Cluster Analysis to Identify Long COVID Phenotypes Using 129Xe Magnetic Resonance Imaging: A Multi-centre Evaluation

Abstract:

Background Long COVID impacts ∼10% of people diagnosed with COVID-19, yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID, therefore we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes.

Methods COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129XeMRI ∼14-months post-acute infection across three centres. Long COVID was defined as persistent dyspnea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully-recovered. 129XeMRI ventilation defect percent (VDP) and membrane (Mem)/Gas, red blood cell (RBC)/Mem and RBC/Gas ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction.

Results We evaluated 135 participants across three centres: 28 COVID-negative (40±16yrs), 34 fully-recovered (42±14yrs) and 73 long COVID (49±13yrs). RBC/Mem (p=0.03) and FEV1 (p=0.04) were different between long- and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster1 was the youngest with normal MRI and mild gas-trapping; Cluster2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster3 had mildly increased Mem/Gas with normal PFTs; and Cluster4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern.

Conclusion We identified four 129XeMRI long COVID phenotypes with distinct characteristics. 129XeMRI can dissect pathophysiologic heterogeneity of long COVID to enable personalised patient care.

Source: Rachel L Eddy, David Mummy, Shuo Zhang, Haoran Dai, Aryil Bechtel, Alexandra Schmidt, Bradie Frizzell, Firoozeh V Gerayeli, Jonathon A Leipsic, Janice M Leung, Bastiaan Driehuys, Loretta G Que, Mario Castro, Don D Sin, Peter J Niedbalski. Cluster Analysis to Identify Long COVID Phenotypes Using 129Xe Magnetic Resonance Imaging: A Multi-centre Evaluation. European Respiratory Journal Jan 2024, 2302301; DOI: 10.1183/13993003.02301-2023 https://erj.ersjournals.com/content/early/2024/02/02/13993003.02301-2023 (Full text)

Dysregulated platelet function in patients with postacute sequelae of COVID-19

Abstract:

Background: Postacute sequelae of COVID-19 (PASC), also referred to as “Long COVID”, sometimes follows COVID-19, a disease caused by SARS-CoV-2. Although SARS-CoV-2 is well known to promote a prothrombotic state, less is known about the thrombosis risk in PASC. Our objective was to evaluate platelet function and thrombotic potential in patients following recovery from SARS-CoV-2, but with clear symptoms of patients with PASC.

Methods: patients with PASC and matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by light transmission aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under shear stress conditions.

Results: A mild increase in platelet aggregation in patients with PASC through the thromboxane receptor was observed, and platelet activation through the glycoprotein VI (GPVI) receptor was decreased in patients with PASC compared to age- and sex-matched healthy controls. Thrombosis under shear conditions as well as Factor Xa activity were reduced in patients with PASC. Plasma from patients with PASC was an extremely potent activator of washed, healthy platelets – a phenomenon not observed when stimulating healthy platelets after incubation with plasma from healthy individuals.

Conclusions: patients with PASC show dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating molecule that promotes thrombosis. A hitherto undescribed protective response appears to exist in patients with PASC to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.

Source: Aggarwal A, Singh TK, Pham M, Godwin M, Chen R, McIntyre TM, Scalise A, Chung MK, Jennings C, Ali M, Park H, Englund K, Khorana AA, Svensson LG, Kapadia S, McCrae KR, Cameron SJ. Dysregulated platelet function in patients with postacute sequelae of COVID-19. Vasc Med. 2024 Feb 9:1358863X231224383. doi: 10.1177/1358863X231224383. Epub ahead of print. PMID: 38334067. https://pubmed.ncbi.nlm.nih.gov/38334067/

Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study

Abstract:

Background: In the Netherlands, the prevalence of post COVID-19 condition is estimated at 12.7% at 90-150 days after SARS-CoV-2 infection. This study aimed to determine the occurrence of fatigue and other symptoms, to assess how many patients meet the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) criteria, to identify symptom-based clusters within the P4O2 COVID-19 cohort and to compare these clusters with clusters in a ME/CFS cohort.

