Since the start of the COVID-19 pandemic, the persistence or appearance of neurologic symptoms following the clearance of SARS-CoV-2 infection has become a serious health challenge for patients and clinicians worldwide. The effects of postacute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, can be debilitating and persist for months after infection, according to a recent review published in Neurology International. Some of these symptoms can include fatigue, neuropsychiatric sequelae, sleep disturbances, sensorimotor symptoms, cognitive impairment/brain fog, hypoguesia/hyposmia, hearing loss, and ocular symptoms.1
Prior literature revealed various reports on the duration of viral shedding from Long COVID, with the longest previously known recorded at about 70 days. A reported case of a 22-year-old health care worker published in SAGE Open Medical Case showed the patient had prolonged multisystemic features of the virus including cardiovascular, respiratory, central nervous system, and musculoskeletal symptoms that lasted about 18 weeks from symptom onset, though the patient was never hospitalized. The patient also had persistent detection of SARS-CoV-2 attributed to viral shedding for over 110 days, the longest duration recorded at the time in the 2021 published case report.2
As emphasized by the research and experts, currently there are no specific tests for the diagnosis of Long COVID, and clinical features such as laboratory findings and biomarkers may not specifically relate to the condition.3 It is important to develop and validate biomarkers for the prediction, diagnosis, and prognosis of Long COVID and its response to therapeutics. Regardless of age or preexisting health conditions, Long COVID can affect anyone, highlighting that this condition is not restricted to any specific demographic and does not discriminate, even against the healthiest individuals.
Most Important Takeaways
- Neurologic symptoms can persist for months after SARS-CoV-2 infection, impacting patient health globally.
- Long COVID includes a range of symptoms such as fatigue, cognitive impairment, sleep disturbances, and sensory issues.
- Cases of prolonged viral shedding, such as the 110-day instance in a 2021 report, highlight the extended impact of COVID-19.
- Currently, there are no specific tests for diagnosing Long COVID; diagnosis relies on patient history and symptom assessment.
- Vaccination reduces the risk of severe outcomes and Long COVID, with fewer PASC events reported among vaccinated individuals.
- Long COVID incidence rates have decreased with new variants, and vaccination contributes significantly to this reduction.
- Research continues into the mechanisms of Long COVID, including potential disruptions to the blood-brain barrier and neuroinflammation.
- Routine laboratory tests are not effective for diagnosing Long COVID, emphasizing the need for detailed patient evaluations.
- Long COVID and ME/CFS have overlapping symptoms but are distinct conditions.
- There are no FDA-approved treatments for Long COVID yet, and managing the condition involves symptom relief, cognitive rehabilitation, and physical therapy.
Preventing Long COVID Before It Happens
Recent findings in Communications Medicine underscore that initial infections with COVID-19 heighten the risk of severe outcomes from reinfections and Long COVID. Those who experienced severe illness during their first infection are 30% to 50% more likely to develop Long COVID, characterized by persistent symptoms such as fatigue and respiratory issues. Additionally, individuals with a history of severe initial infections face a 40% increased risk of severe symptoms in subsequent reinfections. They also have a 20% to 30% higher likelihood of developing chronic health problems, including cardiovascular and pulmonary conditions, after reinfections.4
In a recent interview with Jennifer Frontera, MD, who serves as a professor of neurology at NYU Grossman School of Medicine, she told NeurologyLive® that she and her colleagues “are still investigating the impact of COVID-19 on the brain. While there is evidence that deleterious effects of COVID-19 do not appear to be because of direct brain invasion by the virus, other possible mechanisms of injury are still under investigation.” Frontera’s research has centered around neurological complications of COVID-19 infection since the inception of the 2020 pandemic.
“Some possible mechanisms may be SARS-CoV-2 related blood–brain barrier disruption followed by brain inflammation, microglial and astrocyte activation which augments a neuroinflammatory cascade culminating in increased amyloid and tau deposits, and neurodegeneration,” Frontera, who is also a member of the World Health Organization (WHO) Brain Health Neurology and COVID-19 Forum, said. “Other mechanisms may be hypoxic brain injury in patients with severe COVID-19. It's important to keep in mind that other related factors may cause cognitive impairment, including coexistent depression, anxiety, substance abuse, medication adverse effects, life stressors, or other medical conditions (eg, hypothyroidism, B12 deficiency).”
