Tag: long covid biomarker

Cellular and molecular biomarkers of long COVID: a scoping review

Abstract:

Background: Long-COVID (LC) encompasses diverse symptoms lasting months after the initial SARS-CoV-2 infection. Symptoms can be debilitating and affect the quality of life of individuals with LC and their families. Although the symptoms of LC are well described, the aetiology of LC remains unclear, and consequently, patients may be underdiagnosed. Identification of LC specific biomarkers is therefore paramount for the diagnosis and clinical management of the syndrome. This scoping review describes the molecular and cellular biomarkers that have been identified to date with potential use for diagnosis or prediction of LC.

Methods: This review was conducted using the Joanna Briggs Institute (JBI) Methodology for Scoping Reviews. A search was executed in the MEDLINE and EMBASE databases, as well as in the grey literature for original studies, published until October 5th, 2022, reporting biomarkers identified in participants with LC symptoms (from all ages, ethnicities, and sex), with a previous infection of SARS-CoV-2. Non-English studies, cross-sectional studies, studies without a control group, and pre-prints were excluded. Two reviewers independently evaluated the studies, extracted population data and associated biomarkers.

Findings: 23 cohort studies were identified, involving 2163 LC patients [median age 51.8 years, predominantly female sex (61.10%), white (75%), and non-vaccinated (99%)]. A total of 239 candidate biomarkers were identified, consisting mainly of immune cells, immunoglobulins, cytokines, and other plasma proteins. 19 of the 239 candidate biomarkers identified were evaluated by the authors, by means of receiver operating characteristic (ROC) curves.

Interpretation: Diverse cellular and molecular biomarkers for LC have been proposed. Validation of candidate biomarkers in independent samples should be prioritized. Modest reported performance (particularly in larger studies) suggests LC may encompass many distinct aetiologies, which should be explored e.g., by stratifying by symptom clusters and/or sex.

Source: Espín E, Yang C, Shannon CP, Assadian S, He D, Tebbutt SJ. Cellular and molecular biomarkers of long COVID: a scoping review. EBioMedicine. 2023 Apr 8;91:104552. doi: 10.1016/j.ebiom.2023.104552. Epub ahead of print. PMID: 37037165; PMCID: PMC10082390. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082390/ (Full text)

High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients

Abstract:

Background: Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19.

Methods: In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis.

Results: A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)–categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation.

Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1β, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1β and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1β, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals.

Conclusion: We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.

Source: Gomes SMR, Brito ACdS, Manfro WFP, Ribeiro-Alves M, Ribeiro RSdA, da Cal MS, et al. (2023) High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients. PLoS ONE 18(4): e0283983. https://doi.org/10.1371/journal.pone.0283983 (Full text)

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Abstract:

Background: Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID.

Methods: A case-control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase.

Results: Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P < 0.01). Protein combinations were narrowed down to two optimal models, with nine and five proteins each, and with both having excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, F1 = 1.00). NLP expression analysis highlighted the diffuse organ system involvement in Long-COVID, as well as the involved cell types, including leukocytes and platelets, as key components associated with Long-COVID.

Conclusions: Proteomic analysis of plasma from Long-COVID patients identified 119 highly relevant proteins and two optimal models with nine and five proteins, respectively. The identified proteins reflected widespread organ and cell type expression. Optimal protein models, as well as individual proteins, hold the potential for accurate diagnosis of Long-COVID and targeted therapeutics.

Source: Patel MA, Knauer MJ, Nicholson M, Daley M, Van Nynatten LR, Cepinskas G, Fraser DD. Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning. Mol Med. 2023 Feb 21;29(1):26. doi: 10.1186/s10020-023-00610-z. PMID: 36809921; PMCID: PMC9942653. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942653/ (Full text)

Biomarkers in long COVID-19: A systematic review

Abstract:

Purpose: Long COVID, also known as post-acute sequelae of COVID-19, refers to the constellation of long-term symptoms experienced by people suffering persistent symptoms for one or more months after SARS-CoV-2 infection. Blood biomarkers can be altered in long COVID patients; however, biomarkers associated with long COVID symptoms and their roles in disease progression remain undetermined. This study aims to systematically evaluate blood biomarkers that may act as indicators or therapeutic targets for long COVID.

