Tag: covid-19

A causal link between autoantibodies and neurological symptoms in long COVID

Summary:

Acute SARS-CoV-2 infection triggers the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been found in some individuals with long COVID (LC). Using a >21,000 human protein array, we identified diverse AAB targets in LC patients that correlated with their symptoms.

Elevated AABs to proteins in the nervous system were found in LC patients with neurocognitive and neurological symptoms. Purified Immunoglobulin G (IgG) samples from these individuals reacted with human pons tissue and were cross-reactive with mouse sciatic nerves, spinal cord, and meninges. Antibody reactivity to sciatic nerves and meninges correlated with patient-reported headache and disorientation. Passive transfer of IgG from patients to mice led to increased sensitivity and pain, mirroring patient-reported symptoms. Similarly, mice injected with IgG showed loss of balance and coordination, reflecting donor-reported dizziness. Our findings suggest that targeting AABs could benefit some LC patients.

Source: Keyla Santos Guedes de Sa, Julio Silva, Rafael Bayarri-Olmos, Ryan Brinda, Robert Alec Rath Constable, Patricia A. Colom Diaz, Dong il Kwon, Gisele Rodrigues, Li Wenxue, Christopher Baker, Bornali Bhattacharjee, Jamie Wood, Laura Tabacof, Yansheng Liu, David Putrino, Tamas L. Horvath, Akiko Iwasaki. A causal link between autoantibodies and neurological symptoms in long COVID. medRxiv 2024.06.18.24309100; doi: https://doi.org/10.1101/2024.06.18.24309100 https://www.medrxiv.org/content/10.1101/2024.06.18.24309100v1.full-text (Full text)

Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress

Abstract:

Coronavirus disease 2019 (COVID-19) has resulted in long-term psychiatric symptoms because of the immunologic response to the virus itself as well as fundamental life changes related to the pandemic. This immune response leads to altered tryptophan (TRP)-kynurenine (KYN) pathway (TKP) metabolism, which plays an essential role in the pathophysiology of mental illnesses. We aimed to define TKP changes as a potential underlying mechanism of psychiatric disorders in post-COVID-19 patients.

We measured plasma levels of several TKP markers, including KYN, TRP, kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), as well as the TRP/KYN, KYNA/3-HK, and KYNA/QUIN ratios, in 90 post-COVID-19 patients (on the first day of hospitalization) and 59 healthy controls (on the first admission to the Check-Up Center). An online questionnaire that included the Depression, Anxiety and Stress Scale-21 (DASS-21) was used 6 months after the initial assessment in both groups.

A total of 32.2% of participants with COVID-19 showed depressive symptoms, 21.1% exhibited anxiety, and 33.3% had signs of stress at follow-up, while 6.6% of healthy controls exhibited depressive and anxiety symptoms and 18.6% had signs of stress. TRP and 3-HK were negative predictors of anxiety and stress, but KYN positively predicted anxiety and stress. Moreover, TRP negatively predicted depression, while KYNA/3-HK was a negative predictor of anxiety.

The correlation between depression, anxiety, and stress and TKP activation in COVID-19 could provide prospective biomarkers, especially the reduction in TRP and 3HK levels and the increase in KYN. Our results suggest that the alteration of TKP is not only a potential biomarker of viral infection-related long-term psychiatric disorders but also that the therapy targets future viral infections related to depression and anxiety.

Source: Kucukkarapinar M, Yay-Pence A, Yildiz Y, Buyukkoruk M, Yaz-Aydin G, Deveci-Bulut TS, Gulbahar O, Senol E, Candansayar S. Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress. J Neural Transm (Vienna). 2022 Aug;129(8):1077-1089. doi: 10.1007/s00702-022-02525-1. Epub 2022 Jul 7. PMID: 35796878; PMCID: PMC9261222. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261222/ (Full text)

Cerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue

Abstract:

After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory dysfunction, and fatigue. Despite this, biomarkers and pathophysiological understandings of this condition remain limited. Employing magnetic resonance imaging, we conduct a comparative analysis of cerebral microstructure among patients with Post-COVID-Condition, healthy controls, and individuals that contracted COVID-19 without long-term symptoms.

We reveal widespread alterations in cerebral microstructure, attributed to a shift in volume from neuronal compartments to free fluid, associated with the severity of the initial infection. Correlating these alterations with cognition, olfaction, and fatigue unveils distinct affected networks, which are in close anatomical-functional relationship with the respective symptoms.