Vaccination has been shown to mitigate risks, as fully vaccinated individuals who had severe initial infections tend to experience fewer severe symptoms and Long COVID complications. It is important to minimize the potential of severe health outcomes related to initial infections and reinfections, preventive measures, vaccinations, and early medical intervention. As the virus has mutated and new strains have begun to circulate, this strategy has remained a key aspect of mitigation. Since the FDA has recommended vaccine manufacturers to incorporate the KP2 strain into the 2024-2025 COVID-19 formulation in June, the agency has granted emergency use authorization (EUA) for Moderna, Pfizer, and Novavax, targeting Omicron variants.
The Moderna and Pfizer vaccines offer protection against current variants and aim to reduce severe outcomes. Eligibility varies by age and vaccination history, with specific dosing schedules for different age groups.5 The updated Novavax vaccine targets the Omicron JN1 strain and is approved for individuals 12 years and older, requiring 2 doses for unvaccinated individuals.6
Scope of Long COVID Incidence Rates
Understanding the prevalence and impact of Long COVID is crucial for assessing the ongoing effects of COVID-19 on public health, as studies into these areas explore how widespread Long COVID is and how it varies across different groups.
A recent study published in the New England Journal of Medicine provided valuable insights into the rates of PASC. The research compared the incidence of Long COVID among US veterans with a large cohort of uninfected individuals over nearly 2 years, from March 1, 2020, to January 31, 2022. This group was compared to 4,748,504 uninfected individuals from the same period. They estimated the cumulative incidence of PASC 1 year after SARS-CoV-2 infection during the pre-Delta, Delta (mid-2021 to late 2021), and Omicron eras (late 2021- current) of the COVID-19 pandemic.7
The rate of PASC events for unvaccinated individuals:
- Before the Delta variant: 10.42 events per 100 people.
- During the Delta variant: 9.51 events per 100 people.
- During the Omicron variant: 7.76 events per 100 people.
The rate dropped by 2.66 events per 100 people from before the Delta era to the Omicron era, and by 1.75 events per 100 people from the Delta era to the Omicron era.
For vaccinated individuals:
- During the Delta variant: 5.34 PASC events per 100 people.
- During the Omicron variant: 3.5 PASC events per 100 people.
The rate of PASC events decreased by 1.83 events per 100 people from the Delta to the Omicron era.
When comparing vaccinated to unvaccinated individuals, those who were vaccinated experienced fewer PASC events. During the Delta era, vaccinated individuals had 4.18 fewer PASC events per 100 people compared to their unvaccinated counterparts. This difference increased to 4.26 fewer events per 100 people during the Omicron era.
In comparing the Omicron era to the combined pre-Delta and Delta eras, there were 5.23 fewer PASC events per 100 people in the Omicron era. Of this reduction, 28% was attributed to changes in the virus and other factors, while 72% was because of vaccination.
Based on these results, the decrease in Long COVID rates, particularly among the vaccinated, highlights the ongoing value of vaccination efforts in alleviating long-term COVID-19 symptoms and underscores the need for continued public health measures.
“Long COVID can lead to significant cognitive impairments, most commonly described as ‘brain fog,’ with slowed or interrupted information processing. Those affected also commonly report having memory issues, and difficulties with attention and executive functioning. These problems are thought to stem from the disease's longer-term effects like chronic inflammation or microvascular damage, and in some cases may also be from direct viral invasion of the central nervous system,” Leigh Charvet, PhD, professor of neurology at the NYU Grossman School of Medicine, told NeurologyLive in a recent conversation when expressing her medical viewpoint of the effect of the post-COVID infection in patients.
“These problems are often worsened by other common symptoms like fatigue, as well as psychological factors like anxiety, depression, and PTSD. Current research, including the National Institute for Health RECOVER initiative, is focused on understanding these effects and developing effective management strategies to support affected individuals,” Charvet added.
Diagnosing Patients With Long COVID
Long COVID is not a singular illness and cannot be identified through a specific laboratory test.8A positive SARS-CoV-2 test is not required for diagnosis. Instead, healthcare providers diagnose Long COVID based on health history, previous COVID-19 diagnosis or exposure, and a comprehensive health examination. Routine clinical evaluations, such as blood tests, chest X-rays, and electrocardiograms, may appear normal even in those with Long COVID. It is important for individuals experiencing Long COVID to consult with a healthcare provider to create a personalized management plan to alleviate symptoms and improve quality of life.
“Thinking, special senses such as vision, strength and endurance, sensation (including loss of sensation, and extra sensations such as numbness, tingling and pain) and autonomic functions such as pulse and blood pressure regulation can be affected in certain patients,” Neil A. Busis, MD, the associate chair for technology and innovation in the Department of Neurology at the NYU Grossman School of Medicine, told NeurologyLive. “We are learning more and more as time goes on. We are closer to determining what conventional tests do not help this diagnosis, then we will arrive at tests that definitively diagnose it.”
