key: cord-1022168-d506pe56
authors: Nolte, Frederick S.; Babady, N. Esther; Buchan, Blake W.; Capraro, Gerald A.; Graf, Erin H.; Leber, Amy L.; McElvania, Erin; Yao, Joseph D.C.
title: Responding to the Challenges of SARS-CoV-2: Perspectives from the Association for Molecular Pathology (AMP) Infectious Disease Subdivision Leadership
date: 2020-06-19
journal: J Mol Diagn
DOI: 10.1016/j.jmoldx.2020.06.003
sha: 134691b911218ec753339a9133bcfd76362acfb3
doc_id: 1022168
cord_uid: d506pe56

Clinical molecular laboratory professionals are at the frontline of the response to the SARS-CoV-2 pandemic, providing accurate, high-quality laboratory results to aid in diagnosis, treatment, and epidemiology. In this role, we have encountered numerous regulatory, reimbursement, supply-chain, logistical, and systems challenges that we have struggled to overcome in order to fulfill our calling to provide patient care. In this Perspective from the Association for Molecular Pathology Infectious Disease Subdivision Leadership team we review how our members have risen to these challenges, provide recommendations for managing the current pandemic, and outline the steps we can take as a community to better prepare for future pandemics.

There are many factors as to why the response to SARS-CoV-2 in the United States (US) has been 57 different from previous pandemic responses, and our goal here is to document challenges to the SARS-58

CoV-2 response and provide initial recommendations to better prepare for the next pandemic. In 2009, 59 the influenza A H1N1 pandemic was the first pandemic in the age of molecular diagnostics. The large 60 network of academic and community hospital laboratories throughout the United States was able to 61 develop and validate molecular tests in the first week of the outbreak to rule out H1N1 as the cause of a 62 patient's illness, and this played a critical role in containing the H1N1 pandemic. For example, in Chicago 63 during the first month of the pandemic, 62% of the patients screened for H1N1 influenza were tested by 64 community molecular diagnostics laboratories with a typical turnaround time of 24 hours 1 . The clinical 65 laboratory community rapidly provided widely available H1N1 influenza molecular testing, facilitating a 66 swift pandemic response 2-6 . 67 68 Ten years later, our laboratories are now responding to the SARS-CoV-2 pandemic 7-10 . As we go to press, 69 the US has surpassed all other countries in number of diagnosed infections and deaths 70 (https://coronavirus.jhu.edu/map.html, last accessed 4/28/2020). The US federal government continues 71 to recommend social distancing measures, and many states have taken significant public health 72 measures to slow SARS-CoV-2 spread in their communities 11,12 (https://www.kff.org/health-costs/issue-73 brief/state-data-and-policy-actions-to-address-coronavirus/, last accessed 4/28/2020). The highest rates 74 of infection are currently observed in urban areas, consistent with patterns observed in seasonal flu 75 outbreaks; however, community spread has been identified in all 50 states and reported incidence has 76 increased in areas with smaller population density as testing expands 13 . Experts believe that due to a 77 number of factors we are seeing only the tip of the iceberg with regard to numbers of patients infected 78 using current diagnostic test strategies, and the inability to identify asymptomatic yet SARS-CoV-2 challenges the CDC has released guidance on how to safely reopen the US on May 2020 81 (https://www.cdc.gov/coronavirus/2019-ncov/downloads/php/CDC-Activities-Initiatives-for-COVID-19-82

Response.pdf, last accessed 5/27/2020). Key to this guidance is building more testing capacity for both 83 symptomatic and asymptomatic individuals. 84

This new coronavirus has unique biological characteristics that would challenge any health care system's 87 response, including high levels of infectivity 21 (https://www.ncbi.nlm.nih.gov/books/NBK554776/, last 88 accessed 5/27/2020). As a novel pathogen, existing clinical tests could not identify COVID-19 patients 89 and confirmation of diagnosis required molecular testing for SARS-CoV-2 viral RNA 22,23 . Once the genetic 90 sequence of the virus became available in early January 2020 (http://virological.org/t/genome-91 sequences-by-date-and-location/380, last accessed 4/28/2020) and clinical tests could be developed and 92 performed, reliance on a single assay production and test modality (i.e., Centers for Disease Control and 93