Methods: In this multicentre, prospective, observational cohort in the Netherlands, 95 post COVID-19 patients aged 40-65 years were included. Data collection at 3-6 months after infection included demographics, medical history, questionnaires, and a medical examination. Follow-up assessments occurred 9-12 months later, where the same data were collected. Fatigue was determined with the Fatigue Severity Scale (FSS), a score of ≥ 4 means moderate to high fatigue. The frequency and severity of other symptoms and the percentage of patients that meet the ME/CFS criteria were assessed using the DePaul Symptom Questionnaire-2 (DSQ-2). A self-organizing map was used to visualize the clustering of patients based on severity and frequency of 79 symptoms. In a previous study, 337 Dutch ME/CFS patients were clustered based on their symptom scores. The symptom scores of post COVID-19 patients were applied to these clusters to examine whether the same or different clusters were found.

Results: According to the FSS, fatigue was reported by 75.9% of the patients at 3-6 months after infection and by 57.1% of the patients 9-12 months later. Post-exertional malaise, sleep disturbances, pain, and neurocognitive symptoms were also frequently reported, according to the DSQ-2. Over half of the patients (52.7%) met the Fukuda criteria for ME/CFS, while fewer patients met other ME/CFS definitions. Clustering revealed specific symptom patterns and showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort, where 2 clusters had > 10 patients.

Conclusions: This study shows persistent fatigue and diverse symptomatology in post COVID-19 patients, up to 12-18 months after SARS-CoV-2 infection. Clustering showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort.

Source: Cornelissen MEB, Bloemsma LD, Vaes AW, Baalbaki N, Deng Q, Beijers RJHCG, Noij LCE, Houweling L, Bazdar S, Spruit MA, Maitland-van der Zee AH; on behalf of the P4O2 Consortium. Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study. J Transl Med. 2024 Feb 21;22(1):191. doi: 10.1186/s12967-024-04979-1. PMID: 38383493. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-04979-1 (Full text)

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog.

Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene, C., Connolly, R., Brennan, D. et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01576-9 https://www.nature.com/articles/s41593-024-01576-9 (Full text)

Reaching out to Patients with Long COVID to Better Understand Their Life Experiences and How to Support Their Recovery: A Patient-Oriented Knowledge Sharing Session

Abstract:

This article reports on participants’ experiences with long COVID-19 (LC) (symptoms, impact, healthcare use, and perceived needs) and satisfaction with a patient-oriented knowledge-sharing session organized by a multidisciplinary team of healthcare professionals, researchers, and a patient partner. Twenty-six participants completed a pre-session survey. On average, they were 21 months post-COVID-19 infection (SD 10.9); 81% of them were female, and 84% were 40+ years old. The main symptoms reported included fatigue (96%), cognitive problems (92%), and general pain or discomfort (40%).
More than half of the participants reported that LC has had a significant impact on their health-related quality of life. Eighty-one percent of the participants reported seeking medical help for their LC symptoms and found the services provided by physical therapists, primary care providers, and acupuncturists to be helpful in managing their condition. Participants would like to have access to healthcare providers and clinics specializing in LC. They liked the session and found the information presented useful. This information helps to better understand the experiences of people living with LC and how to support their recovery.
Source: Pommer A, Halas G, Mendis R, Campbell C, Semenko B, Stadnyk B, Thalman L, Mair S, Sun Y, Johnston N, et al. Reaching out to Patients with Long COVID to Better Understand Their Life Experiences and How to Support Their Recovery: A Patient-Oriented Knowledge Sharing Session. International Journal of Environmental Research and Public Health. 2024; 21(2):187. https://doi.org/10.3390/ijerph21020187  https://www.mdpi.com/1660-4601/21/2/187 (Full text)

NIH study offers new clues into the causes of post-infectious ME/CFS

Press Release:

In a detailed clinical study, researchers at the National Institutes of Health have found differences in the brains and immune systems of people with post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS). They also found distinct differences between men and women with the disease. The findings were published in Nature Communications.