Source: Hosp JA, Reisert M, Dressing A, Götz V, Kellner E, Mast H, Arndt S, Waller CF, Wagner D, Rieg S, Urbach H, Weiller C, Schröter N, Rau A. Cerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue. Nat Commun. 2024 May 18;15(1):4256. doi: 10.1038/s41467-024-48651-0. PMID: 38762609; PMCID: PMC11102465. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11102465/ (Full text)

Long-COVID autonomic syndrome in working age and work ability impairment

Abstract:

Long-COVID19 has been recently associated with long-sick leave and unemployment. The autonomic nervous system functioning may be also affected by SARS-CoV-2, leading to a chronic autonomic syndrome. This latter remains widely unrecognized in clinical practice. In the present study, we assessed the occurrence of Long-COVID19 Autonomic Syndrome in a group of active workers as well as the relationships between their autonomic dysfunction and work ability.

This prospective observational study was conducted during the 2nd wave of the pandemic in Italy. Forty-five patients (53.6 ± 8.4 years; 32 M) hospitalized for COVID19, were consecutively enrolled at the time of their hospital discharge (T0) and followed-up for 6 months. Autonomic symptoms and work ability were assessed by COMPASS31 and Work Ability Index questionnaires at T0, one (T1), three and six (T6) months after hospital discharge and compared to those retrospectively collected for a period preceding SARS-CoV-2 infection. Clinical examination and standing test were also performed at T1 and T6.

One in three working-age people developed a new autonomic syndrome that was still evident 6 months after the acute infection resolution. This was associated with a significant reduction in the work ability. Recognition of Long-COVID19 Autonomic Syndrome may promote early intervention to facilitate return to work and prevent unemployment.

Source: Rinaldi L, Rigo S, Pani M, Bisoglio A, Khalaf K, Minonzio M, Shiffer D, Romeo MA, Verzeletti P, Ciccarelli M, Bordoni MG, Stranges S, Riboli E, Furlan R, Barbic F. Long-COVID autonomic syndrome in working age and work ability impairment. Sci Rep. 2024 May 23;14(1):11835. doi: 10.1038/s41598-024-61455-y. PMID: 38782998; PMCID: PMC11116376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11116376/ (Full text)

The risks of autoimmune- and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the US, and Korea

ABSTRACT

Objectives We aimed to assess the risk of autoimmune- and inflammatory post-acute COVID-19 conditions.

Design Descriptive network cohort study.

Setting Electronic health records from UK and Dutch primary care, Norwegian linked health registry, hospital records of specialist centres in Spain, France, and Korea, and healthcare claims from Estonia and the US.

Participants We followed individuals between September 2020 and the latest available data from the day they fulfilled at least 365 days of prior observation (general population), additionally from day 91 after a SARS-Cov-2 negative test (comparator) or a COVID-19 record (exposed patients).

Main outcome measures We assessed postural orthostatic tachycardia syndrome (POTS) diagnoses/symptoms, myalgic encephalomyelitis / chronic fatigues syndrome (ME/CFS) diagnoses/symptoms, multi-inflammatory syndrome (MIS), and several autoimmune diseases. For contextualisation, we assessed any diabetes mellitus (DM).

Meta-analysed crude incidence rate ratios (IRR) of outcomes measures after COVID-19 versus negative testing yield the ratios of absolute risks. Furthermore, incidence rates (IR) of the outcomes in the general population describe the total disease burden.

Results We included 34’549’575 individuals of whom 2’521’812 had COVID-19, and 4’233’145 a first negative test. After COVID-19 compared to test negative patients, we observed IRRs of 1.24 (1.23-1.25), 1.22 (1.21-1.23), and 1.12 (1.04-1.21) for POTS symptoms, ME/CFS symptoms and diagnoses, respectively. In contrast, autoimmune diseases and DM did not yield higher rates after COVID-19. In individual general database populations, IRs of POTS and ME/CFS diagnoses were 17-1’477/100’000 person-years (pys) and 2-473/100’000 pys, respectively. IRs of MIS were lowest with IRs 0.4-16/100’000 pys, those of DM as a benchmark 8-86/100’000 pys. IRs largely depended on the care setting.

Conclusion In our unmatched comparison, we observed that, following COVID-19, POTS and ME/CFS yielded higher rates than after negative testing. In absolute terms, we observed POTS and ME/CFS diagnoses to have a similar disease burden as DM.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Observational research suggested positive associations between COVID-19 and so called post-acute COVID-19 conditions, whose spectrum is yet to be established

  • Basic research suggested pathways that link COVID-19 with autoimmune- and inflammatory diseases such as postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis / chronic fatigues syndrome (ME/CFS), multiple inflammatory syndrome (MIS), and autoimmune diseases

WHAT THIS STUDY ADDS

  • After COVID-19, the rates of POTS symptoms and ME/CFS symptoms/diagnoses was higher than those after negative testing

