Lingering Effects of SARS-CoV-2 Infection

By: Audie Atienza, Ph.D., NCATS Program Officer; Sanae ElShourbagy Ferreira, Ph.D., NCATS Health Specialist; and Michael G. Kurilla, M.D., Ph.D., NCATS Director of the Division of Clinical Innovation

While SARS-CoV-2 has demonstrated remarkable tenacity in terms of successfully navigating pharmaceutical as well as non-pharmaceutical interventions with waves of new variants throughout this pandemic, preliminary studies also report that approximately 1/3 of those infected with SARS-CoV-2 remain symptomatic four or more months after the infection, with continued symptoms that negatively impact daily functioning, regardless of the severity of the initial acute infection.

This phenomenon of persistent COVID-19 symptoms that impact daily life months after initial infection, and sometime after initial abatement of symptoms or only mild initial symptoms, has become known colloquially by several names: “long COVID,” “long-haul COVID,” “chronic COVID,” and “post-COVID-19 syndrome.” The Centers for Disease Control and Prevention coined the term “Post-COVID Conditions” as an umbrella term to group these various conditions, defining it as “a wide range of new, returning, or ongoing health problems people can experience four or more weeks after first being infected with the virus that causes COVID-19.” NIH, recognizing that chronic symptoms may emerge even among initially asymptomatic SARS-CoV-2 individuals, prefers Post-Acute Sequalae of SARS-CoV-2 Infection (or PASC) as an umbrella term to capture the various ongoing symptoms: “PASC refers to what happens after the acute infection with the virus and is relevant whether a person has been diagnosed with COVID-19 or not. Even if someone did not experience symptoms, PASC is still relevant because there could be effects after acute infection.”

Yet, this phenomenon named PASC or Post-COVID Conditions leaves so many questions unanswered: Why do some individuals recover fully from COVID-19, while others experience significant lingering symptoms? Why do some with mild or asymptomatic infection go on to develop debilitating chronic symptoms? Are there different categories or phenotypes of PASC/Post-COVID Conditions given the heterogeneity of symptoms reported? What are the pathobiological mechanisms responsible for these persistent symptoms? Are there certain groups or populations more at risk for developing PASC/Post-COVID Conditions?  Why do 30-40% of vaccinated PASC/Post-COVID Conditions patients report improvements in their symptoms, while others continue to experience persistent symptoms? How does PASC/Post-COVID Conditions differ from other disorders with similar symptom characteristics (e.g., PICS, MIS-C, ME/CFS). To begin to systematically address these fundamental questions, NIH has launched an ambitious nation-wide research effort to study tens of thousands of patients – The Researching COVID to Enhance Recovery (RECOVER) Initiative. Rest assured that NIH devoted considerable brain power and resources to this acronym selection.

NCATS researchers are already hot on the trail with preliminary findings to address some of these key questions. N3C has conducted a literature review of 39 studies and found “that there is not agreement on the definition of Long COVID,” and subsequently conducted an electronic health record (EHR) analysis of nearly 300,000 patients in the N3C data enclave using 76 standardized terms to establish and operationalize a preliminary empirical definition of long COVID to identify potential patients.

The Scripps hub began looking at physiological and behavioral changes associated with COVID-19 recovery, using commercial wearable sensors (e.g., eFitbits, Apple Watches). They found prolonged physiological impact (i.e., resting heart rate differences) of COVID-19 infection, lasting approximately 2-3 months on average. DCI’s Audie Atienza has been selected to co-lead the mobile health platform component of the NIH RECOVER Initiative to leverage mobile and wearable devices.

Other CTSA investigators have started to examine the pathobiology of SARS-COV-2 infection that may have implications for PASC/Post-COVID Conditions. The Arkansas hub has reported antibodies specific for ACE2 in the plasma of patients hospitalized due to SARS-CoV-2 infection (vs. patients without a history of infection). While still to be confirmed as an etiologic agent of PASC, these results provide support for the autoimmune hypothesis for PASC. Multiple CTSA hubs are involved with the soon-to-be-launched observational cohorts under RECOVER to more precisely define this puzzling clinical syndrome. In addition, the biorepositories, EHR data repositories (e.g., N3C), digital/mobile health data repositories (e.g., DETECT) and telehealth research networks (e.g., SPROUT, Project ECHO) coming out of the CTSA Program will be invaluable research resources to help us understand, prevent, manage and treat PASC/Post-COVID Conditions in the future.

Once again, the CTSA’s hubs, partners, and collaborators have risen to the challenge of emerging public health concerns.

                                                                                                                                                                 For truly on countless occasions throughout my life I have had
                                                                                                                                                                 this experience; persons for a time talk pleasantly with me
                                                                                                                                                                 because of my work among the sick, in which they think me very
                                                                                                                                                                 well trained, but when they learn later on that I am also trained in
                                                                                                                                                                 mathematics, they avoid me for the most part and are no longer
                                                                                                                                                                 at all glad to be with me. 

                                                                                                                                                                 -       Claudius Galenus, better known as Galen, the early Greek
                                                                                                                                                                  physician who made the observation that blood moves.


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