The Race to Understand Post–COVID-19 Conditions

Abstract

For more than a decade after the 1918 influenza pandemic, a mysterious Parkinson-like syndrome with sleep disturbance, hypomimia, and a high mortality rate developed in thousands of people across the globe. In 1920 the U.S. Surgeon General declared that the syndrome, popularly termed “encephalitis lethargica,” was caused by influenza. However, opinions varied, mainly as cases of encephalitis lethargica frequently differed from respiratory infections thought to represent influenza (1). More than a century later, questions remain regarding the cause, transmission, and availability of effective treatments, and lastly, will it happen again? While still amid the COVID-19 pandemic globally, postinfectious sequelae may again be a thorny and more longlasting issue with little current understanding or treatment to offer patients. The pandemic s terrible human impact has been most frequently measured in deaths and hospitalizations. However, consequences affect both those with and those without COVID-19, with spillover effects not only on postponed health care and prevention but socioeconomic disruption that may prompt anxiety, depression, and posttraumatic stress disorder. In studies of SARS-CoV-2 infections, up to 61% of patients have experienced symptoms that persist formonths after COVID-19, occurring in hospitalized and nonhospitalized adults, adolescents, and children. However, the absence of well-defined control groups or reliance on serologic testing or self-reporting will limit improving our current understanding (2–5). Even if only 10% of patients experience persistent symptoms after COVID-19, the number afflicted will easily be tens of millions. Described symptoms are wide-ranging from depression and anxiety to rashes, cardiac issues, and gastrointestinal distress. The Centers for Disease Control and Prevention lists 18 new or ongoing, andmostly subjective, symptoms that may arise even after asymptomatic infection (6). Many patients could be easily diagnosed with common disorders other than COVID-19, such as myalgic encephalomyelitis or chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome,migraine disorder, or anxiety or depression. How to tease out directly what is a post–COVID-19 disorder versus the indirect impact of the pandemic on human life is more than a tall order. Simple explanations are unlikely for wide-ranging disease manifestations (7). For example, the hope of precision medicine to offer a straightforward approach to acute SARS-CoV-2 infection means subtyping that may include differences in viral variants, host responses, and treatment effects. Factor then additional influences in recuperation, premorbid health, and external stressors may mean galactic complexities for enumerating post–COVID-19 phenotypes. Despite these challenges, opportunities exist to leverage the already substantial knowledge and scientific resources gained from the coronavirus to understand mechanisms that produce such problems as fatigue and pain. Perhaps there are common mechanisms, whether an aberrant response to viral infection or loss of a job? Many postinfectious disorders have defied detailed scientific understanding or precise diagnosis, causing contention among clinicians, researchers, and patients. Some, such as the common cold due to rhinovirus infection, appear to have little effect on health. In contrast, others, such as primary Epstein–Barr virus infection and Coxiella burnetii (Q fever), precipitate a postinfectious syndrome infection in 11% to 12% of patients (8). Both infectiousmononucleosis and Lyme disease may cause persistent symptoms after the resolution of acute illness in the minority. Frustration frequently arises in these often marginalized patients with symptoms that some clinicians dismiss as only nonphysiologic or related to mental health. On another angle, some alternative practitioners offer false hope with antibiotic treatments, using Lyme disease as a stand-in for chronic, medically unexplained symptomswithout a basis in demonstrable infection. Moreover, desperate patients seek information through social media and take non–evidence-based treatments for chronic Lyme disease, partly due tomodernmainstreammedicine s lack of effective approaches (9). As a clinician who has evaluated patients who may or may not have Lyme disease, Epstein–Barr virus, or other infections as causes for their symptoms, I see there are gaps in the field s knowledge that should inform research priorities into the aftermath of COVID-19. More important, if science does not move with dispatch in addressing post– COVID-19 care in a multidisciplinary manner, the vacuum will be quickly filled by pseudoscience and quackery. Moreover, engagement of patients and advocates early in the design of studies, clinical guidelines, and public messaging may lessen the development of a parallel universe of care through a cottage industry. Studies that lead to clear casedefinitions for apost–COVID19diagnosismaywell be split intoobjectivepathologicfindings and those with only apparent subjective symptoms. Then, understanding risk factors leading to post–COVID-19 problems will also help guide vaccine-hesitant people toward immunization or greater care to avoid contracting the infection. While diagnostic tests that solidly confirm prior SARS-CoV-2 infection are essential for those without such documentation, the diagnostic Holy Grail would be biomarkers that could implicate a postviral explanation or, better yet, a predisposition to such an outcome. Validated assays may then help inform appropriate interventions. Regardless, prospective longitudinal studies should lead to key findings, including patient cohorts with asymptomatic, mild, and severe COVID-19. Accompanying biorepositories that include viral and human samples of well-characterized cohorts will also facilitate research and aid U.S. FoodandDrugAdministration approval of diagnostic tests. While a basic understanding of postinfectious fatiguemay inform novel approaches to treatment, effective interventions