Almost 3 years since the beginning of the pandemic, continuous research efforts have begun to paint a better picture of the impact the virus has on the brain and the central nervous system.
When the COVID-19 pandemic was formally declared by the Centers for Disease Control in March 2020, countless questions swirled around what sort of short- and long-term effects the virus could have on an individual and their brain.
Vaccines aside, the symptoms of the COVID-19 have been well documented, even in the early stages of the pandemic. Infected patients can experience a range of symptoms—from mild to severe—that include fever or chills, cough, shortness of breath, fatigue, muscle or body aches, headache, loss of taste or smell, sort throat, congestion, nausea or vomiting, and diarrhea that can last from anywhere between 2 to 14 days.
As evidence began to pile up, it became clear that individuals who are immunocompromised may be more prone to a severe case of COVID-19, which could lead to hospitalization, intensive care, ventilator use, and death. Older adults have been proven to be at the highest risk for severe COVID-19. In fact, more than 81% of COVID-19 deaths occur in people over 65, and the number of deaths among people over that age is 97 times higher than the number of deaths in those between the ages of 18 and 29 years.1
After closely following people who contracted the virus, the clinical community started to gain a better understanding of potential post-acute sequelae (PASC). PASC of COVID-19 has had a wide prevalence range reported, mainly due to the heterogenous definitions of the condition, differences in populations being assessed, and types of symptoms or signs included in rate estimates. Some patients have had more than 20 different symptoms, indicating that COVID-19 is a multisystem disease.2
Men and women can both be affected by PASC. A recent meta-narrative review showed that men are at a greater risk for increased symptom severity and death; however, PASC is more common in women, and women are more likely to have persistent fatigue, anxiety, and depression and at a 6-month follow-up.3 Additionally, individuals with underlying pulmonary conditions, obesity, and older age are at increased risk for developing PASC.
For the management of PASC, clinicians have generally recommended controlling comorbid conditions, such as diabetes, hypertension, kidney disease, respiratory diseases, and ischemic heart disease, and treating specific complications when necessary. Anosmia and ageusia, otherwise known as the loss of sense of smell and taste, have been other PASC symptoms that had shown persistence even after recovery from COVID-19; although, it’s uncertain whether these symptoms are permanent or transient.4
Over time, the FDA began to authorize certain medications for emergency use to treat COVID-19 and thus, the subsequent issues that follow. Nirmatrelvir (Paxlovid), an oral protease inhibitor that is active against MPRO, is packaged with ritonavir, a strong cytochrome P450 3A4 inhibitor that has been used to boost HIV protease inhibitors, was among those to receive authorization.5 A recently published large-scale trial included those treated with oral nirmatrelvir within 5 days after a positive test (n = 9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of their infection (n = 47,123).
The findings were a success, as nirmatrelvir-treated patients showed a reduced risk of PASC (HR, 0.74; 95% CI, 0.69-0.81) including a reduced risk of 10 of 12 post-acute sequelae in the cardiovascular system, coagulation and hematologic disorders, fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Additionally, mirmatrlevir was associated with a decreased risk of post-acute death (HR, 0.52) and post-acute hospitalization (HR, 0.70). These associations remained true in unvaccinated, vaccinated, and boosted individuals, and in those with primary SARS-CoV-2 infection and reinfection.6
At first, researchers believed that SARS-CoV-2 infection primarily affected the pulmonary system, but accumulating evidence suggested that it also affects the panvasculature in the extrapulmonary systems by directly or indirectly causing endothelial dysfunction and multi-organ injury. The consequential endotheliitis/endotheliopathy can incite multiple instances of endothelial dysfunction, including altered vascular tone, oxidative stress, inflammation/leukocyte adhesion, endothelial mesenchymal transition, mitochondria dysfunction, virus-induced senescence, cytokine storm, and coagulopathy.7
"It can also ramp up amyloid deposition or decrease breakdown of amyloid, and potentially also tau tangle formulation," said Jennifer Frontera, MD. "That’s the whole kind of viral or inflammatory hypothesis of Alzheimer [disease]. It’s led to people doing studies with valacyclovir for patients with HSE (herpes simplex encephalitis) and mild cognitive impairment. Just to see if treating the chronic infection or the reactivation of that infection will ameliorate some of the pathological changes."
Frontera, a neuro-critical care specialist at NYU Langone, has experience on all levels of the pandemic, serving both on the front lines during some of the earliest days, to being a leader in the research field, where she’s conducted multiple trials exploring the effects of the virus on the brain and body. She believes the general concept of increased microglial activation from inflammatory states could be “in-play” when it comes to post-COVID cognitive disorders.
"The more we understand about what’s happening in COVID-19, or hypoxia, for example, may help us understand other Alzheimer-type pathologies and what interventions might be useful in people with sporadic Alzheimer [disease], for example," Frontera added. "Hopefully there will be more evolution in terms of our understanding of cognitive processes in general, even as they relate to post-ICU patients."