Methods: A systematic literature review in PubMed, Embase, and CINAHL was performed on 18 August 2022. The search keywords long COVID-19 symptoms and biomarkers were used to filter out the eligible studies, which were then carefully evaluated.

Results: Identified from 28 studies and representing six biological classifications, 113 biomarkers were significantly associated with long COVID: (1) Cytokine/Chemokine (38, 33.6%); (2) Biochemical markers (24, 21.2%); (3) Vascular markers (20, 17.7%); (4) Neurological markers (6, 5.3%); (5) Acute phase protein (5, 4.4%); and (6) Others (20, 17.7%). Compared with healthy control or recovered patients without long COVID symptoms, 79 biomarkers were increased, 29 were decreased, and 5 required further determination in the long COVID patients. Of these, up-regulated Interleukin 6, C-reactive protein, and tumor necrosis factor alpha might serve as the potential diagnostic biomarkers for long COVID. Moreover, long COVID patients with neurological symptoms exhibited higher levels of neurofilament light chain and glial fibrillary acidic protein whereas those with pulmonary symptoms exhibited a higher level of transforming growth factor beta.

Conclusion: Long COVID patients present elevated inflammatory biomarkers after initial infection. Our study found significant associations between specific biomarkers and long COVID symptoms. Further investigations are warranted to identify a core set of blood biomarkers that can be used to diagnose and manage long COVID patients in clinical practice.

Source: Lai YJ, Liu SH, Manachevakul S, Lee TA, Kuo CT, Bello D. Biomarkers in long COVID-19: A systematic review. Front Med (Lausanne). 2023 Jan 20;10:1085988. doi: 10.3389/fmed.2023.1085988. PMID: 36744129; PMCID: PMC9895110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9895110/ (Full text)

Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers

Abstract:

Severe acute respiratory syndrome coronavirus 2 may inflict a post-viral condition known as post-COVID-19 syndrome (PCS) or long-COVID. Studies measuring levels of inflammatory and vascular biomarkers in blood, serum, or plasma of COVID-19 survivors with PCS versus non-PCS controls have produced mixed findings. Our review sought to meta-analyse those studies. A systematic literature search was performed across five databases until 25 June 2022, with an updated search on 1 November 2022.

Data analyses were performed with Review Manager and R Studio statistical software. Twenty-four biomarkers from 23 studies were meta-analysed. Higher levels of C-reactive protein (Standardized mean difference (SMD) = 0.20; 95% CI: 0.02-0.39), D-dimer (SMD = 0.27; 95% CI: 0.09-0.46), lactate dehydrogenase (SMD = 0.30; 95% CI: 0.05-0.54), and leukocytes (SMD = 0.34; 95% CI: 0.02-0.66) were found in COVID-19 survivors with PCS than in those without PCS. After sensitivity analyses, lymphocytes (SMD = 0.30; 95% CI: 0.12-0.48) and interleukin-6 (SMD = 0.30; 95% CI: 0.12-0.49) were also significantly higher in PCS than non-PCS cases. No significant differences were noted in the remaining biomarkers investigated (e.g., ferritin, platelets, troponin, and fibrinogen). Subgroup analyses suggested the biomarker changes were mainly driven by PCS cases diagnosed via manifestation of organ abnormalities rather than symptomatic persistence, as well as PCS cases with duration of <6 than ≥6 months.

In conclusion, our review pinpointed certain inflammatory and vascular biomarkers associated with PCS, which may shed light on potential new approaches to understanding, diagnosing, and treating PCS.

Source: Yong SJ, Halim A, Halim M, Liu S, Aljeldah M, Al Shammari BR, Alwarthan S, Alhajri M, Alawfi A, Alshengeti A, Khamis F, Alsalman J, Alshukairi AN, Abukhamis NA, Almaghrabi FS, Almuthree SA, Alsulaiman AM, Alshehail BM, Alfaraj AH, Alhawaj SA, Mohapatra RK, Rabaan AA. Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers. Rev Med Virol. 2023 Jan 27:e2424. doi: 10.1002/rmv.2424. Epub ahead of print. PMID: 36708022. https://pubmed.ncbi.nlm.nih.gov/36708022/ 

T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID

Abstract:

Many people experiencing long COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), suffer from debilitating neurologic symptoms (Neuro-PASC). However, whether virus-specific adaptive immunity is affected in Neuro-PASC patients remains poorly understood. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated humoral and cellular responses toward SARS-CoV-2 Nucleocapsid protein at an average of 6 months post-infection compared to healthy COVID convalescents. Neuro-PASC patients also had enhanced virus-specific production of IL-6 from and diminished activation of CD8+ T cells.

