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, Laffan A, O’Keeffe E, Zaporojan L, O’Callaghan J, Thomson B, Connolly E, Argue R, Martin-Loeches I, Long A, Cheallaigh CN, Conlon N, Doherty CP, Campbell M. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci. 2024 Mar;27(3):421-432. doi: 10.1038/s41593-024-01576-9. Epub 2024 Feb 22. PMID: 38388736; PMCID: PMC10917679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917679/ (Full text)

What is the impact of long-term COVID-19 on workers in healthcare settings? A rapid systematic review of current evidence

Abstract:

Background: Long COVID is a devastating, long-term, debilitating illness which disproportionately affects healthcare workers, due to the nature of their work. There is currently limited evidence specific to healthcare workers about the experience of living with Long COVID, or its prevalence, pattern of recovery or impact on healthcare.

Objective: Our objective was to assess the effects of Long COVID among healthcare workers and its impact on health status, working lives, personal circumstances, and use of health service resources.

Methods: We conducted a systematic rapid review according to current methodological standards and reported it in adherence to the PRISMA 2020 and ENTREQ statements.

Results: We searched relevant electronic databases and identified 3770 articles of which two studies providing qualitative evidence and 28 survey studies providing quantitative evidence were eligible. Thematic analysis of the two qualitative studies identified five themes: uncertainty about symptoms, difficulty accessing services, importance of being listened to and supported, patient versus professional identity and suggestions to improve communication and services for people with Long COVID. Common long-term symptoms in the survey studies included fatigue, headache, loss of taste and/or smell, breathlessness, dyspnoea, difficulty concentrating, depression and anxiety.

Conclusion: Healthcare workers struggled with their dual identity (patient/doctor) and felt dismissed or not taken seriously by their doctors. Our findings are in line with those in the literature showing that there are barriers to healthcare professionals accessing healthcare and highlighting the challenges of receiving care due to their professional role. A more representative approach in Long COVID research is needed to reflect the diverse nature of healthcare staff and their occupations. This rapid review was conducted using robust methods with the codicil that the pace of research into Long COVID may mean relevant evidence was not identified.

Source: Cruickshank M, Brazzelli M, Manson P, Torrance N, Grant A. What is the impact of long-term COVID-19 on workers in healthcare settings? A rapid systematic review of current evidence. PLoS One. 2024 Mar 5;19(3):e0299743. doi: 10.1371/journal.pone.0299743. PMID: 38442116; PMCID: PMC10914278. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10914278/ (Full text)

Management of severe ME/CFS in children and young people in the UK: a British Paediatric Surveillance Unit study

Abstract:

Objective: Severe myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) in children and young people (CYP) is a little-understood condition which significantly impacts education, development and quality of life. We used data from a population-wide surveillance study to explore the screening investigation, referral and management of suspected cases of paediatric severe ME/CFS.

Methods: A British Paediatric Surveillance Unit (BPSU) study reported cases of CYP with suspected severe ME/CFS between February 2018 and February 2019. Paediatricians reporting cases to BPSU and allied healthcare professionals in two large specialist paediatric ME/CFS centres were invited to complete questionnaires for CYP meeting the surveillance case definition. The study focused primarily on CYP with confirmed severe ME/CFS and the extent to which their care met NICE (The National Institute for Health and Care Excellence) recommendations but also considered separately those with probable or possible severe ME/CFS.

Results: This study includes a total of 92 CYP with suspected severe ME/CFS; 33 meeting criteria for severe ME/CFS and an additional 59 classified as probable or possible severe ME/CFS. For 16 possible cases, incomplete investigation to exclude alternative diagnoses prevented confirmation of a severe ME/CFS diagnosis. Only 21 of 33 (64%) confirmed severe ME/CFS cases had been referred to specialist services. The management provided varied considerably between patients and four received nothing at all. Of the management provided, the most frequent approaches were medication (67%), activity management (61%) and physiotherapy (61%). Domiciliary assessments and support, and social services referrals were received by 12% and 6% of confirmed severe cases. Similar proportions of management approaches were seen in probable/possible severe ME/CFS.

Conclusion: Full investigation is frequently incomplete in CYP with suspected severe ME/CFS and recommendations for referral and management are poorly implemented, in particular the needs of CYP who are unable to leave their home might be poorly met.

Source: Royston AP, Burge S, Idini I, Brigden A, Pike KC. Management of severe ME/CFS in children and young people in the UK: a British Paediatric Surveillance Unit study. BMJ Paediatr Open. 2024 Mar 7;8(1):e002436. doi: 10.1136/bmjpo-2023-002436. PMID: 38453418. https://bmjpaedsopen.bmj.com/content/8/1/e002436 (Full text)

Burnout, Compassion Fatigue, and the Long Haul of Caring for Long COVID

Abstract:

The current landscape of clinician burnout is prompting the need for our health care system to revise its approach toward complex conditions such as long coronavirus disease (COVID), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other postinfectious fatiguing illnesses (PIFIs). We discuss our efforts here at Family Health Center of San Diego (FHCSD) to help share insight and glean perspective from clinicians who have participated in our Centers for Disease Control and Prevention (CDC)-funded 3-year continuing professional development initiative.

