Welcome to Edition #110 of Emerge Australia’s Research Digest. This month’s edition offers insights into long-term observations and potential biomarkers for long COVID, alongside an in-depth review of ME/CFS—ideal for those new to ME/CFS—covering its challenging diagnosis and the need for enhanced research and treatment strategies.
Contributing Digesters: Ryan, Shan, Solène and Jyothsna.
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Three-year outcomes of post-acute sequelae of COVID-19
Authors: Cai M, Xie Y, Eric J. Topol EJ & Al-Aly Z (Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO, USA.
Publication: Nature Medicine
Link: https://www.nature.com/articles/s41591-024-02987-8.pdf
Post-acute sequelae of COVID-19 (PASC), or long Covid, refers to persistent symptoms, affecting multiple organ systems, following SARS-CoV-2 infection. Notably, PASC shares much of the same symptomatology with ME/CFS, making research on one potentially beneficial for the other.
This study examined the risk and burden of PASC three years post-COVID-19 infection. It followed 135,161 individuals, compared to a control group of 5,206,508, all sourced from the US Department of Veteran Affairs database. Participants were infected before the availability of vaccines and anti-virals and categorised into two groups: hospitalised (severe infection), and non-hospitalised (mild infection) groups.
Three metrics were analysed: incidence of sequelae, number of sequelae by year, and disability-adjusted life years (DALYs). While all metrics showed a gradual decline in PASC, the hospitalised group had experienced worse outcomes, including a 29% risk of death after three years, compared to none in the non-hospitalised group. The incidence rate ratio fell from 1.23 to 1.05 for the hospitalised group and from 2.82 to 1.34 for the non-hospitalised. The hospitalised cohort experienced 6.3 times more sequelae and 8.4 times higher DALYs (90 vs 9.6 DALYs per 1,000 persons). Additionally, seven organs were affected in the hospitalised group compared to three in the non-hospitalised.
These findings align with existing literature on PASC multisystem effects. This study suggests that post-acute sequelae may diminish over time but underscores the importance of the initial infection’s severity in determining long-term outcomes. Persisting symptoms could emerge for years, highlighting the need for future studies. While severe cases contribute to a higher disease burden, mild COVID-19 cases still represent the majority of PASC sufferers, necessitating efforts to address symptoms in this group. The study’s limitations include its predominantly older, White, male cohort, requiring further research for broader applicability.
Figure 1. The number of cumulative excess deaths per 1,000 persons over the three-year period.
Figure 2. The incidence rate ratio, number of sequelae, and DALY of specific organ systems across the three-year period between hospitalised and non-hospitalised groups.
Long COVID: plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms
Authors: Gutman EG, Salvio AL, Fernandes RA, Duarte LA, Rasposo-Vedovi JV, Alcaraz HF, … Alves-Leon SV (Federal University of the State of Rio de Janeiro/UNIRIO, Brazil)
Publication: Molecular Psychiatry
Link: https://doi.org/10.1038/s41380-024-02554-0
Plasma levels of a highly specific structural neural protein, neurofilament light chain (NfL), has been a long-accepted biomarker of neuroinflammation and neuroaxonal degeneration, used commonly for Multiple Sclerosis and Alzheimer’s disease. Recent studies have shown that pNfL levels increase with central nervous system (CNS) damage in hospitalised patients with acute COVID-19. This study specifically examines whether pNfL can indicate CNS injury in long COVID patients who experience ongoing cognitive symptoms after a mild illness, highlighting its potential as a biomarker for monitoring brain damage in non-hospitalized patients.
The study comprised a cohort of 63 adult long COVID patients who had previously been clinically diagnosed with mild acute COVID-19, were never hospitalised, and who now met the World Health Organisation definition of post-COVID-19 syndrome. Comparisons were made against 32 healthy control (HC) blood samples that had been taken before the pandemic to ensure they had never contracted SARS-CoV-2. Blood was drawn from study participants on the same day they completed three validated tests, to assess their level of cognitive impairment of attention, processing, and motor skills (SDMT); level of fatigue (FSS); and levels of anxiety and depression (HADS). The authors classed the patients in groups based on the neurocognitive test results and compared the pNfL measurements accordingly.
Among the cohort, 69.8% experienced fatigue, 65.1% experienced cognitive impairment, 52.4% developed anxiety, and 39.7% developed depression, where none of these symptoms had been experienced before. Long COVID patients with one or more of these symptoms displayed significantly higher pNfL levels, as compared with HC. Elevated pNfL levels were particularly noticeable in patients who reported cognitive impairment or fatigue, and the pNfL levels correlated with the severity of these symptoms. However, anxiety and depression appeared to not correlate with pNfL levels.
Though they admit there could be multiple ways in which SARS-CoV-2 damages neuronal tissue, the authors believe these results are consistent with their previous findings in which they showed that SARS-CoV-2 spike-induced cognitive impairment increased pNfL (and thus, increased risk for cognitive impairment), and was dependent on immune system activation via the TLR4 receptor. Early TLR4 inhibition reduced changes to pNfL levels. Overall, the authors recommend pNfL as a potential biomarker for ongoing CNS injury, in the hopes that it will allow swift identification of individuals who will require ongoing treatment support and monitoring.
Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.
Authors: Epsi NJ, Chenoweth JG, Blair PW, Lindholm DA, Ganesan A, Lalani T… Richard SA (Uniformed Services University of the Health Sciences, Bethesda, USA
Publication: The Journal of Infectious Diseases
Link: https://doi.org/10.1093/infdis/jiae318
Post-COVID conditions (PCC), also known as long-COVID, are complex to predict, diagnose, and treat due to overlapping symptoms. Definitions are currently broad and nonspecific in order to capture all PCC manifestations, but this limits our understanding of the disease. In this study, the authors aim to refine the definition of PCC using a data-driven approach to identify distinct symptom-based phenotypes among individuals with PCC and then identify early clinical and inflammatory predictors associated with the different PCC phenotypes.
A total of 1988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with PCC were enrolled from March 2020 through May 2022. Surveys about the duration and severity of symptoms were sent to participants at 1, 3, 6, 9, and 12 months after enrolment. A principal component analysis followed by k-means clustering of survey responses identified patterns differentiating PCC participants based on their reported symptoms and assigned them to ‘clusters’. A broad panel of early inflammatory markers were also analysed from plasma specimens taken from a subset of participants from each symptom-based cluster.
Three symptom-based clusters (stable up to 12 months post-enrolment) were identified: (1) a sensory cluster with a higher frequency of loss of smell or taste, (2) a fatigue/difficulty thinking cluster with a higher frequency of mental and physical fatigue, and (3) a difficulty breathing/exercise intolerance cluster.
The authors then went on to examine the clinical and demographic characteristics of individuals within each of the different clusters and showed that obesity was significantly more prevalent in the fatigue/difficulty thinking and the difficulty breathing/exercise intolerance clusters compared to the sensory cluster. Vaccination rates were significantly lower in the sensory cluster while Omicron infections were significantly more common in the other two clusters. Higher levels of D-dimer and IL-1RA were significantly associated with the fatigue/difficulty thinking cluster, while higher levels of ICAM-1 were significantly and independently associated with the sensory cluster. Finally, obesity and hospitalisation were strong predictors for the difficulty breathing/exercise intolerance cluster.
These findings underscore the presence of distinct phenotypes with varying risk factors and inflammatory responses, emphasising the need for more precise definitions of PCC. The authors highlight that further research is needed to dive deeper into the mechanisms of these different phenotypes, identify and evaluate related therapeutic interventions, and improve the prevention of PCC.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease
Authors: Arron H.E, Marsh B.D, Kell D. B, Khan M.A, Jaeger B.R and Pretorius. E (University of Liverpool, Liverpool, United Kingdom)
Publication: Frontiers in Immunology
Link: https://doi.org/10.3389/fimmu.2024.1386607
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remains a baffling and challenging condition, despite affecting millions globally. This summary highlights a comprehensive review article that examines research from the 1980s to 2022, drawing from some 600 studies.
ME/CFS impacts between 0.1% and 0.8% of people globally, with women, and Black and Hispanic communities experiencing higher rates and greater severity. While the condition can develop in childhood, most diagnoses occur in middle age, with cases ranging from as young as three, to as old as 77 years. A hallmark symptom of ME/CFS is post-exertional malaise (PEM), where even minor activities can trigger a severe, delayed worsening of symptoms. Depending on its stage, ME/CFS can range from mild to very severe, with some individuals completely dependent on caregivers.
The economic and personal impact of ME/CFS is profound. Patients often have a lower quality of life than those with conditions like multiple sclerosis or cancer.
Diagnosing ME/CFS is difficult due to the lack of standardised criteria. Initially thought to be neurological, recent brain scans have shown neuroinflammation and brain abnormalities linked to cognitive issues. Diagnosis involves a detailed medical history, physical exams, and ruling out other conditions, with PEM being a crucial indicator. However, the variability of PEM and limited diagnostic tools often result in long delays.
The causes of ME/CFS appear to be a mix of genetic, viral, and environmental factors. Possible triggers include Epstein-Barr virus (EBV), environmental toxins, and occasionally vaccinations too. The condition involves multiple disruptions, including gut imbalances, oxidative stress, and mitochondrial dysfunction.
Managing ME/CFS is challenging due to the absence of FDA-approved treatments. The focus is on symptom management, with pacing strategies to prevent/minimise PEM being key. Outdated therapies like graded exercise therapy (GET) are no longer recommended.
The authors suggest that ME/CFS research needs to address challenges such as inconsistent methods, small study sizes, and insufficient funding. Standardised research criteria, increased funding, and large-scale genome-wide studies like DecodeME are also needed. Future research should prioritise the microbiome, address stigma, evaluate existing treatments, improve diagnostic tests and work closely with patients to prioritise understanding PEM.
