Tag: long covid biomarker

Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism

Abstract:

Background: Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients.

Methods: A case–control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D.

Results: Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P < 0.05). A unique two biomarker profile consisting of ANG-1/P-SEL was developed with machine learning, providing a classification accuracy for Long-COVID status of 96%. Individually, ANG-1 and P-SEL had excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, P < 0.0001; validated in a secondary cohort). Specific to Long-COVID, ANG-1 levels were associated with female sex and a lack of disease interventions at follow-up (P < 0.05).

Conclusions: Long-COVID patients suffer prolonged, diffuse symptoms and poorer health. Vascular transformation blood biomarkers were significantly elevated in Long-COVID, with angiogenesis markers (ANG-1/P-SEL) providing classification accuracy of 96%. Vascular transformation blood biomarkers hold potential for diagnostics, and modulators of angiogenesis may have therapeutic efficacy.

Source: Patel, M.A., Knauer, M.J., Nicholson, M. et al. Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol Med 28, 122 (2022). https://doi.org/10.1186/s10020-022-00548-8 https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00548-8 (Full text)

Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID

Abstract:

While significant attention has been paid to the immunologic determinants of disease states associated with COVID-19, their contributions to post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, it is critical to understand if specific features of the disease are associated with discrete immune processes, and whether those processes may be therapeutically targeted. To this end, we performed wide immunologic and serological characterization of patients in the early recovery phase of COVID-19 across a breadth of symptomatic presentations.

Using high-parameter proteomics screening and applied machine learning (ML), we identify clear signatures of immunologic activity between PASC patients and uncomplicated recovery, dominated by inflammatory cytokine signaling, neutrophil activity, and markers of cell death. Consistent with disease complexity, heterogeneity in plasma profiling reveals distinct PASC subsets with striking divergence in these ongoing inflammatory processes, here termed plasma quiescent (plaq) and inflammatory (infl) PASC.

In addition to elevated inflammatory blood proteomics, inflPASC patients display positive clinical tests of acute inflammation including C-reactive protein and fibrinogen, increased B cell activity with extrafollicular involvement coupled with elevated targeting of viral nucleocapsid protein and clinical autoreactivity. Further, the unique plasma signatures of PASC patients allowed for the creation of refined models with high sensitivity and specificity for the positive identification of inflPASC with a streamlined assessment of 12 blood markers. Additionally, refined ML modeling highlights the unexpected significance of several markers of potential diagnostic or therapeutic use for PASC in general, including the peptide hormone, epiregulin.

In all, this work identifies clear biological signatures of PASC with potential diagnostic and therapeutic potential and establishes clear disease subtypes that are both easily identifiable and highly relevant to ongoing efforts in both therapeutic targeting and epidemiological investigation of this highly complex disease.

Source: Matthew Woodruff, Kevin S Bonham, Fabliha A Anam, Tiffany Walker, Yusho Ishii, Candice Y Kaminski, Martin Runnstrom, Alexander Truong, Adviteeya Dixit, Jenny Han, Richard Ramonell, Natalie S. Haddad, Mark Rudoloph, Arezou Khosroshahi, Scott A Jenks, F. Eun-Hyung Lee, Ignacio Sanz. Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID. medRxiv 2021.09.21.21263845; doi: https://doi.org/10.1101/2021.09.21.21263845.  (Full text available as PDF file)

Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue

Abstract:

Post-COVID-19 syndrome (PCS) summarizes persisting sequelae after infection with the severe-acute-respiratory-syndrome-Coronavirus-2 (SARS-CoV-2). PCS can affect patients of all covid-19 disease severities. As previous studies revealed impaired blood flow as a provoking factor for triggering PCS, it was the aim of the present study to investigate a potential association of self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker.

A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT-Angiography (OCT-A) and quantified by the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic Fatigue (CF) was assessed with the variables ‘Bell score’, age and gender. The VD in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed considering the repetitions (12 times). Taking in account of such repetitions a mixed model was performed to detect possible differences in the least square means between different groups of analysis.

An age effect on VD was observed between patients and controls (p<0.0001). Gender analysis yielded that women with PCS showed lower VD levels in SVP compared to male patients (p=0.0015). The PCS patients showed significantly lower VD of ICP as compared to the controls (p=0.0001, [CI: 0.32; 1]). Moreover, considering PCS patients, the mixed model reveals a significant difference between chronic fatigue (CF) and without CF in VD of SVP (p=0.0033, [CI: -4.5; -0.92]). The model included age, gender and the variable ‘Bell score’, representing a subjective marker for CF. Consequently, the retinal microcirculation might be an objective biomarker in subjective-reported chronic fatigue of patients with PCS.