  • After COVID-19 versus negative testing, rates of ME/CFS diagnoses were increased in the working age group and rates of symptoms of POTS and ME/CFS were increased in children and elderly

  • Disease burdens of POTS and ME/CFS diagnoses in the general population were higher among women than among men and overall similar to that of diabetes mellitus

Source: Theresa Burkard, Kim López-Güell, Martí Català, Edward Burn, Antonella Delmestri, Sara Khalid, Annika M Joedicke, Daniel Dedman, Jessie O Oyinlola, Alicia Abellan, Laura Pérez-Crespo, Núria Mercadé-Besora, Talita Duarte-Salles, Daniel Prieto-Alhambra, Johnmary T Arinze, Mees Mosseveld, Raivo Kolde, Jaime Meléndez-Cardiel, Raúl López-Blasco, Álvaro Martínez, Bernardo Valdivieso, Dominique Delseny, Gregoire Mercier, Chungsoo Kim, Ji-woo Kim, Kristin Kostka, Juan Manuel Ramírez-Anguita, Miguel A Mayer, Nhung TH Trinh, Hedvig ME Nordeng, Roger Paredes, Anneli Uusküla, Akihiko Nishimura, Cora Loste, Lourdes Mateu, Junqing Xie. The risks of autoimmune- and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the US, and Korea. medRxiv 2024.05.15.24307344; doi: https://doi.org/10.1101/2024.05.15.24307344 https://www.medrxiv.org/content/10.1101/2024.05.15.24307344v1.full-text (Full text)

Impact of inflammatory response in the acute phase of COVID-19 on predicting objective and subjective post-COVID fatigue

Abstract:

The biological predictors of objective and subjective fatigue in individuals with post-COVID syndrome remains unclear. This study aims to ascertain the predictive significance of the immune response measured during the acute phase of SARS-CoV-2 infection on various dimensions of fatigue 6–9 months post-infection.

We examined the association between immune markers obtained from the serum of 54 patients (mean age: 58.69 ± 10.90; female: 31%) and objective and subjective chronic fatigue using general linear mixed models. Level of IL-1RA, IFNγ and TNFα in plasma and the percentage of monocytes measured in the acute phase of COVID-19 predicted physical and total fatigue.

Moreover, the higher the concentration of TNFα (r=-0.40 ; p = .019) in the acute phase, the greater the lack of awareness of cognitive fatigue 6–9 months post-infection. These findings shed light on the relationship between acute inflammatory response and the persistence of both objective and subjective fatigue.

Source: Julie Péron, Anthony Nuber-Champier, Gautier Breville et al. Impact of inflammatory response in the acute phase of COVID-19 on predicting objective and subjective post-COVID fatigue, 28 May 2024, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-4374986/v1] https://www.researchsquare.com/article/rs-4374986/v1 (Full text)

Longitudinal Progression of Patients with Long COVID Treated in a Post-COVID Clinic: A Cross-Sectional Survey

Abstract:

Background: In addition to the morbidity and mortality associated with acute infection, COVID-19 has been associated with persistent symptoms (>30 days), often referred to as Long COVID (LC). LC symptoms often cluster into phenotypes, resembling conditions such as fibromyalgia, postural orthostatic tachycardiac syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). LC clinics have been established to best address the needs of LC patients and continuity of care. We developed a cross-sectional survey to assess treatment response through our LC Clinic (LCC).

Methods: A 25-question survey (1-10 Likert scale) was expert- and content-validated by LCC clinicians, patients, and patient advocates. The survey assessed LC symptoms and the helpfulness of different interventions, including medications and supplements. A total of 852 LCC patients were asked to complete the survey, with 536 (62.9%) responding.

Results: The mean time from associated COVID-19 infection to survey completion was 23.2 ± 6.4 months. The mean age of responders was 52.3 ± 14.1 (63% females). Self-reported symptoms were all significantly improved (P < .001) from the initial visit to the LCC (baseline) to the time of the follow-up survey. However, only 4.5% (24/536) of patients rated all symptoms low (1-2) at the time of the survey, indicating low levels of full recovery in our cohort. The patients rated numerous interventions as being helpful, including low-dose naltrexone (45/77; 58%), vagal nerve stimulation (18/34; 53%), and fisetin (28/44; 64%).

Conclusions: Patients report general improvements in symptoms following the initial LCC visit, but complete recovery rates remain low at 23.2 ± 6.4 months.