“People with ME/CFS have very real and disabling symptoms, but uncovering their biological basis has been extremely difficult,” said Walter Koroshetz, M.D., director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “This in-depth study of a small group of people found a number of factors that likely contribute to their ME/CFS. Now researchers can test whether these findings apply to a larger patient group and move towards identifying treatments that target core drivers of the disease.”

A team of multidisciplinary researchers discovered how feelings of fatigue are processed in the brains of people with ME/CFS. Results from functional magnetic resonance imaging (fMRI) brain scans showed that people with ME/CFS had lower activity in a brain region called the temporal-parietal junction (TPJ), which may cause fatigue by disrupting the way the brain decides how to exert effort.

They also analyzed spinal fluid collected from participants and found abnormally low levels of catecholamines and other molecules that help regulate the nervous system in people with ME/CFS compared to healthy controls. Reduced levels of certain catecholamines were associated with worse motor performance, effort-related behaviors, and cognitive symptoms. These findings, for the first time, suggest a link between specific abnormalities or imbalances in the brain and ME/CFS.

“We think that the immune activation is affecting the brain in various ways, causing biochemical changes and downstream effects like motor, autonomic, and cardiorespiratory dysfunction,” said Avindra Nath, M.D., clinical director at NINDS and senior author of the study.

Immune testing revealed that the ME/CFS group had higher levels of naive B cells and lower levels of switched memory B cells—cells that help the immune system fight off pathogens—in blood compared to healthy controls. Naive B cells are always present in the body and activate when they encounter any given antigen, a foreign substance that triggers the immune system. Memory B cells respond to a specific antigen and help maintain adaptive or acquired immunity. More studies are needed to determine how these immune markers relate to brain dysfunction and fatigue in ME/CFS.

To study fatigue, Dr. Nath and his team asked participants to make risk-based decisions about exerting physical effort. This allowed them to assess the cognitive aspects of fatigue, or how an individual decides how much effort to exert when given a choice. People with ME/CFS had difficulties with the effort choice task and with sustaining effort. The motor cortex, a brain region in charge of telling the body to move, also remained abnormally active during fatiguing tasks. There were no signs of muscle fatigue. This suggests that fatigue in ME/CFS could be caused by a dysfunction of brain regions that drive the motor cortex, such as the TPJ.

“We may have identified a physiological focal point for fatigue in this population,” said Brian Walitt, M.D., M.P.H., associate research physician at NINDS and first author of the study. “Rather than physical exhaustion or a lack of motivation, fatigue may arise from a mismatch between what someone thinks they can achieve and what their bodies perform.”

Deeper analyses revealed differences between men and women in gene expression patterns, immune cell populations, and metabolic markers. Males had altered T cell activation, as well as markers of innate immunity, while females had abnormal B cell and white blood cell growth patterns. Men and women also had distinct markers of inflammation.

“Men and women were quite divergent in their data, and that tells you that ME/CFS is not one-size-fits-all,” said Dr. Nath. “Considering male and female immune differences in ME/CFS, the results may open up new avenues of research that could provide insight into other infection-associated chronic diseases.”

The study, which was conducted at the NIH Clinical Center, took a comprehensive look at ME/CFS that developed after a viral or bacterial infection. The team used state-of-the-art techniques to examine 17 people with PI-ME/CFS who had been sick for less than five years and 21 healthy controls. Participants were screened and medically evaluated for ME/CFS over several days and underwent extensive tests, including clinical exams, fMRI brain imaging, physical and cognitive performance tests, autonomic function tests, skin and muscle biopsies, and advanced analyses of blood and spinal fluid. Participants also spent time in metabolic chambers where, under controlled conditions, their diet, energy consumption, metabolism, sleep patterns, and gut microbiome were evaluated. During a second visit, they completed a cardiopulmonary exercise test to measure the body’s response to exercise.

Many studies have identified immune, microbiome, and other abnormalities in ME/CFS, but the results tend to be inconsistent and exactly how these markers relate to or cause fatigue and other symptoms is unknown. By using a rigorous phenotyping approach to pull out meaningful differences, this study helps validate prior results and may identify new ways to target the brain or immune system therapeutically.