Furthermore, the severity of cognitive deficits or quality of life disturbances in Neuro-PASC patients were associated with a reduced diversity of effector molecule expression in T cells but elevated IFN-γ production to the C-terminal domain of Nucleocapsid protein. Proteomics analysis showed enhanced plasma immunoregulatory proteins and reduced pro-inflammatory and antiviral response proteins in Neuro-PASC patients compared with healthy COVID convalescents, which were also correlated with worse neurocognitive dysfunction. These data provide new insight into the pathogenesis of long COVID syndrome and a framework for the rational design of predictive biomarkers and therapeutic interventions.

One Sentence Summary Adaptive immunity is altered in patients with neurologic manifestations of long COVID.

Source: Lavanya Visvabharathy, Barbara A. Hanson, Zachary S. Orban, Patrick H. Lim, Nicole M. Palacio, Millenia Jimenez, Jeffrey R. Clark, Edith L. Graham, Eric M. Liotta, George Tachas, Pablo Penaloza-MacMaster, Igor J. Koralnik. T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID. medRxiv 2021.08.08.21261763; doi: https://doi.org/10.1101/2021.08.08.21261763 https://www.medrxiv.org/content/10.1101/2021.08.08.21261763v4.full-text (Full text)

Pharmacological Mechanism of NRICM101 for COVID-19 Treatments by Combined Network Pharmacology and Pharmacodynamics

Abstract:

Symptom treatments for Coronavirus disease 2019 (COVID-19) infection and Long COVID are one of the most critical issues of the pandemic era. In light of the lack of standardized medications for treating COVID-19 symptoms, traditional Chinese medicine (TCM) has emerged as a potentially viable strategy based on numerous studies and clinical manifestations. Taiwan Chingguan Yihau (NRICM101), a TCM designed based on a medicinal formula with a long history of almost 500 years, has demonstrated its antiviral properties through clinical studies, yet the pharmacogenomic knowledge for this formula remains unclear. The molecular mechanism of NRICM101 was systematically analyzed by using exploratory bioinformatics and pharmacodynamics (PD) approaches.

Results showed that there were 434 common interactions found between NRICM101 and COVID-19 related genes/proteins. For the network pharmacology of the NRICM101, the 434 common interacting genes/proteins had the highest associations with the interleukin (IL)-17 signaling pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Moreover, the tumor necrosis factor (TNF) was found to have the highest association with the 30 most frequently curated NRICM101 chemicals.

Disease analyses also revealed that the most relevant diseases with COVID-19 infections were pathology, followed by cancer, digestive system disease, and cardiovascular disease. The 30 most frequently curated human genes and 2 microRNAs identified in this study could also be used as molecular biomarkers or therapeutic options for COVID-19 treatments.

In addition, dose-response profiles of NRICM101 doses and IL-6 or TNF-α expressions in cell cultures of murine alveolar macrophages were constructed to provide pharmacodynamic (PD) information of NRICM101. The prevalent use of NRICM101 for standardized treatments to attenuate common residual syndromes or chronic sequelae of COVID-19 were also revealed for post-pandemic future.

Source: Singh S, Yang YF. Pharmacological Mechanism of NRICM101 for COVID-19 Treatments by Combined Network Pharmacology and Pharmacodynamics. Int J Mol Sci. 2022 Dec 6;23(23):15385. doi: 10.3390/ijms232315385. PMID: 36499711; PMCID: PMC9740625. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740625/ (Full text)

Recommendations for Successful Implementation of the Use of Vocal Biomarkers for Remote Monitoring of COVID-19 and Long COVID in Clinical Practice and Research

Abstract:

The COVID-19 pandemic accelerated the use of remote patient monitoring in clinical practice or research for safety and emergency reasons, justifying the need for innovative digital health solutions to monitor key parameters or symptoms related to COVID-19 or Long COVID. The use of voice-based technologies, and in particular vocal biomarkers, is a promising approach, voice being a rich, easy-to-collect medium with numerous potential applications for health care, from diagnosis to monitoring.