Recent research published in the Annals of Internal Medicine reveals that routine laboratory tests are ineffective for diagnosing PASC. A national cohort study conducted by lead author Kristine M Erlandson, MD, and colleagues, found only minor differences in lab values among individuals with a history of SARS-CoV-2 infection, and these differences were not significant enough to be reliable diagnostic markers. The study highlights the need for diagnosis to be based on a detailed patient history and physical examination rather than routine lab results.9
Erlandson, a professor of medicine specializing in infectious disease at the University of Colorado School of Medicine, discussed the findings with ContagionLive® that no routine lab values are useful for diagnosing PASC, and what clinicians should do to identify and manage patients with suspected Long COVID effectively, “A Long COVID diagnosis should be based on a detailed history and physical to understand a patient’s symptoms and physical exam findings, in relation to COVID infection. Routine laboratory work can rule out other easily treatable causes, but the diagnosis is really symptom-based.”
Among 10,094 participants, those with prior SARS-CoV-2 infection showed slight differences in laboratory results compared to uninfected individuals, but these differences were not significant enough to be considered reliable biomarkers for Long COVID. The study suggests that ongoing inflammation, rather than persistent viral presence, may play a key role in Long COVID symptoms. Additionally, it could not determine whether the observed lab value differences are consequences of or risk factors for SARS-CoV-2 infection.
Since routine tests are not effective in identifying Long COVID, healthcare providers must rely on detailed patient histories and symptom assessments to accurately diagnose and manage this condition. This approach ensures that patients receive appropriate and personalized care to address their unique needs and improve their quality of life.
“Though research is ongoing, a definitive test for Long COVID has not yet been developed. Currently, diagnosis relies on clinical evaluation of symptoms, patient history, and ruling out other conditions,” Charvet told NeurologyLive. In her role, Charvet specializes in noninvasive brain stimulation techniques, specifically transcranial direct current stimulation (tDCS), that integrate with home-based telerehabilitation for patients who have a wide range of neurological and psychiatric conditions.
“Studies are investigating potential biomarkers and diagnostic tools, such as blood tests and imaging techniques, to better identify Long COVID. Efforts continue to create standardized diagnostic criteria to improve the identification and treatment of Long COVID patients,” Charvet said.
Differentiating Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) both present with persistent fatigue and other symptoms, which can complicate their differentiation. While there are similarities in their symptom profiles, underlying mechanisms, and diagnostic criteria, there are also notable differences. Research has shown that Long COVID can cooccur with other diagnoses, meaning it is not an exclusive condition. But is ME/CFS the same thing as Long COVID?
“I don’t think we are at a point where we can equate the 2 conditions,” Alba Azola, MD, the lead author of the autonomic dysfunction guidance statement and member of the Johns Hopkins Post-Acute COVID-19 Team, specializing in treating Long COVID and ME/CFS, told ContagionLive. “There is a large group of Long COVID patients who meet criteria for ME/CFS, and symptom management used for prepandemic ME/CFS patients can be very effective for these patients as well. We don’t know if the pathophysiology is the same; this will be clarified through research.”
Understanding these distinctions is crucial for accurate diagnosis and effective treatment, as each condition may require different management approaches. “ME/CFS, by the 2015 definition, requires loss of function and severe fatigue for more than six months,” Azola said. “You need to have postexertional malaise, which is also one of the most predominant symptoms in Long COVID. Postexertional malaise is not just feeling tired or like you can’t walk up the steps. It’s an out-of-proportion onset of symptoms that range from neurological to musculoskeletal, which arise from activity that was previously tolerated.”
As for defining Long COVID, Azola described the June 2024 definition as broad. The definition, coined by The National Academies of Sciences, Engineering, and Medicine (NASEM)’s aims to set a course for unified care and research:10
“Long COVID is an ‘infection-associated chronic condition’ (IACC), which can be triggered by viruses, bacteria, funding, or parasites. Examples of other IACCs include Lyme-associated chronic illnesses or various disorders after Giardia infections.The 2024 NASEM committee hopes that the use of IACC in the definition of Long COVID can promote research across what previously were considered largely different diseases, allowing for cross-disease learning and actionable insights.”
While both Long COVID and ME/CFS involve persistent fatigue and related symptoms, Long COVID is specifically defined as postinfection conditions, with an emphasis on standardizing diagnosis and promoting focused research into infection-related chronic conditions. In contrast, ME/CFS encompasses a broader spectrum of unexplained chronic fatigue without necessarily linking it to a specific infection.