The highly collaborative project involved 75 investigators across 15 institutes and centers in the NIH Intramural Research Program, and at national and international institutions. Dr. Nath and his colleagues plan to publish additional findings from the data that was collected during this study.

The study was supported in part by the Intramural Research Program at the NIH.

Article:

Walitt, B., et al. “Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” Nature Communications. February 21, 2024. DOI: 10.1038/s41467-024-45107-3

NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation

Abstract:

Background: Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain. The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning.

Methods: Sickness behavior was quantified using the sickness questionnaire (SicknessQ). Self-ratings were collected at one time-point in 6 different samples. Levels of sickness behavior in patients with ME/CFS (n ​= ​38) and patients with chronic pain (n ​= ​190) were compared to healthy subjects with lipopolysaccharide(LPS)-induced inflammation (n ​= ​29), primary care patients (n ​= ​163), individuals from the general population (n ​= ​155) and healthy subjects (n ​= ​48), using linear regression. Correlations and moderated regression analyses were used to investigate associations between sickness behavior and self-rated health and health-related functioning in ME/CFS, chronic pain and the general population.

Results: LPS-injected individuals (M ​= ​16.3), patients with ME/CFS (M ​= ​16.1), chronic pain (M ​= ​16.1) and primary care patients (M ​= ​10.7) reported significantly higher SicknessQ scores than individuals from the general population (M ​= ​5.4) and healthy subjects (M ​= ​3.6) all p‘s ​< ​0.001). In turn, LPS-injected individuals, patients with ME/CFS and chronic pain reported significantly higher SicknessQ scores than primary care patients (p’s ​< ​0.01). Higher levels of sickness behavior were associated with poorer self-rated health and health-related functioning (p’s ​< ​0.01), but less so in patients with ME/CFS and chronic pain than in individuals from the general population.

Conclusions: Patients with ME/CFS and chronic pain report similar high levels of sickness behavior; higher than primary care patients, and comparable to levels in experimental inflammation. Further study of sickness behavior in ME/CFS and chronic pain populations is warranted as immune-to-brain interactions and sickness behavior may be of importance for functioning as well as in core pathophysiological processes in subsets of patients.

Source: Jonsjö MA, Åström J, Jones MP, Karshikoff B, Lodin K, Holmström L, Agréus L, Wicksell RK, Axelsson J, Lekander M, Olsson GL, Kemani M, Andreasson A. Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation. Brain Behav Immun Health. 2019 Dec 17;2:100028. doi: 10.1016/j.bbih.2019.100028. PMID: 38377418; PMCID: PMC8474484. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474484/ (Full text)

Comparing surveyed adults with long COVID and those with just a positive test helps put COVID into perspective

Abstract:

Introduction Among adults who test positive for COVID-19, some develop long COVID (symptoms lasting ≥3 months), and some do not. We compared 3 groups on selected measures to help determine strategies to reduce COVID impact.

Methods Using Stata and data for 385,617 adults from the 2022 Behavioral Risk Factor Surveillance System, we compared adults reporting long COVID, those with just a positive test, and those who never tested positive, on several health status and risk factor measures plus vaccination rates (data for 178,949 adults in 29 states).

Results Prevalence of just COVID was 26.5% (95% CI 26.2-26.8) and long COVID was 7.4% (7.3-7.6). Compared with adults with just COVID those with long COVID had worse rates for 13 of 17 measures of chronic disease, disability, and poor health status, while those with just COVID had the best results for 15 of the 17 measures among all 3 groups. The 5 risk factors (obesity, diabetes, asthma, cardiovascular disease, and COPD) previously associated with COVID deaths, increased long COVID but not just COVID rates, which were highest among younger and higher income adults. Adults with long COVID had the highest rate among the 3 groups for any COVID risk factors and data from 29 states showed they had the lowest rates for ≥3 vaccine doses of 35.6%, vs. 42.7% and 50.3% for those with just a positive test, and neither, respectively. Vaccination with ≥3 vaccines vs. <3 reduced long COVID rates by 38%, and just COVID rates by 16%.

Conclusions Results show the seriousness of long COVID vs. just a positive test and that increasing vaccine coverage by targeting adults with risk factors shows promise for reducing COVID impact.