Source: Hurt RT, Yadav S, Schroeder DR, Croghan IT, Mueller MR, Grach SL, Aakre CA, Gilman EA, Stephenson CR, Overgaard J, Collins NM, Lawson DK, Thompson AM, Natividad LT, Mohamed Elfadil O, Ganesh R. Longitudinal Progression of Patients with Long COVID Treated in a Post-COVID Clinic: A Cross-Sectional Survey. J Prim Care Community Health. 2024 Jan-Dec;15:21501319241258671. doi: 10.1177/21501319241258671. PMID: 38813984. https://journals.sagepub.com/doi/10.1177/21501319241258671 (Full text)

Circulating microaggregates as biomarkers for the Post‐COVID syndrome

Abstract:

CoVID-19 can develop into Post-COVID syndrome of potentially high morbidity, with procoagulation and reactivation of dormant viral infections being hypothesized pathophysiological mechanisms. We report on a patient suffering from fatigue, post exertional malaise, pain and neurological symptoms as a consequence of the second CoVID infection. Using live confocal microscopy on native whole blood samples we detected microaggregates of thrombocytes, leukocytes and plasma proteins in peripheral blood.

In addition, there was specific cellular immunological reactivity to EBV. Upon anticoagulatory and virustatic pharmacological therapy we observed dissolution of microaggregates and significant stable clinical remission. We suggest to consider circulating microaggregates as a morphological indicator of chronic post-COVID syndrome.

Source: M. Hermann , C. Lisch, R. Gerth, G. Wick, D. Fries, N. Wick. Circulating microaggregates as biomarkers for the Post‐COVID syndrome. IDCases, Volume 36, 2024, e02000. https://www.sciencedirect.com/science/article/pii/S2214250924000763 (Full text)

Long-Term Impairment of Working Ability in Subjects under 60 Years of Age Hospitalised for COVID-19 at 2 Years of Follow-Up: A Cross-Sectional Study

Abstract:

Background: Coronavirus disease 2019 (COVID-19) can lead to persistent and debilitating symptoms referred to as Post-Acute sequelae of SARS-CoV-2 infection (PASC) This broad symptomatology lasts for months after the acute infection and impacts physical and mental health and everyday functioning. In the present study, we aimed to evaluate the prevalence and predictors of long-term impairment of working ability in non-elderly people hospitalised for COVID-19.

Methods: This cross-sectional study involved 322 subjects hospitalised for COVID-19 from 1 March 2020 to 31 December 2022 in the University Hospital of Bari, Apulia, Italy, enrolled at the time of their hospital discharge and followed-up at a median of 731 days since hospitalization (IQR 466-884). Subjects reporting comparable working ability and those reporting impaired working ability were compared using the Mann-Whitney test (continuous data) and Fisher’s test or Chi-Square test (categorical data). Multivariable analysis of impaired working ability was performed using a logistic regression model.

Results: Among the 322 subjects who were interviewed, 184 reported comparable working ability (57.1%) and 134 reported impaired working ability (41.6%) compared to the pre-COVID-19 period. Multivariable analysis identified age at hospital admission (OR 1.02, 95% CI 0.99 to 1.04), female sex (OR 1.90, 95% CI 1.18 to 3.08), diabetes (OR 3.73, 95% CI 1.57 to 9.65), receiving oxygen during hospital stay (OR 1.76, 95% CI 1.01 to 3.06), and severe disease (OR 0.51, 95% CI 0.26 to 1.01) as independent predictors of long-term impaired working ability after being hospitalised for COVID-19.

Conclusions: Our findings suggest that PASC promotes conditions that could result in decreased working ability and unemployment. These results highlight the significant impact of this syndrome on public health and the global economy, and the need to develop clinical pathways and guidelines for long-term care with specific focus on working impairment.

Source: Frallonardo L, Ritacco AI, Amendolara A, Cassano D, Manco Cesari G, Lugli A, Cormio M, De Filippis M, Romita G, Guido G, Piccolomo L, Giliberti V, Cavallin F, Segala FV, Di Gennaro F, Saracino A. Long-Term Impairment of Working Ability in Subjects under 60 Years of Age Hospitalised for COVID-19 at 2 Years of Follow-Up: A Cross-Sectional Study. Viruses. 2024 Apr 26;16(5):688. doi: 10.3390/v16050688. PMID: 38793570; PMCID: PMC11125725. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11125725/ (Full text)

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome

Abstract:

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC.

The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group.

Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Source: Saito S, Shahbaz S, Osman M, Redmond D, Bozorgmehr N, Rosychuk RJ, Lam G, Sligl W, Cohen Tervaert JW, Elahi S. Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome. J Autoimmun. 2024 May 25;147:103267. doi: 10.1016/j.jaut.2024.103267. Epub ahead of print. PMID: 38797051. https://www.sciencedirect.com/science/article/pii/S089684112400101X (Full text)