Treatments/Interventions for Long COVID
In most cases, effective treatments have remained elusive for patients who experienced symptoms of Long COVID in the following years from the pandemic's onset. Thus, clinicians emphasized that additional strategies are needed to effectively treat and manage the long-term neurologic sequelae of COVID-19 infection reported by patients. Furthermore, providers also want to highlight the importance of awareness in being able to recognize the chronic neurological manifestations of COVID-19 in the clinical setting for neurologists as this knowledge would help guide diagnosis and management of the condition.
“There are no FDA-approved treatments for Long COVID currently,” Frontera said. She mentioned some clinical studies that are investigating therapies for Long COVID, though, noting that “there are several RECOVER trials underway. RECOVER-NEURO and subgroups of RECOVER-VITAL (cognitive, exercise intolerance) are closed to enrollment, meaning that data analysis is ongoing and we can expect results in the next few months. RECOVER-Autonomic, RECOVER-Energize, and RECOVER-Sleep are other NIH-sponsored studies that may be coming online soon.”
RECOVER-NEURO (NCT05965752) is a phase 2 study aimed to investigate whether cognitive dysfunction symptoms can be alleviated by pragmatic and established interventions, with different mechanisms of action and with previous evidence of improving cognitive function, in patients with neurocognitive disorder.11 The trial plans to assess 5 treatment arms for 10 weeks, including the cognitive training program BrainHQ and tDCS, alone and in combination, delivered at home to enrolled participants in the US. Investigators will assess participants through cognitive testing and patient-reported surveys at baseline and the end of intervention. If the findings from the study are positive, they will provide evidence of the benefits of these treatments for PASC-related cognitive dysfunction.
“Managing Long COVID primarily involves symptom relief and quality of life improvements, as there is no single cure. Common treatments include cognitive rehabilitation, physical therapy, mental health support, and medications for pain, sleep disturbances, and inflammation. The RECOVER-NEURO study explores interventions like tDCS, cognitive remediation with BrainHQ, and the PASC-CoRE (PASC Cognitive Recovery) program. These aim to boost cognitive function and reduce neurological symptoms,” Charvet, who is also one of the investigators in the RECOVER-NEURO trial, added.
A prior study published in 2023 in Brain Stimulation demonstrated the efficacy of high-definition tDSC (HD-tDCS) paired with a rehabilitation program for reducing fatigue and anxiety among patients with PASC.12 Conducted by Charvetand colleagues, 70 patients with PASC-related fatigue were randomized to receive 3 mA node currents or sham HD-tDCS targeting the left primary motor cortex (M1) for 30 minutes paired with a rehabilitation program. Each participant underwent 10 sessions, 2 sessions per week, over 5 weeks. Researchers measured fatigue, the primary outcome, using the Modified Fatigue Impact Scale (MFIS). Secondary outcomes assessed included pain level, anxiety severity, and quality of life through the McGill Questionnaire, Hamilton Anxiety Rating Scale and World Health Organization Quality of Life, respectively.
In the study, active HD-tDCS showed a significantly greater reduction in fatigue compared with the sham HD-tDCS (mean group MFIS reduction of 22.11 points vs 10.34 points). The investigators observed distinct effects of HD-tDCS in fatigue domains with greater effect on cognitive (mean group difference, 8.29 points; effect size, 1.1; 95% CI, 3.56-13.01; P <.0001) and psychosocial domains (mean group difference, 2.37 points; effect size, 1.2; 95% CI, 1.34-3.40; P <.0001), with no significant difference observed between the groups in the physical subscale (mean group difference, 0.71 points; effect size, 0.1; 95% CI, 4.47-5.90; P = .09).
Additional findings showed that the active HD-tDCS group showed a significant reduction in anxiety (mean group difference 4.88; effect size 0.9; 95% CI 1.93-7.84; P <.0001) and improvement in quality of life (mean group difference 14.80; effect size .7; 95% CI 7.87-21.73; P <.0001) compared with the sham. Notably, researchers observed no significant difference in pain (mean group difference, -.74; no effect size; 95% CI, 3.66-5.14; P = .09) between the active HD-tDCS group and the sham group.
It is also noted that there are “many different treatments are being evaluated” but that thus far, none of them have built a compelling base of evidence. “Eventually, treatments will be tailored to patients' individual symptoms. It will not be a one-size-fits-all approach. Since COVID affects different patients in different ways, they will require individualized treatments,” he said.
