Tag: long covid biomarker

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

Abstract:

Introduction: Persistent symptoms after COVID-19 infection (“long COVID”) negatively affects almost half of COVID-19 survivors. Despite its prevalence, its pathophysiology is poorly understood, with multiple host systems likely affected. Here, we followed patients from hospital to discharge and used a systems-biology approach to identify mechanisms of long COVID.

Methods: RNA-seq was performed on whole blood collected early in hospital and 4-12 weeks after discharge from 24 adult COVID-19 patients (10 reported post-COVID symptoms after discharge). Differential gene expression analysis, pathway enrichment, and machine learning methods were used to identify underlying mechanisms for post-COVID symptom development.

Results: Compared to patients with post-COVID symptoms, patients without post-COVID symptoms had larger temporal gene expression changes associated with downregulation of inflammatory and coagulation genes over time. Patients could also be separated into three patient endotypes with differing mechanistic trajectories, which was validated in another published patient cohort. The “Resolved” endotype (lowest rate of post-COVID symptoms) had robust inflammatory and hemostatic responses in hospital that resolved after discharge. Conversely, the inflammatory/hemostatic responses of “Suppressive” and “Unresolved” endotypes (higher rates of patients with post-COVID symptoms) were persistently dampened and activated, respectively. These endotypes were accurately defined by specific blood gene expression signatures (6-7 genes) for potential clinical stratification.

Discussion: This study allowed analysis of long COVID whole blood transcriptomics trajectories while accounting for the issue of patient heterogeneity. Two of the three identified and externally validated endotypes (“Unresolved” and “Suppressive”) were associated with higher rates of post-COVID symptoms and either persistently activated or suppressed inflammation and coagulation processes. Gene biomarkers in blood could potentially be used clinically to stratify patients into different endotypes, paving the way for personalized long COVID treatment.

Source: An AY, Baghela A, Zhang PGY, Blimkie TM, Gauthier J, Kaufmann DE, Acton E, Lee AHY, Levesque RC, Hancock REW. Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation. Front Immunol. 2023 Aug 23;14:1243689. doi: 10.3389/fimmu.2023.1243689. PMID: 37680625; PMCID: PMC10482103. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10482103/ (Full text)

Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization

Abstract:

Post-COVID cognitive deficits, including ‘brain fog’, are clinically complex, with both objective and subjective components. They are common and debilitating, and can affect the ability to work, yet their biological underpinnings remain unknown.

In this prospective cohort study of 1,837 adults hospitalized with COVID-19, we identified two distinct biomarker profiles measured during the acute admission, which predict cognitive outcomes 6 and 12 months after COVID-19.

A first profile links elevated fibrinogen relative to C-reactive protein with both objective and subjective cognitive deficits. A second profile links elevated D-dimer relative to C-reactive protein with subjective cognitive deficits and occupational impact. This second profile was mediated by fatigue and shortness of breath. Neither profile was significantly mediated by depression or anxiety.

Results were robust across secondary analyses. They were replicated, and their specificity to COVID-19 tested, in a large-scale electronic health records dataset. These findings provide insights into the heterogeneous biology of post-COVID cognitive deficits.

Source: Taquet, M., Skorniewska, Z., Hampshire, A. et al. Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization. Nat Med (2023). https://doi.org/10.1038/s41591-023-02525-y https://www.nature.com/articles/s41591-023-02525-y (Full text)

Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID

Abstract:

While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important.

Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types.

Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.

Source: Woodruff MC, Bonham KS, Anam FA, Walker TA, Faliti CE, Ishii Y, Kaminski CY, Ruunstrom MC, Cooper KR, Truong AD, Dixit AN, Han JE, Ramonell RP, Haddad NS, Rudolph ME, Yalavarthi S, Betin V, Natoli T, Navaz S, Jenks SA, Zuo Y, Knight JS, Khosroshahi A, Lee FE, Sanz I. Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID. Nat Commun. 2023 Jul 14;14(1):4201. doi: 10.1038/s41467-023-40012-7. PMID: 37452024; PMCID: PMC10349085. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349085/ (Full text)

A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms

Abstract:

Approximately 30% of COVID-19 cases may experience chronic symptoms, known as post-COVID-19 syndrome (PCS). Common PCS symptoms can include fatigue, cognitive impairment, and persistent physical, neurological, and neuropsychiatric complaints.

To improve healthcare and management of the current and future pandemics, we highlight the need for establishing interdisciplinary post-viral outpatient clinics comprised of specialists in fields such as psychiatry, psychotherapy, neurology, cardiology, pneumology, and immunology. In this way, PCS patients with a high health burden can receive modern diagnostics and targeted therapeutic recommendations. A key objective is to distinguish the “sick recovered” from the “healthy recovered.”

Our hypothesis is that there is a PCS subgroup with autoimmune-mediated systemic and brain-vascular dysregulation, which may lead to circulatory disorders, fatigue, cognitive impairment, depression, and anxiety. This can be clarified using a combination of specific antibody diagnostics and precise clinical, psychological, and apparative testing.

Source: Guest PC, Neyazi A, Braun-Dullaeus RC, Müller P, Schreiber J, Haghikia A, Vasilevska V, Steiner J. A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms. Adv Exp Med Biol. 2023;1412:97-115. doi: 10.1007/978-3-031-28012-2_5. PMID: 37378763. https://pubmed.ncbi.nlm.nih.gov/37378763/

Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy

Background: The negative impact of long COVID on social life and human health is increasingly prominent, and the elevated risk of cardiovascular disease in patients recovering from COVID-19 has also been fully confirmed. However, the pathogenesis of long COVID-related inflammatory cardiomyopathy is still unclear. Here, we explore potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy.