The link between COVID-19 and Alzheimer disease is still being understood, with some studies signaling a connection and others pumping the breaks. A retrospective study published in September 2022 suggested that individuals at least 65 years infected with the virus are at an increased risk for the neurodegenerative disorder. That trial, which included 6,245,282 older adults, also showed an elevated risk when stratified by age groups (65-74, 75-84, ≥85 years), race or ethnicity (Black, White, Hispanic), with the highest risk in those above 85 years old (HR, 1.89; 95% CI, 1.73-2.07), and in women (HR, 1.82; 95% CI, 1.69-1.97).8
Some of the fears of long-term development of Alzheimer disease stem from "brain fog," a term commonly used to describe the sluggish, fuzzy feelings patients experience weeks, and sometimes months after infection. Headed by the National Institutes of Health, a mouse study showed that even a mild case of COVID-19 could cause long-term changes to the immune system and neurons. Weeks after being infected, the microglia in the mice stayed reactive. Investigators concluded that this reactivation caused trouble with completing tasks, such as making new neurons in the hippocampus, a region of the brain that plays an important role in learning and memory.9
Although the pathological mechanisms of COVID-19 still remain a question, research has debunked, or at least cleared up, some of the initial thoughts, the biggest being the virus’s role in central nervous system (CNS) invasion, according to Frontera. "We really don’t think that’s a major player here, or a pathological driver. Encephalitis, meningitis, that are related to direct SARS-CoV-2 is really not a thing," she said.
A 2021 paper by Conor McQuaid et al reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions, neurological COVID-19 manifestation, and the aging cerebrovascularture.10 After sifting through the literature, the authors concluded that there is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus.
The paper highlighted that although unknown, the normal route of infection and presence of SARS-CoV-2 in severely infected patients could be from the olfactory mucosa, an idea that has been brought up previously before. “It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure," McQuaid et al wrote. "Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19."
Throughout the pandemic, it has been widely understood that the severity of COVID-19 is one of, if not the, greatest predictors of long-term prognosis. In December 2020, the FDA issued the first emergency use authorization for a vaccine for the prevention of COVID-19 in individuals aged 16 years and older, with the goal to lower hospitalization rates, ventilation rates, and ultimately, death.11
In fact, it worked. A 2022 retrospective study of nearly 200,000 hospitalizations showed that COVID-19-associated hospitalization rates ranged from 3.5 times to 17.7 times higher in unvaccinated persons than vaccinated persons regardless of booster dose status. Among sampled cases, vaccinated hospitalized patients with the virus were older than those who were vaccinated (mean age, 70 years vs 58 years; P <.001) were more likely to have 3 or more underlying medical conditions (77.8% vs 51.6; P <.001).12
As more vaccines were authorized over time, some were curious whether they could have a positive impact on the symptoms of long COVID in those already infected. "Vaccines are lowering the severity of COVID-19 if you do get it, and therefore you’re less likely to have long COVID, but I don’t think that if you already had long COVID and get vaccinated that it’s necessarily improving anything," Frontera added.
"Theoretically, it could still, but I think the interest in that area kind of fell off as people weren’t seeing an association between post COVID vaccination and long-term outcomes. I don’t know if it’s a myth, but we probably underestimate the impact of pandemic-related stressors on outcomes and how people are doing. Are there comorbidities like mood disorders, anxiety, depression, and so forth, that exacerbate symptoms or are even sometimes, the progenitor of symptoms. For example, untreated depression can present as brain fog. That doesn’t mean everyone with brain fog has depression, and that’s the reason there are comorbidities that should be looked at and addressed."
While severe COVID-19 cases continued to cause concern, researchers started to uncover that even those with a mild case or no symptoms can develop long COVID. In a 2022 study that featured 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no evidence of infection, a total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks.13
The trial, led by Anuradhaa Subramanian, MSc, a research fellow at the University of Birmingham, also showed that the risk of developing long COVID increased along a gradient of decreasing age. The largest adjusted HRs for symptoms of long COVID included anosmia (6.49; 95% CI, 5.02-8.39), hair loss (3.99; 95% CI, 3.63-4.39), sneezing (2.77; 95% CI, 1.40-5.50), ejaculation difficulty (2.63; 95% CI, 1.61-4.28) and reduced libido (2.36; 95% CI, 1.61-3.47). In a post-hoc subgroup analysis of patients infected during the first and second stages of the pandemic in the United Kingdom, the association between SARS-CoV-2 infection and the reported symptoms was more pronounced among those infected during the second wave of the pandemic.
There are several aspects of COVID-19 that are still not fully understood and will continue to be researched in the coming years. “There’s been a lot of press related to the neurological aspect, and at the end of the day, the shortness of breath and pulmonary recovery is probably the main issue people are facing," Frontera added. "The neurological components are probably a factor for some percentage of people. How much of them are directly related to COVID? It’s hard to know."