Source: Mary L. Adams, Joseph Grandpre. Comparing surveyed adults with long COVID and those with just a positive test helps put COVID into perspective. medRxiv 2024.02.02.24302216; doi: https://doi.org/10.1101/2024.02.02.24302216 https://www.medrxiv.org/content/10.1101/2024.02.02.24302216v1.full-text (Full text)

Cognitive and Mental Health Trajectories of COVID-19: Role of Hospitalisation and Long-COVID Symptoms

Abstract:

Background: There is considerable evidence of cognitive impairment post COVID-19, especially in individuals with long-COVID symptoms, but limited research objectively evaluating whether such impairment attenuates or resolves over time, especially in young and middle-aged adults.

Methods: Follow-up assessments (T2) of cognitive function (processing speed, attention, working memory, executive function, memory) and mental health were conducted in 138 adults (18-69 years) who had been assessed six months earlier (T1). Of these, 88 had a confirmed history of COVID-19 at T1 assessment (≥20 days post-diagnosis) and were also followed-up on COVID-19 related symptoms (acute and long-COVID); 50 adults had no known COVID-19 history at any point up to their T2 assessment.

Results: From T1 to T2, a trend-level improvement occurred in intra-individual variability in processing speed in the COVID, relative to the non-COVID group. However, longer response/task completion times persisted in participants with COVID-19 related hospitalisation relative to those without COVID-19 related hospitalisation and non-COVID controls. There was a significant reduction in long-COVID symptom load, which correlated with improved executive function in non-hospitalised COVID-19 participants. The COVID group continued to self-report poorer mental health, irrespective of hospitalisation history, relative to non-COVID group.

Conclusions: Although some cognitive improvement has occurred over a six-month period in young and middle-aged COVID-19 survivors, cognitive impairment persists in those with a history of COVID-19 related hospitalisation and/or long-COVID symptoms. Continuous follow-up assessments are required to determine whether cognitive function improves or possibly worsens, over time in hospitalised and long-COVID participants.

Source: Vakani K, Ratto M, Sandford-James A, Antonova E, Kumari V. Cognitive and Mental Health Trajectories of COVID-19: Role of Hospitalisation and Long-COVID Symptoms. Eur Psychiatry. 2024 Feb 5:1-40. doi: 10.1192/j.eurpsy.2024.7. Epub ahead of print. PMID: 38312039. https://www.researchgate.net/publication/377977040_Cognitive_and_Mental_Health_Trajectories_of_COVID-19_Role_of_Hospitalisation_and_Long-COVID_Symptoms (Full text)

Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report

As COVID-19 continues, an increasing number of patients develop long COVID symptoms varying in severity that last for weeks, months, or longer. Symptoms commonly include lingering loss of smell and taste, hearing loss, extreme fatigue, and “brain fog.” Still, persistent cardiovascular and respiratory problems, muscle weakness, and neurologic issues have also been documented. A major problem is the lack of clear guidelines for diagnosing long COVID. Although some studies suggest that long COVID is due to prolonged inflammation after SARS-CoV-2 infection, the underlying mechanisms remain unclear.

The broad range of COVID-19’s bodily effects and responses after initial viral infection are also poorly understood. This workshop brought together multidisciplinary experts to showcase and discuss the latest research on long COVID and chronic inflammation that might be associated with the persistent sequelae following COVID-19 infection.

Source: Pushpa Tandon, Natalie D. Abrams, Leela Rani Avula, Danielle M. Carrick, Preethi Chander, Rao L. Divi, Johanna T. Dwyer, Gallya Gannot, Nataliya Gordiyenko, Qian Liu, Kyung Moon, Mercy PrabhuDas, Anju Singh, Mulualem E. Tilahun, Merriline M. Satyamitra, Chiayeng Wang, Ronald Warren, Christina H. Liu; Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report. J Immunol 15 February 2024; 212 (4): 505–512. https://doi.org/10.4049/jimmunol.2300804 https://journals.aai.org/jimmunol/article/212/4/505/266648 (Full text)