Prevention (CDC) test kit performed at CDC laboratories; https://www.cdc.gov/coronavirus/2019-94 ncov/lab/rt-pcr-panel-primer-probes.html, last accessed 4/28/2020) provided inadequate testing and 95 SARS-CoV-2 detection capacity, ultimately hindering the public health system response (e.g., 96

https://www.nytimes.com/2020/03/28/us/testing-coronavirus-pandemic.html, subscription required, 97 last accessed 4/28/2020). 98

With the lack of access at local levels, high complexity clinical diagnostic laboratories began 100 appropriately developing their own tests but faced additional regulatory hurdles due to the invocation 101 of Emergency Use Authorization (EUA) requirements by the US Food and Drug Administration (FDA) 102 (e.g., https://www.gq.com/story/inside-americas-coronavirus-testing-crisis, last accessed 5/27/2020). US public health laboratories; however, this kit was subsequently found to have a manufacturing 105 problem (https://www.cnn.com/2020/04/18/politics/cdc-coronavirus-testing-106 contamination/index.html, last accessed 5/27/2020). On February 24, the Association of Public Health 107

Laboratories wrote a letter to the FDA requesting enforcement discretion to allow state and local public 108 health laboratories the ability to create a laboratory-developed test for the detection of SARS-CoV-2, 109 which was denied (https://www.360dx.com/clinical-lab-management/aphl-asks-fda-make-own-tests-110 cdc-struggles-provide-sars-cov-2-test-kits#.Xp4d2chKiUl and https://www.360dx.com/regulatory-news-111 fda-approvals/fda-declines-aphl-request-make-own-sars-cov-2-test-kits#.XqLiUWhKiUk, last accessed 112 4/28/2020, registration required). Once the remanufactured CDC test was available to public health labs 113 on February 28, 2020, use of the test was initially restricted to specific reagent lots, extraction 114 platforms, and real-time PCR instruments which placed significant additional barriers on widespread 115 implementation (https://www.reuters.com/investigates/special-report/health-coronavirus-hospital-116 test/, last accessed 5/27/2020). The need for SARS-CoV-2 testing in the community resulted in FDA 117 changing their EUA policy and procedure at the end of February, allowing some academic laboratories to 118 rapidly make their test available. It was not until March 12, 2020 that the FDA granted the first EUA for 119 commercial test kits, and multiple molecular platforms became available for use by clinical diagnostic 120 laboratories (https://www.wsj.com/articles/how-washington-failed-to-build-a-robust-coronavirus-121

testing-system-11584552147?mod=article_inline, subscription required, last accessed 4/28/2020). 122 123 While clinical laboratories rapidly responded to make SARS-CoV-2 diagnostic testing available for 124 patients, supply chain issues have limited testing capacity and led to bottlenecks that hindered 125 widespread availability of these necessary tests (e.g., https://abcnews.go.com/Health/wireStory/us-126 virus-testing-faces-headwind-lab-supply-shortages-69710161, last accessed 5/27/2020). This situation (https://oig.hhs.gov/oei/reports/oei-06-20-00300.pdf, last accessed 5/28/2020). Because of these 129 critical shortages and CDC recommendations providing specific clinical presentation and epidemiological 130 criteria to identify those eligible for diagnostic testing (https://www.cdc.gov/coronavirus/2019-131 nCoV/hcp/clinical-criteria.html, last accessed 4/28/2020), the initial data set on the performance of 132 SARS-CoV-2 diagnostics reflected only symptomatic patients biased towards the very ill. Diagnostic data 133 critical to determinations of mortality rate, infection rates, and other critical metrics -upon which 134 existing modeling and predictions are based -therefore potentially contains a testing bias that we do 135 not yet fully comprehend 24-26 (https://www.statnews.com/2020/03/31/covid-19-overcoming-testing-136 challenges/, last accessed 4/28/2020). Full diagnostic testing capacity, to include serological screening to 137 identify persons in the community who have been exposed and recovered from SARS-CoV-2, is only now 138 becoming available, many months after the first confirmed US case of SARS-CoV-2 23,27,28 . Recent autopsy 139 data indicates the earliest identified death was weeks earlier 140 (https://www.npr.org/sections/coronavirus-live-updates/2020/04/22/840836618/1st-known-u-s-covid-141 19-death-was-on-feb-6-a-post-mortem-test-reveals, last accessed 4/28/2020). Only with additional 142 testing and research on disease pathogenesis can we fully understand the scope and pathogenicity of 143 COVID-19 disease. 144

