Shortly after SARS-CoV-2 began spreading worldwide in early 2020, clinicians noted that some seemingly recovered patients had prolonged neurological, cardiovascular, and metabolic sequelae. The syndrome was given various names, including “long-haul COVID,” “long COVID,” and “post-acute COVID-19.” Over the past two years, it has become evident that the sequalae of COVID-19 represent a significant disease burden for the world's population. A recent review estimated that the prevalence may be as high as 40% in adults and 3.5% in children (Public Health Rev 2022;43:1604501). The study concluded that there will be a “substantial public health impact” from long COVID.
Online surveys: an important tool for assessing long COVID
Investigators from the United Kingdom conducted an online survey among patients who had lab-confirmed (antibody or PCR) COVID-19 in order to assess the prevalence and nature of long COVID (PLoS One 2022;17:e0264331). These researchers tallied self-reported clinical data via an online survey portal using “non-probability sampling.” The analyses included only non-hospitalized adults (first two weeks of illness) who reported a suspected or antibody/PCR-confirmed case of COVID-19 with long COVID. Most patients (roughly 90%) characterized their health as excellent, very good, or good prior to COVID-19. The median duration of long COVID was 7.6 months. Initial symptoms included chest pressure/tightness, dyspnea, exhaustion, and headache. Later in the course of long COVID, subjects presented with cognitive dysfunction and heart palpitations. Over half of the subjects described fluctuation in their symptoms. Exacerbations were triggered by physical activity, sleep disturbance, and stress.
“Long COVID had a strongly detrimental impact on the participants' well-being. Approximately one-third were unable to live without assistance at six weeks after illness onset. More than a third reported income loss, and two-thirds were unable to perform their usual activities or duties. Significant portions of participants reported illness-affected self-care issues (50%), mental health issues (64%), and work issues (75%).”
Long COVID had a strongly detrimental impact on the participants' well-being. Approximately one-third were unable to live without assistance at six weeks after illness onset. More than a third reported income loss, and two-thirds were unable to perform their usual activities or duties. Significant portions of participants reported illness-affected self-care issues (50%), mental health issues (64%), and work issues (75%). The authors concluded that “long COVID is a debilitating multisystem illness for many of those experiencing it.”
Another online survey performed by U.S. and U.K.-based researchers assessed the symptoms and impacts of long COVID in an international cohort of patients for seven months (EClinicalMedicine 2021;38:101019). Their online survey was disseminated through social media and COVID-19 support groups to those with confirmed or suspected cases of COVID-19. Data were collected from September 6, 2020, to November 25, 2020. There were a total 3,762 participants from 56 countries. Sixty-six symptoms were tracked over the course of seven months. More than 90% of participants had recovery times that exceeded 35 weeks. Frequently cited symptoms after six months included cognitive dysfunction, fatigue, and post-exertional malaise. The authors identified three symptom clusters, each of which had distinct temporal profiles. As with the previously described online survey, approximately 86% of participants experienced relapses that were often triggered by exercise, physical/mental exertion, or stress. A majority of participants had altered work schedules; almost half of the participants required a reduced work schedule, and an additional 22% were not working due to illness.
These authors also noted multisystem involvement leading to disability. “Patients with long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden.”
Post-COVID neurological symptoms
A recent literature review documented involvement of both the central and peripheral nervous systems in long COVID (Ther Adv Chronic Dis 2022;13:20406223221076890). The authors noted that “neurological symptoms are often inextricable from ‘long COVID’ manifestations that involve other organ systems, while nonspecific symptoms, including fatigue, ‘brain fog,’ post-exertional malaise, and sleep disorders, may comprise epiphenomena of underlying respiratory, cardiovascular, endocrine, renal, hematologic, autoimmune, or psychiatric diseases.”
A systematic review/meta-analysis in Scientific Reports (Nature) incorporating data from 47,910 patients estimated that 80% (yes, 80%, that is not a typo) of patients have at least one symptom for a minimum of two weeks following infection (Sci Rep 2021;11:16144). The most common symptoms were fatigue (58%), headache (44%), and attention disorder (27%). Other neurological sequelae included ageusia (23%), anosmia (21%), memory loss (16%), and hearing loss or tinnitus (15%).
A recent comprehensive review of fatigue following COVID-19 found that “persistent fatigue was reported by a significant minority of patients, ranging from 13% to 33% at 16-20 weeks post-symptom onset” (Open Forum Infect Dis 2021;8:ofab440).