Source: Sarah Schlick, Marianna Lucio, Alexander Bartsch, Adam Skornia, Jakob Hoffmanns, Charlotte Szewczykowski, Thora Schröder, Franziska Raith, Lennart Rogge, Felix Heltmann, Michael Moritz, Lorenz Beitlich, Julia Schottenhamml, Martin Herrmann, Thomas Harrer, Marion Ganslmayer, Friedrich E. Kruse, Robert Lämmer, Christian Mardin, Bettina Hohberger. Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue. medRxiv 2022.09.23.22280264; doi: https://doi.org/10.1101/2022.09.23.22280264 https://www.medrxiv.org/content/10.1101/2022.09.23.22280264v1.full-text (Full text)

Targeting endothelial dysfunction and oxidative stress in Long-COVID

Comment:

We thank Dr. Hsu and Dr. Lai for their interest in our work on COVID-19 and Long-COVID.

We fully agree with them on the fact that several factors need to be pondered in order to evaluate the risk of developing Long-COVID , . However, we respectfully believe that these considerations are not pertinent to our study . Indeed, we designed the LINCOLN (l-Arginine and Vitamin C improves Long-COVID) survey to determine whether a supplementation combining l-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects in patients with Long-COVID . Thus, in our study we did not assess the risk of developing Long-COVID; in fact, as clearly specified in our article, all the enrolled patients had Long-COVID when the survey was administered. Nevertheless, potential differences in health conditions between the group that had received l-Arginine + Vitamin C and the group that had received the alternative treatment were ruled out by their family physicians. When comparing the two groups, we did not observe any significant difference in terms of age, sex, hospitalization due to COVID-19, and time from SARS-Cov-2 negativization. Moreover, bearing in mind the limitations that all surveys have, we had concluded our article stating that further dedicated interventional studies were warranted to endorse our findings.

Of note, we have previously conducted a randomized, double-blind, placebo-controlled, parallel-group, clinical trial testing the effects of l-Arginine oral supplementation in patients hospitalized for COVID-19, demonstrating that this treatment significantly decreases the length of hospitalization and reduces the respiratory support . Additionally, we have identified endothelial exosomes enriched in miR-24 as a reliable biomarker to predict cerebrovascular complications of COVID-19 , corroborating the fundamental role of endothelial dysfunction in the pathobiology of COVID-19 and its clinical sequelae .

Source: Trimarco V, Izzo R, Mone P, Trimarco B, Santulli G. Targeting endothelial dysfunction and oxidative stress in Long-COVID. Pharmacol Res. 2022 Sep 13;184:106451. doi: 10.1016/j.phrs.2022.106451. Epub ahead of print. PMID: 36108875; PMCID: PMC9467917. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467917/ (Full text)

Distinguishing features of Long COVID identified through immune profiling

Abstract:

SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID.

Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus.

Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.

Source: Jon Klein, Jamie Wood, Jillian Jaycox, Peiwen Lu, Rahul M. Dhodapkar, Jeffrey R. Gehlhausen, Alexandra Tabachnikova, Laura Tabacof, Amyn A. Malik, Kathy Kamath, Kerrie Greene, Valter Silva Monteiro, Mario Pena-Hernandez, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Julio Silva, Dayna Mccarthy, Erica Breyman, Jenna Tosto-Mancuso, Yile Dai, Emily Perotti, Koray Akduman, Tiffany Tzeng, Lan Xu, Inci Yildirim, Harlan M. Krumholz, John Shon, Ruslan Medzhitov, Saad B. Omer, David van Dijk, Aaron M. Ring, David Putrino, Akiko Iwasaki. Distinguishing features of Long COVID identified through immune profiling. medRxiv 2022.08.09.22278592; doi: https://doi.org/10.1101/2022.08.09.22278592

Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae

Abstract:

The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. Identifying biomarkers associated with PASC would immensely improve the classification of PASC patients and provide the means to evaluate treatment strategies. We analyzed plasma samples collected from a cohort of PASC and COVID-19 patients (n = 63) to quantify circulating viral antigens and inflammatory markers. Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir. Furthermore, temporal antigen profiles for many patients show the presence of spike at multiple time points over several months, highlighting the potential utility of the SARS-CoV-2 full spike protein as a biomarker for PASC

Source: Zoe Swank, Yasmeen Senussi, Galit Alter, David R. Walt. Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae. medRxiv 2022.06.14.22276401; doi: https://doi.org/10.1101/2022.06.14.22276401 https://www.medrxiv.org/content/10.1101/2022.06.14.22276401v1 (Full text available as PDF file)

Autoantibodies against apolipoprotein A-1 after COVID-19 predict symptoms persistence

Abstract:

Background: SARS-CoV-2 infection triggers different auto-antibodies, including anti-apolipoprotein A-1 IgGs (AAA1), which could be of concern as mediators of persistent symptoms. We determined the kinetics of AAA1 response over after COVID-19, and the impact of AAA1 on the inflammatory response and symptoms persistence.