The Long COVID and Fatiguing Illness Recovery Program uses multidisciplinary team-based case consultation and peer-to-peer sharing of emerging best and promising practices (ie, teleECHO [Extension for Community Healthcare Outcomes]) to support the management of complex cases associated with long COVID, ME/CFS, and other PIFIs. We believe that this perspective captures a key moment in the trajectory of postpandemic clinician burnout and prompts further reflection and action from the health care system to improve clinician- and patient-level outcomes related to the care of patients with postinfectious fatiguing illnesses.

Source: Ramers CB, Scott JD, Struminger BB. Burnout, Compassion Fatigue, and the Long Haul of Caring for Long COVID. Open Forum Infect Dis. 2024 Feb 7;11(3):ofae080. doi: 10.1093/ofid/ofae080. PMID: 38449917; PMCID: PMC10917153. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917153/ (Full text)

‘The world was going through what we go through everyday’: The experiences of women with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) living with their partners during the COVID-19 lockdown in the United Kingdom

Abstract:

Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term debilitating illness characterised by profound and persistent fatigue (JAMA: The Journal of the American Medical Association, 313, 2015, 1101). The current study aims to explore the experiences of women with ME/CFS living with their partners during the COVID-19 pandemic in the United Kingdom.

Design: The study adopted a qualitative design comprising semi-structured interviews with participants. Interviews were analysed using thematic analysis (TA).

Methods: Participants were women with ME/CFS (n = 21) recruited through ME/CFS support groups in the United Kingdom. All participants were in romantic relationships and lived with their partners.

Results: Data were organised into three themes: (1) lockdown disrupting routine, (2) reducing difference and (3) fear of getting COVID-19. People with ME/CFS found that lockdown disrupted their well-established routines. Although routines were disrupted by partners and increased working-from-home practices, participants found having partners at home helpful. People with ME/CFS believed that the changes induced by the pandemic reduced the differences between themselves and the outside world which, prior to lockdown, had felt prominent. They were fearful of getting COVID-19 as they believed this would make their ME/CFS worse. This meant that for people with ME/CFS, the lifting of the lockdown restrictions was an anxiety-provoking time, hence impacting symptoms. People with ME/CFS continued to adhere to government guidelines after national restrictions were eased.

Conclusions: This study outlines the experiences of women with ME/CFS during COVID-19, alongside the long-term impact this has had due to the changes that the pandemic imposed. These findings may have implications for those with long COVID.

Source: Sehmbi T, Wearden A, Peters S, Dienes K. ‘The world was going through what we go through everyday’: The experiences of women with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) living with their partners during the COVID-19 lockdown in the United Kingdom. Br J Health Psychol. 2024 Mar 6. doi: 10.1111/bjhp.12717. Epub ahead of print. PMID: 38448223. https://bpspsychub.onlinelibrary.wiley.com/doi/10.1111/bjhp.12717 (Full text)

Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Abstract:

Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of a variety of chronic, inflammatory diseases, including long COVID, as are small, insoluble, ‘fibrinaloid’ microclots.
We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block the flow of blood through microcapillaries and thus cause tissue hypoxia, are not simply correlated with but in fact, by preceding it, may be a chief intermediary cause of POTS, in which tachycardia is simply the body’s exaggerated ‘physiological’ response to hypoxia. Similar reasoning accounts for the symptoms bundled under the term ‘fatigue’.
Amyloids are known to be membrane disruptors, and when their targets are nerve membranes, this can explain neurotoxicity and hence the autonomic nervous system dysfunction that contributes to POTS. Taken together as a system view, we indicate that fibrinaloid microclots can serve to link POTS and fatigue in long COVID in a manner that is at once both mechanistic and explanatory. This has clear implications for the treatment of such diseases.
Source: Kell DB, Khan MA, Kane B, Lip GYH, Pretorius E. Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID. Journal of Personalized Medicine. 2024; 14(2):170. https://doi.org/10.3390/jpm14020170 https://www.mdpi.com/2075-4426/14/2/170 (Full text)

Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed ‘long COVID’ (LC). Both ME/CFS and LC share many clinical similarities.

Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.

Source: Annesley SJ, Missailidis D, Heng B, Josev EK, Armstrong CW. Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies. Trends Mol Med. 2024 Mar 4:S1471-4914(24)00028-5. doi: 10.1016/j.molmed.2024.02.003. Epub ahead of print. PMID: 38443223. https://www.sciencedirect.com/science/article/pii/S1471491424000285 (Full text)

Ebbing Strength, Fading Power: Unveiling the Impact of Persistent Fatigue on Muscle Performance in COVID-19 Survivors

Abstract:

The total number of confirmed cases of COVID-19 caused by SARS-CoV-2 virus infection is over 621 million. Post-COVID-19 syndrome, also known as long COVID or long-haul COVID, refers to a persistent condition where individuals experience symptoms and health issues after the acute phase of COVID-19.

