklyn Methodist, and Lower Manhattan campuses of NewYork-Presbyterian Hospital. The trial now has approximately 80 participants worldwide with ongoing enrollment.
The pace of effort required to provide patient care during the COVID-19 pandemic has left little time for reflection and “lessons learned”. Our team experienced every type of shortage you can imagine, from personnel (due to illness amongst our highly trained team and availability of new talent to recruit for the additional testing), equipment, space, and supplies in the midst of an overwhelming pandemic. If we were to credit one thing with helping us make it through, it was the team mentality across the clinical laboratories. All the labs came together to help each other, including our laboratory at Lower Manhattan Hospital, lead by Dr. Jacob Rand, Dr. Ljiljana Vasovic and Daniel Alvarado. Some labs were less busy during the pandemic (cytogenetics, blood bank, cellular therapy, point-of-care, anatomic pathology, clinical genomics) and immediately volunteered to help the labs bear the brunt of testing during the pandemic (central lab, microbiology, molecular). Every day was unpredictable, stressful, high risk, but knowing that we were all “in it together” helped morale and kept up motivation.
The international collaboration of the medical and scientific community, at the time of geopolitical tension, has been another source of inspiration. Our team has helped labs around the world with advice and support, and they have helped us.
Now with over 200,000 SARS-CoV-2 tests under our belt, 5 RT-PCR test options and 3 test options for antibody testing we hope we are prepared for the fall of 2020 in NYC and whatever it will bring.
Autopsy Service Operations During COVID-19 Pandemic
During the COVID-19 pandemic in New York City, Weill Cornell Medicine and NewYork-Presybterian Hospital increased our medical services in all areas related to diagnosing, learning about, and subsequently treating the viral infection. Unfortunately, as is well documented, COVID-19 can in some severely affected patients be a deadly disease, and therefore the autopsy service saw increased volumes during this period of deceased patients with known or suspected infection.
While many hospitals across the country suspended their autopsy services, we confidently and carefully continued to provide post-mortem examinations to respectfully fulfill the wishes of our most affected patients and their families, to help our clinicians learn more about what they are treating, and to provide researchers material to make new discoveries. In many cases, families just wanted to know what happened to their loved ones, which we could answer for them. Others wanted everything possible done to have their unfortunate illness lead to better outcomes and more knowledge about the disease. On the autopsy service, it is a paramount goal to provide answers to families and clinicians, and to fulfill and respect the wishes of our patients and their families during their most challenging and difficult times.
Additionally, autopsy results improved healthcare operations through several teaching conferences and individual discussions with the clinical teams. Our autopsy pathologists were able to describe findings in COVID-19 that helped lead to improvements in therapeutic regimens offered to our patients. Important basic science research through our associated research labs, both completed and ongoing, has benefited from the altruistic contributions of these patients, their families, and our pathologists. We are proud to be making a contribution wherever possible.