The Association for Molecular Pathology (AMP)'s Infectious Diseases Subdivision Leadership is aware of 147 and involved in multiple efforts to address SARS-CoV-2 testing development, test quality and 148 interpretation, operation, and limited resource management. During the pandemic, guidance from AMP 149 subject matter experts will continue to be provided in multiple formats. The authors anticipate providing 150 additional communications as needed to document and to address emerging challenges. Throughout related scientific, regulatory, and reimbursement resources (https://www.amp.org/clinical-153 practice/testing-resources-for-covid-19/, last accessed 4/28/2020). On February 20 and May 14, AMP 154 provided freely accessible online education regarding the COVID-19 pandemic 155 (https://educate.amp.org/local/catalog/view/product.php?productid=4, last accessed 5/5/2020 and 156 https://educate.amp.org/local/catalog/view/product.php?productid=183, last accessed 5/27/2020); 157 additional webinars will provide periodic updates. AMP has conducted a robust COVID-19 testing survey 158 designed to identify and understand the laboratory community's challenges, with initial data from over 159 100 US-based laboratories available (https://www.amp.org/advocacy/sars-cov-2-survey/, last accessed 160 5/28/2020). AMP member peer-to-peer listserv communications have been robust as colleagues rapidly 161 shared concerns, challenges, knowledge, experience, and solutions to support the clinical laboratory 162 community's COVID-19 testing response. Multiple AMP subject matter experts have been featured in 163 media interviews and are interacting on social media outlets, effectively communicating laboratory 164 community concerns and highlighting numerous success stories in spite of challenging conditions (e.g., 165

https://www.cnn.com/2020/04/09/politics/coronavirus-testing-cdc-fda-red-tape-invs/index.html, last 166 accessed 4/28/2020). We applaud the efforts of AMP members from all over the world, other 167 professional societies, and laboratory professionals around the world for their leadership and dedication 168 to patient care during this time of rapid change and instability. Clinical laboratory physicians and professionals are in the vanguard of the response to the SARS-CoV-2 302 pandemic, providing accurate, high-quality laboratory results to aid in diagnosis, treatment, and 303 epidemiology. In this role, we have encountered numerous regulatory, reimbursement, supply-chain, 304 logistical, and systems problems that we have struggled to overcome in order to fulfill our calling to 305 provide patient care. Despite the challenges and setbacks, the cadre of highly-trained and dedicated 306 molecular diagnostic professionals of the AMP have risen to the challenge and are providing the vital 307 diagnostic intelligence needed for effective management of this pandemic. While the current successes 308 were achieved through determination and ingenuity, our experiences suggest that the hurdles and 309 obstacles that have been encountered were not inevitable and certainly impaired our national 310 recognition of and response to the pandemic. In order to prepare for the next unexpected challenges, 311 thoughtful retrospection and intervention into key areas will improve our ability to care for patients and 312 our society when the next crisis arises. 313 314 On behalf of AMP, we recognize and thank our members and all members of the multidisciplinary 315 medical teams for their expertise, dedication, and service. Organizationally, AMP will continue to 316 proactively provide critical information and resources in support of all laboratory professionals involved 317 in COVID-19 response activities. We will also continue to engage in, encourage, and support DISCLAIMER: The Association for Molecular Pathology (AMP) Perspectives are developed to be of 327 assistance to laboratory and other health care professionals by providing guidance and 328 recommendations for particular areas of practice. The Perspectives should not be considered inclusive 329 of all proper approaches or methods, or exclusive of others. The Perspectives cannot guarantee any 330 specific outcome, nor do they establish a standard of care. The Perspectives are not intended to dictate 331 the treatment of a particular patient. Treatment decisions must be made on the basis of the 332 independent judgment of health care providers and each patient's individual circumstances. The AMP 333 makes no warranty, express or implied, regarding the Perspectives and specifically excludes any 334 warranties of merchantability and fitness for a particular use or purpose. The AMP shall not be liable for 335 direct, indirect, special, incidental, or consequential damages related to the use of the information 336 contained herein. 337

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