The aim of this study was to assess the strength and fatigue of skeletal muscles in people recovered from COVID-19. A total of 94 individuals took part in this cross-sectional study, with 45 participants (referred to as the Post-COVID Cohort, PCC) and 49 healthy age-matched volunteers (Healthy Control Cohort, HCC).

This research article uses the direct dynamometry method to provide a detailed analysis of post-COVID survivors’ strength and power characteristics. The Biodex System 4 Pro was utilized to evaluate muscle strength characteristics during the fatigue test. The fatigue work in extensors and flexors was significantly higher in the PCC.  The PCC also showed significantly less power in both extensors and flexors compared to the HCC.

In conclusion, this study provides compelling evidence of the impact of post-COVID-19 fatigue on muscle performance, highlighting the importance of considering these effects in the rehabilitation and care of individuals recovering from the virus. PCC achieved lower muscle strength values than HCC.

Source: Kowal M, Morgiel E, Winiarski S, Dymarek R, Bajer W, Madej M, Sebastian A, Madziarski M, Wedel N, Proc K, Madziarska K, Wiland P, Paprocka-Borowicz M. Ebbing Strength, Fading Power: Unveiling the Impact of Persistent Fatigue on Muscle Performance in COVID-19 Survivors. Sensors (Basel). 2024 Feb 15;24(4):1250. doi: 10.3390/s24041250. PMID: 38400407; PMCID: PMC10892381. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10892381/ (Full text)

Sex differences in symptomatology and immune profiles of Long COVID

Abstract:

Strong sex differences in the frequencies and manifestations of Long COVID (LC) have been reported with females significantly more likely than males to present with LC after acute SARS-CoV-2 infection1-7. However, whether immunological traits underlying LC differ between sexes, and whether such differences explain the differential manifestations of LC symptomology is currently unknown.

Here, we performed sex-based multi-dimensional immune-endocrine profiling of 165 individuals8 with and without LC in an exploratory, cross-sectional study to identify key immunological traits underlying biological sex differences in LC.

We found that female and male participants with LC experienced different sets of symptoms, and distinct patterns of organ system involvement, with female participants suffering from a higher symptom burden. Machine learning approaches identified differential sets of immune features that characterized LC in females and males. Males with LC had decreased frequencies of monocyte and DC populations, elevated NK cells, and plasma cytokines including IL-8 and TGF-β-family members.

Females with LC had increased frequencies of exhausted T cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including EBV, HSV-2, and CMV, and lower testosterone levels than their control female counterparts. Testosterone levels were significantly associated with lower symptom burden in LC participants over sex designation.

These findings suggest distinct immunological processes of LC in females and males and illuminate the crucial role of immune-endocrine dysregulation in sex-specific pathology.

Source: Julio Silva, Takehiro Takahashi, Jamie Wood, Peiwen Lu, Sasha Tabachnikova, Jeffrey Gehlhausen, Kerrie Greene, Bornali Bhattacharjee, Valter Silva Monteiro, Carolina Lucas, Rahul Dhodapkar, Laura Tabacof, Mario Pena-Hernandez, Kathy Kamath, Tianyang Mao, Dayna Mccarthy, Ruslan Medzhitov, David van Dijk, Harlan Krumholz, Leying Guan, David Putrino, Akiko Iwasaki. Sex differences in symptomatology and immune profiles of Long COVID. medRxiv 2024.02.29.24303568; doi: https://doi.org/10.1101/2024.02.29.24303568 https://www.medrxiv.org/content/10.1101/2024.02.29.24303568v1 (Full study available as PDF file)

Cognition and Memory after Covid-19 in a Large Community Sample

Abstract:

Background: Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear.

Methods: We invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting ≥12 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating (“brain fog”).

Results: Of the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no-Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (-0.23 SD [95% confidence interval {CI}, -0.33 to -0.13] and -0.24 SD [95% CI, -0.36 to -0.12], respectively); larger deficits as compared with the no-Covid-19 group were seen in participants with unresolved persistent symptoms (-0.42 SD; 95% CI, -0.53 to -0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., -0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, -0.20 to -0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, -0.35 SD; 95% CI, -0.49 to -0.20). Results of the analyses were similar to those of propensity-score-matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no-Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (-0.33 to -0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported.

Conclusions: Participants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. (Funded by the National Institute for Health and Care Research and others.).

Source: Hampshire A, Azor A, Atchison C, Trender W, Hellyer PJ, Giunchiglia V, Husain M, Cooke GS, Cooper E, Lound A, Donnelly CA, Chadeau-Hyam M, Ward H, Elliott P. Cognition and Memory after Covid-19 in a Large Community Sample. N Engl J Med. 2024 Feb 29;390(9):806-818. doi: 10.1056/NEJMoa2311330. PMID: 38416429. https://www.nejm.org/doi/10.1056/NEJMoa2311330 (Full text)