COVID-19: A Year in Review, Part II: The Emerging Science of SARS-CoV-2 and COVID-19

By Roger Bertholf and Steven Kroft - June 16, 2021

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Editor’s Note: In early 2020, the SARS-CoV-2 virus, and the ensuing COVID-19 pandemic swept the nation. In our second installment of a three-part series looking at how different areas of pathology and laboratory medicine have been affected over the past 12 months, Dr. Roger L. Bertholf, PhD, MASCP, Editor in Chief of Lab Medicine, and Dr. Steven H. Kroft, MD, MASCP, Editor in Chief of AJCP, look at the research that has been published over the past year related to the virus and disease, and what we have learned from it.

An April 2021 search of the MEDLINE database revealed that more than 125,000 scientific papers mentioning either SARS-CoV-2 or COVID-19 have been published in the biomedical literature indexed by the National Library of Medicine. Through April 21, 2021, Laboratory Medicine (LM) and the American Journal of Clinical Pathology (AJCP) published 79 papers related to SARS-CoV-2 or COVID-19, the virus and disease, respectively, that have caused more than 3 million deaths worldwide. We reviewed these 79 papers, and noticed trends that reflect how our understanding of the novel coronavirus has evolved since the early days of the global pandemic it caused. Our review also provided some insight into the future directions of research on the properties of the virus, and the diagnosis and treatment of COVID-19.

The first paper in AJCP citing the novel coronavirus was published online February 13, 2020, and was a brief review comparing severe adult respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19.1 At that early stage in the pandemic, little was known about the virus, and laboratory tests to detect it were just becoming available. Notable papers in AJCP during this early period included a discussion of laboratory safety requirements that should be observed when handling specimens submitted for coronavirus testing;2 this paper was co-published in LM.3 In April 2020, a highly-cited report of autopsy findings in COVID-19 patients appeared in AJCP, describing diffuse alveolar damage and airway inflammation.4

Not surprisingly, during the first several months of the pandemic, many of the coronavirus-related papers in both AJCP and LM focused primarily on the laboratory methods for detecting SARS-CoV-2.5-8 In addition to selecting the most useful tests for detecting the virus, laboratories also were exploring ways to manage the unprecedented number of tests being ordered to detect SARS-CoV-2. Molecular pathology laboratories that previously accounted for only a small fraction of total laboratory services suddenly had test volumes comparable to chemistry and hematology. Shortages of reagents and other supplies were common. One laboratory used a 3D printer to produce nasopharyngeal swabs to collect specimens for SARS-CoV-2 testing, and described their innovative solution in LM.9 Other authors described strategies for specimen pooling to maximize testing capacity during the period of massive demand but unreliable supply chains.6,10-12

Serological tests for the novel coronavirus were relatively easy to produce, and were marketed as rapid and economical methods to screen individuals for infection with the virus, but there were concerns among laboratorians about the reliability of these tests, which had been granted emergency use authorization by the FDA after minimal review. Concerns about the limited specificity of serological assays, and the correspondingly low predictive value of positive results in low-prevalence populations, were expressed in editorials that appeared in both AJCP and LM.7,13-15 The journals also published several performance evaluations of individual automated serological tests for SARS-CoV-2 (32462195).8,16,17 At this point in the pandemic, it was not clear whether plausible uses could be developed for serologic tests beyond their applicability to epidemiologic studies. Notably, however, laboratory professionals began to extrapolate performance characteristics of various types of tests to the task of managing public health, as opposed to individual patient management.18

In the U.S., COVID-19 cases (and deaths) peaked in the early summer of 2020, but began to decline in August and September, presumably because most states enacted more aggressive measures to limit transmission of the virus. At the same time, laboratories began to realize that the pandemic was not a short-term challenge, but rather would affect laboratory services for many months to come. Several papers in AJCP and LM addressed operational issues associated with laboratory response to the pandemic. These papers described various aspects of laboratory practice that were affected by the pandemic, including remote education,19,20 incident command centers,21 specimen delivery problems,22 effects on anatomic23 and forensic24 pathology services, impacts on transfusion services,25 and the overall adaptation of laboratory management to the radically altered workflow.26

As the pandemic duration neared the one-year mark, knowledge of the both the pathology and pathophysiology of COVID-19 began to mature. An important paper in AJCP described the specific types of acute lung injury seen in 40 autopsies of COVID-19 patients, determining that about one fourth of the cases did not have evidence of acute lung injury, suggesting secondary causes of death in those patients.27 COVID-19 was known to cause coagulopathies in some patients, and one study published in AJCP focused on platelet deposition in the pulmonary vasculature in these patients.28 Another paper addressed the cardiotoxicity of hydroxychloroquine, a controversial treatment for COVID-19.29 The use of convalescent plasma obtained from donors who recovered from COVID-19 expanded, and the performance of commercial serological assays for determining the potency of the donated plasma was assessed in a study reported in AJCP in February 2021.30