What We Know, But Still Have to Learn
Since the initiation of the 2020 pandemic, research has shown that Long COVID is an often-debilitating illness that has impacted more than 65 million individuals globally and the number is expected to increase in the future. In studies, various investigators have made significant progress in research and have identified more than 200 symptoms with impacts on multiple organ systems in Long COVID, many of which can cause lifelong disabilities among patients with the condition if no intervention is taken.13 Although there are consensus guidelines for Long COVID published in PM&R, the current realm of care with diagnosis and therapies for the condition is still insufficient, as voiced by the clinicians treating it.14 Presently, there are ongoing clinical trials assessing potential treatments that could potentially address the hypothesized underlying biological mechanisms of the condition, including viral persistence, neuroinflammation, excessive blood clotting, and autoimmunity.
"We still need to garner a better understanding of the underlying pathophysiology of cognitive abnormalities post-COVID, particularly since brain fog stands out as a common and long-lasting complication,” Frontera said.
“Long COVID presents such a wide array of ongoing symptoms like fatigue and brain fog it's been hard to identify targets. While we have some understanding by characterizing these symptoms, we still need to pinpoint specific biomarkers for diagnosis, develop targeted treatments, comprehend the underlying mechanisms, establish prevention strategies, and assess long-term health outcomes. Continued research is essential to bridge these knowledge gaps and enhance care for Long COVID patients,” Charvet added.
Ultimately, Long COVID is a global health challenge marked by symptoms like cognitive impairment and fatigue that persist long after the initial infection. Despite progress in understanding the condition, effective diagnosis and treatment are still evolving. Research is focused on finding biomarkers and evaluating new therapies. Vaccination continues to be important in reducing severe outcomes and Long COVID rates. Ongoing research and development of diagnostic and treatment methods to address the complexities of Long COVID.
“As Winston Churchill said in another context, ‘We are at the end of the beginning.’ We have the broad outlines of what questions to ask, and now we will need to ask and answer them. There is hope,” Busis said, looking into the future with Long COVID care for patients impacted by the condition.
References
Reiss AB, Greene C, Dayaramani C, et al. Long COVID, the Brain, Nerves, and Cognitive Function. Neurol Int. 2023;15(3):821-841. July 6, 2023. Accessed September 10, 2024.doi:10.3390/neurolint15030052
Omololu A, Ojelade B, Ajayi O, et al. “Long COVID”: A case report of persistent symptoms in a patient with prolonged SARS-CoV-2 shedding for over 110 days. SAGE Open Medical Case Reports. 2021;9. Accessed September 10, 2024. doi:10.1177/2050313X211015494
Tsilingiris D, Vallianou NG, Karampela I, et al. Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges. Int J Mol Sci. 2023;24(13):10458. July 21, 2023. Accessed September 10, 2024. doi:10.3390/ijms241310458
Hadley E, Yoo YJ, Patel S, et al. Insights from an N3C RECOVER EHR-based cohort study characterizing SARS-CoV-2 reinfections and Long COVID. Commun Med 4, 129 (2024). July 11, 2024. Accessed September 10, 2024. doi: https://doi.org/10.1038/s43856-024-00539-2
Xie Y, Choi T, Al-Aly Z. Postacute Sequelae of SARS-CoV-2 Infection in the Pre-Delta, Delta, and Omicron Eras. N Engl J Med. July 17, 2024. Accessed September 10, 2024. doi:10.1056/NEJMoa2403211
Erlandson KM, Geng LN, Selvaggi CA, et al. Standard Clinical Laboratory Measurements Do Not Differentiate Prior SARS-CoV-2 Infection and Post-Acute Sequelae among Adults in the RECOVER Cohort. Annals of Internal Medicine. 2024. Accessed September 5, 2024.https://doi.org/10.7326/M24-0737
Knopman DS, Laskowitz DT, Koltai DC, et al. RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC). Trials. 2024;25(1):326. May 17, 2024. Accessed September 10, 2024. doi:10.1186/s13063-024-08156-z
Santana K, França E, Sato J, et al. Non-invasive brain stimulation for fatigue in post-acute sequelae of SARS-CoV-2 (PASC). Brain Stimul. 2023;16(1):100-107. Accessed September 10, 2024. doi:10.1016/j.brs.2023.01.1672
Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations [published correction appears in Nat Rev Microbiol. 2023 Jun;21(6):408. doi: 10.1038/s41579-023-00896-0]. Nat Rev Microbiol. 2023;21(3):133-146. Accessed September 10, 2024. doi:10.1038/s41579-022-00846-2