Methods: Datasets that met the study requirements were identified in Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) were obtained by the algorithm. Then, functional enrichment analysis was performed to explore the basic molecular mechanisms and biological processes associated with DEGs. A protein–protein interaction (PPI) network was constructed and analyzed to identify hub genes among the common DEGs. Finally, a third dataset was introduced for validation.

Results: Ultimately, 3,098 upregulated DEGs and 1965 downregulated DEGs were extracted from the inflammatory cardiomyopathy dataset. A total of 89 upregulated DEGs and 217 downregulated DEGs were extracted from the dataset of convalescent COVID patients. Enrichment analysis and construction of the PPI network confirmed VEGFA, FOXO1, CXCR4, and SMAD4 as upregulated hub genes and KRAS and TXN as downregulated hub genes. The separate dataset of patients with COVID-19 infection used for verification led to speculation that long COVID-associated inflammatory cardiomyopathy is mainly attributable to the immune-mediated response and inflammation rather than to direct infection of cells by the virus.

Conclusion: Screening of potential biomarkers and therapeutic targets sheds new light on the pathogenesis of long COVID-associated inflammatory cardiomyopathy as well as potential therapeutic approaches. Further clinical studies are needed to explore these possibilities in light of the increasingly severe negative impacts of long COVID.

Source: Peng Qi, Mengjie Huang and Haiyan Zhu. Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy. Front. Med., 29 June 2023. Sec. Infectious Diseases: Pathogenesis and Therapy. Volume 10 – 2023 | https://doi.org/10.3389/fmed.2023.1191354 https://www.frontiersin.org/articles/10.3389/fmed.2023.1191354/full (Full text)

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID

Abstract:

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.

In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3–10 months after remission of acute infection.

We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome.

Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19).

In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.

Source: Al-Hakeim HK, Khairi Abed A, Rouf Moustafa S, Almulla AF, Maes M. Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID. Front Mol Neurosci. 2023 Jun 2;16:1194769. doi: 10.3389/fnmol.2023.1194769. PMID: 37333619; PMCID: PMC10272345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272345/ (Full text)

Increasing serum soluble CD40 ligand (sCD40L) may be a biomarker of ME/CFS and chronic Long COVID progression

Abstract:

To date, no single blood lab test exists to diagnose or track ME/CFS or chronic Long COVID. Based on existing literature, this article brings together evidence that a molecule secreted by the immune system called sCD40L tends to become increasingly elevated in ME/CFS, Long COVID, and Multiple Sclerosis.

These studies, along with what’s known about the role of sCD40L in health and other diseases, suggest sCD40L may be useful to track over time in ME/CFS and Long COVID patients.

Source: Vijay Iyer. Increasing serum soluble CD40 ligand (sCD40L) may be a biomarker of ME/CFS and chronic Long COVID progression. Patient-Generated Hypotheses Journal | Issue 1, May 2023. https://patientresearchcovid19.com/storage/2023/05/Patient-Generated-Hypotheses-Issue-1-May-2023.pdf#page=42 (Full text)

The plasma metabolome of long COVID-19 patients two years after infection

Abstract:

Background One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. The World Health Organization (WHO) recognized long COVID as a distinct clinical entity in 2021. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. This has put a tremendous strain on still-overstretched healthcare systems around the world.

Methods In this study, our goal was to assess the plasma metabolome in a total of 108 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC-MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin concentrations were measured in long COVID patients by immunoenzymatic assay.

Results The comparison of paired COVID-19/post-COVID-19 samples revealed 53 metabolites that were statistically different (FDR < 0.05). Compared to controls, 29 metabolites remained dysregulated even after two years. Notably, glucose, kynurenine, and certain acylcarnitines continued to exhibit altered concentrations similar to the COVID-19 phase, while sphingomyelins and long saturated and monounsaturated LysoPCs, phenylalanine, butyric acid, and propionic acid levels normalized. Post-COVID-19 patients displayed a heterogeneous metabolic profile, with some showing no symptoms while others exhibiting a variable number of symptoms. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, sarcosine, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients.

Conclusions Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.

Source: Yamilé López-Hernández, Joel Monárrez Aquino, David Alejandro García López, Jiamin Zheng, Juan Carlos Borrego, Claudia Torres-Calzada, José Pedro Elizalde-Díaz, Rupasri Mandal, Mark Berjanskii, Eduardo Martínez-Martínez, Jesús Adrián López, David S. Wishart. The plasma metabolome of long COVID-19 patients two years after infection. doi: https://doi.org/10.1101/2023.05.03.23289456 (Full text)

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Abstract:

Background: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.

Methods: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n=41, matched out of n = 204).

Measurements and main results: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vmax; 3.42% ± 1.77% vs. 4.64 % ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5 – 190.2] vs. 189.1 [179.4 – 197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8 – 0.9] vs. 0.88 [0.8 – 0.9], p = 0.007). When combining AVR and vmax, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R= -0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.

Conclusion: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.

Source: Timon Kuchler, Roman Günthner, Andrea Ribeiro et al. Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation, 22 May 2023, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2952588/v1 (Full text)

Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges

Abstract:

Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction.

There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner.

Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.

Source: Tsilingiris, D.; Vallianou, N.G.; Karampela, I.; Christodoulatos, G.S.; Papavasileiou, G.; Petropoulou, D.; Magkos, F.; Dalamaga, M. Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights Into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges. Preprints.org 2023, 2023051487. https://doi.org/10.20944/preprints202305.1487.v1 (Full text available as PDF file)