Of great interest, as the proportion of previously infected and vaccinated individuals continued to grow, was the nature of the immune response to the coronavirus. The duration of immunity following infection was addressed in a February 2021 paper in AJCP, and the authors concluded that mild cases of the disease may not elicit long-lasting immunity,31 a finding that likely contributed to the current recommendation that individuals who have recovered from COVID-19 should still be vaccinated. A March 15, 2021 editorial in AJCP discussed the prospects for achieving herd immunity against the virus, and included a cautionary note that vaccination alone may be insufficient to quickly overcome the pandemic.32

The most recent papers published in AJCP and LM on topics related to the pandemic include an assessment of how the lockdown measures affected the ongoing care of cancer patients,33 application of CRISPR-based technology to SARS-CoV-2 detection and measurement,34 long-term pulmonary consequences of COVID-19,35 and strategies for convalescent plasma donor recruitment.36 Also notable among recently published papers are the use of machine learning techniques and data analytics to manage laboratory resources during the pandemic. Tschoellitsch and co-workers used machine learning to analyze routine laboratory tests to predict positive PCR SARS-CoV-2 results.37 Lippi et al., used Google Trends to predict the demand for SARS-CoV-2 testing.38

What we learned

These papers published in AJCP and LM since February 2020 reflect the evolution of our knowledge about SARS-CoV-2, the multifaceted disease it causes, and the methods to detect the virus and treat infected patients. At the beginning of the pandemic, enormous effort was directed toward rapid detection of the virus. For many clinical laboratories, molecular diagnostic tests to detect SARS-CoV-2 quickly became one of the most common requests received, forcing extreme reallocation of resources and a desperate scramble to secure adequate supplies necessary to run the tests. Once testing capacity ramped up to meet demand, attention began to focus more on the pathophysiology of COVID-19, as it became clear that respiratory distress was only one feature of the disease, which also involves cardiovascular, renal, gastrointestinal, immunohematological, and neurological manifestations. At the same time, there were numerous studies that searched for relevant biochemical markers that could predict the clinical outcome in COVID-19 patients; most of these studies focused on relatively nonspecific markers of inflammation, and few offered any substantial benefit in the treatment of the disease.

When vaccines against the SARS-CoV-2 virus became available in late 2020, some of the laboratory interest shifted toward measuring the intensity of the immune response following vaccination. In the early stages of the pandemic, immunoassays to detect anti-SARS-CoV-2 antibodies were some of the first analytical methods available to detect infection with the coronavirus, but these were quickly replaced by more specific tests to detect the viral RNA. However, there now is renewed interest in use of tests that measure antibodies against the spike protein, which is the target of vaccines, because of their ability to quantify the serological response to both SARS-CoV-2 infection and vaccination. Therapeutic use of convalescent plasma from patients who recovered from COVID-19 also created a need for quantitative serological assays, as a means to establish the immunopotency of the collected plasma.

Recently, there is great interest in refining our analytical methods for detecting the virus by applying the most current and sophisticated technologies available, such as CRISPR and machine learning. The emergence of SARS-CoV-2 variants is also the focus of much activity, and sequence data for these variants are being generated and reported with unprecedented speed through resources designed specifically for the rapid dissemination of such data.

Laboratories have been leaders during the pandemic

The response of the medical laboratory community to the SARS-CoV-2 pandemic has been breathtaking. The in vitro diagnostics industry produced methods to detect the novel coronavirus, and antibodies to the virus, within weeks of its discovery. The U.S. Food and Drug Administration (FDA) expedited approval of these methods for emergency use, recognizing the importance of an immediate response to the rapidly spreading virus. Clinical laboratories re-engineered their operations to serve the expanding need for SARS-CoV-2 testing. Blood banks established convalescent plasma donor programs within the guidelines specified by the FDA. A vaccine to the virus, predicted to take years to develop, was available in less than a year, and its safety and effectiveness exceeded all expectations. With sequencing technology, the inevitable mutations producing variants of the coronavirus have been tracked in real time, so changes in the transmissibility of the virus or its susceptibility to the vaccine can be detected early. Finally, at every stage of the pandemic, laboratory professionals were instrumental in guiding and advising providers, hospitals, healthcare systems, community leaders, and policy makers in their responses to the pandemic.

Clinical laboratories have been at the forefront of the response to this pandemic. As journal editors, it has been our privilege to witness first-hand the evolution of our knowledge about the SARS-CoV-2 virus: how the infection is detected, how the laboratory monitors the disease it causes, the pathophysiological consequences of COVID-19, and the likely direction of future research into its prevention. The papers published in AJCP and LM represent a small but revealing sample of the literature describing the evolution of our knowledge about the novel coronavirus.

We would close by reflecting on the extraordinarily rapid pace at which both the pandemic and the body of knowledge related to it evolved, which necessitated putting reliable information in the hands of healthcare practitioners as quickly as possible. To that end, AJCP and LM, as well as many other scientific journals, responded by creating streamlined editorial and production processes to publish high quality, peer-reviewed science nearly in real time. We thank our authors, reviewers, editors, managing editors, and publisher for making this possible.

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Roger Bertholf and Steven Kroft

Editors in Chief