The neurological effects of SARS-CoV-2 are probably not a result of direct infection of brain tissue, since available evidence strongly suggests that the virus does not directly infect brain parenchyma (Nature 2021;595:565-71). As suggested in a recent paper in Molecular Neurobiology, the neurological sequelae of COVID-19 could instead be due to toxic effects of the SARS-CoV-2 spike protein itself on neural tissue (Mol Neurobiol 2022;59:1850-61).
A paper in Nature Communications documented direct toxicity of the spike protein on brain tissue (Nat Commun 2022;13:1745). Eight non-human primates (four Rhesus macaques and four wild-caught African green monkeys) were inoculated with SARS-CoV-2 via aerosol and by multi-route exposure (conjunctival, intratracheal, nasal, and pharyngeal mucosa). All SARS-CoV-2-exposed animals developed infection within the first week of exposure. Microscopic analysis of the brains on autopsy documented hemorrhages, microinfarcts, vascular leakage, neuronal injury, and cell death consistent with hypoxic injury in all animals. The autopsy results were consistent with reports of human brains following death from COVID-19. Brain injury was seen even in the absence of severe respiratory disease. There was no evidence that SARS-CoV-2 infected neuronal tissue.
“Substantial evidence suggests that the protean neurological manifestations of long COVID are not a result of brain infection, but instead reflect a toxic response to the spike protein. The neurological sequelae may develop even when the initial presentation of SARS-CoV-2 is clinically unremarkable.”
Similarly, a paper in Scientific Reports (Nature) found that direct injection of the spike protein into the mouse hippocampus induced cognitive deficits and anxiety-like behavior, accompanied by neuronal cell death (Sci Rep 2022;12:5496). Cell death was not directly mediated by the spike protein, but rather by the glial cell activation.
Thus, substantial evidence suggests that the protean neurological manifestations of long COVID are not a result of brain infection, but instead reflect a toxic response to the spike protein. The neurological sequelae may develop even when the initial presentation of SARS-CoV-2 is clinically unremarkable.
A recent paper in Lancet Diabetes & Endocrinology looked at the relative risk of diabetes in 181,280 patients following a laboratory-confirmed diagnosis of COVID-19 compared to a contemporary control cohort (N = 4,118,441) (Lancet Diabetes Endocrinol March 2022). The cohort with laboratory-diagnosed COVID-19 had an elevated risk (hazard ratio [HR] = 1.40) of diabetes compared with the control cohort, associated with an excess disease burden at 12 months of 13.46 patients per 1,000. The hazard ratio for diabetes or anti-hyperglycemic drug use at 12 months was 1.46, with an excess burden of 18.03 per 1,000 at 12 months. The authors concluded that “Post-acute COVID-19 care should involve identification and management of diabetes.”
Presidential long COVID initiative
On April 5, 2022, the White House issued a Presidential Memorandum that directed the Secretary of Health and Human Services (HHS) to develop and coordinate the first interagency research plan for long COVID (asamonitor.pub/3k6UmLP). This effort will address many areas involving long COVID and its associated conditions, including prevention, treatment, support, and services. In addition, the memorandum also orders HHS to outline the services available to those directly or indirectly affected by long COVID.
One aspect of this directive is the “delivery of high-quality care for individuals experiencing long COVID.” To that end, actions to be taken include launching centers of excellence for the promotion of evidence-based care models; establishing and expanding clinics for long COVID; promoting provider education and clinical support where needed; and bolstering insurance coverage for the extensive medical costs associated with long COVID.
The memorandum includes recommendations for supporting individuals experiencing long COVID. Recommendations include the raising of awareness of long COVID as a disability; protecting individuals with long COVID from discrimination; translating research into an effective and inclusive disability policy; connecting people with the appropriate resources available; and strengthening support for workers experiencing long COVID.
The Presidential Memorandum promotes advancing knowledge concerning long COVID. Toward this goal, the Secretary of HHS will coordinate federal efforts for the first interagency research action plan on long COVID, increase investments in long COVID research and surveillance, and leverage the use of federal health care databases (e.g., U.S. Department of Veterans Affairs). Lastly, enrollment in the RECOVER initiative, a $1.5 billion program to enhance the “understanding of and ability to predict, treat, and prevent long COVID,” will be accelerated.
Long COVID is a new disease. The long-term trajectory and prognosis of long COVID remain unknown. Long COVID will challenge patients, physicians, and health care providers in the coming years. However, the challenges arising from long COVID extend well beyond medicine. Long COVID will affect the cost of health care, the productivity of the workforce, and the well-being of patients, families, colleagues, businesses, and institutions for many years.
Richard Simoneaux is a freelance writer with an MS in organic chemistry from Indiana University. He has more than 15 years of experience covering the pharmaceutical industry and an additional seven years as a laboratory-based medicinal chemist.