Methods: All serologies were assessed at one, three, six, and twelve months in 193 hospital employees with COVID-19. ROC curve analyses and logistic regression models (LRM) were used to determine the prognostic accuracy of AAA1 and their association with patient-reported COVID-19 symptoms persistence at 12 months. Interferon (IFN)-α and-γ production by AAA1-stimulated human monocyte-derived macrophages (HMDM) was assessed in vitro.

Results: AAA1 seropositivity was 93% at one month and declined to 15% at 12 months after COVID-19. Persistent symptoms at 12 months were observed in 45.1% of participants, with a predominance of neurological (28.5%), followed by general (15%) and respiratory symptoms (9.3%). Over time, strength of correlations between AAA1 and anti-SARS-COV2 serologies decreased, but remained significant. From the 3rd month on, AAA1 levels predicted persistent respiratory symptoms (area under the curves 0.72-0.74; p<0.001), independently of disease severity, age and gender (adjusted odds ratios 4.81-4.94; p=0.02), while anti-SARS-CoV-2 serologies did not. AAA1 increased IFN-α production by HMDMs (p=0.03), without affecting the IFN-γ response.

Conclusion: COVID-19 induces a marked though transient AAA1 response, independently predicting one-year persistence of respiratory symptoms. By increasing IFN-α response, AAA1 may contribute to persistent symptoms. If and how AAA1 levels assessment could be of use for COVID-19 risk stratification remains to be determined

Source: L’Huillier AG, Pagano S, Baggio S, Meyer B, Andrey DO, Nehme M, Guessous I, Eberhardt CS, Huttner A, Posfay-Barbe KM, Yerly S, Siegrist CA, Kaiser L, Vuilleumier N. Autoantibodies against apolipoprotein A-1 after COVID-19 predict symptoms persistence. Eur J Clin Invest. 2022 May 22:e13818. doi: 10.1111/eci.13818. Epub ahead of print. PMID: 35598178.  https://pubmed.ncbi.nlm.nih.gov/35598178/ (Full text available as PDF file)

Serum NGF and BDNF in Long-COVID-19 Adolescents: A Pilot Study

Abstract:

COVID-19 (COronaVIrus Disease 19) is an infectious disease also known as an acute respiratory syndrome caused by the SARS-CoV-2. Although in children and adolescents SARS-CoV-2 infection produces mostly mild or moderate symptoms, in a certain percentage of recovered young people a condition of malaise, defined as long-COVID-19, remains. To date, the risk factors for the development of long-COVID-19 are not completely elucidated. Neurotrophins such as NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) are known to regulate not only neuronal growth, survival and plasticity, but also to influence cardiovascular, immune, and endocrine systems in physiological and/or pathological conditions; to date only a few papers have discussed their potential role in COVID-19.

In the present pilot study, we aimed to identify NGF and BDNF changes in the serum of a small cohort of male and female adolescents that contracted the infection during the second wave of the pandemic (between September and October 2020), notably in the absence of available vaccines. Blood withdrawal was carried out when the recruited adolescents tested negative for the SARS-CoV-2 (“post-infected COVID-19”), 30 to 35 days after the last molecular test. According to their COVID-19 related outcomes, the recruited individuals were divided into three groups: asymptomatics, acute symptomatics and symptomatics that over time developed long-COVID-19 symptoms (“future long-COVID-19”). As a control group, we analyzed the serum of age-matched healthy controls that did not contract the infection. Inflammatory biomarkers (TNF-α, TGF-β), MCP-1, IL-1α, IL-2, IL-6, IL-10, IL-12) were also analyzed with the free oxygen radicals’ presence as an oxidative stress index.

We showed that NGF serum content was lower in post-infected-COVID-19 individuals when compared to healthy controls; BDNF levels were found to be higher compared to healthy individuals only in post-infected-COVID-19 symptomatic and future long-COVID-19 girls, leaving the BDNF levels unchanged in asymptomatic individuals if compared to controls. Oxidative stress and inflammatory biomarkers were unchanged in male and female adolescents, except for TGF-β that, similarly to BDNF, was higher in post-infected-COVID-19 symptomatic and future long-COVID-19 girls. We predicted that NGF and/or BDNF could be used as early biomarkers of COVID-19 morbidity in adolescents.

Source: Petrella C, Nenna R, Petrarca L, Tarani F, Paparella R, Mancino E, Di Mattia G, Conti MG, Matera L, Bonci E, Ceci FM, Ferraguti G, Gabanella F, Barbato C, Di Certo MG, Cavalcanti L, Minni A, Midulla F, Tarani L, Fiore M. Serum NGF and BDNF in Long-COVID-19 Adolescents: A Pilot Study. Diagnostics (Basel). 2022 May 7;12(5):1162. doi: 10.3390/diagnostics12051162. PMID: 35626317. https://www.mdpi.com/2075-4418/12/5/1162/htm (Full text)