In this viewpoint, we provide an overview of the potential benefits and limitations of using voice to monitor COVID-19, Long COVID, and related symptoms. We then describe an optimal pipeline to bring a vocal biomarker candidate from research to clinical practice and discuss recommendations to achieve such a clinical implementation successfully.

Source: Fischer A, Elbeji A, Aguayo G, Fagherazzi G. Recommendations for Successful Implementation of the Use of Vocal Biomarkers for Remote Monitoring of COVID-19 and Long COVID in Clinical Practice and Research. Interact J Med Res. 2022 Nov 15;11(2):e40655. doi: 10.2196/40655. PMID: 36378504; PMCID: PMC9668331. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9668331/ (Full text)

HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms

Abstract:

Due to the wide scope and persistence of COVID-19´s pandemic, post-COVID-19 condition represents a post-viral syndrome of unprecedented dimensions. SARS-CoV-2, in line with other infectious agents, has the capacity to activate dormant human endogenous retroviral sequences ancestrally integrated in human genomes (HERVs). This activation was shown to relate to aggravated COVID-19 patient´s symptom severity.

Despite our limited understanding of how HERVs are turned off upon infection clearance, or how HERVs mediate long-term effects when their transcription remains aberrantly on, the participation of these elements in neurologic disease, such as multiple sclerosis, is already settling the basis for effective therapeutic solutions. These observations support an urgent need to identify the mechanisms that lead to HERV expression with SARS-CoV-2 infection, on the one hand, and to answer whether persistent HERV expression exists in post-COVID-19 condition, on the other.

The present study shows, for the first time, that the HERV-W ENV protein can still be actively expressed long after SARS-CoV-2 infection is resolved in post-COVID-19 condition patients. Moreover, increased anti-SARS-CoV-2 immunoglobulins in post-COVID-19 condition, particularly high anti-SARS-CoV-2 immunoglobulin levels of the E isotype (IgE), seem to strongly correlate with deteriorated patient physical function (r=-0.8057, p<0.01).

These results indicate that HERV-W ENV antigenemia and anti-SARS-CoV-2 IgE serology should be further studied to better characterize post-COVID-19 condition pathogenic drivers potentially differing in subsets of patients with various symptoms. They also point out that such biomarkers may serve to design therapeutic options for precision medicine in post-COVID-19 condition.

Source: Giménez-Orenga K, Pierquin J, Brunel J, Charvet B, Martín-Martínez E, Perron H, Oltra E. HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms. Front Immunol. 2022 Oct 27;13:1020064. doi: 10.3389/fimmu.2022.1020064. PMID: 36389746; PMCID: PMC9647063.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647063/ (Full text)

Serological biomarkers of COVID-19 severity at hospital admission are not related to long-term post-COVID pain symptoms in hospitalized COVID-19 survivors

Abstract:

This study investigated the association between serological biomarkers at hospital admission with the development of long-term post-COVID pain symptoms in previously hospitalized coronavirus disease, 2019 (COVID-19) survivors. A cohort study including patients hospitalised because of COVID-19 in 1 urban hospital of Madrid (Spain) during the first wave of the outbreak was conducted. Hospitalisation data, clinical data, and 11 serological biomarkers were collected at hospital admission. Participants were scheduled for an individual telephone interview after hospital discharge for collecting data about post-COVID pain symptoms.

A total of 412 patients (mean age: 62, SD: 15 years; 46.1% women) were assessed twice, at a mean of 6.8 and 13.2 months after discharge. The prevalence of post-COVID pain symptoms was 42.7% (n = 176) and 36.2% (n = 149) at 6.8 and 13.2 months after hospital discharge. Patients reporting post-COVID pain exhibited a greater number of COVID-19-associated symptoms at hospital admission, more medical comorbidities, higher lymphocyte count, and lower glucose and creatine kinase levels (all, P < 0.01) than those not reporting post-COVID pain. The multivariate analysis revealed that lower creatine kinase and glucose levels were significantly associated, but just explaining 6.9% of the variance of experiencing post-COVID pain.

In conclusion, the association between serological biomarkers associated with COVID-19 severity at hospital admission and the development of post-COVID pain is small. Other factors, eg, higher number of COVID-19 onset symptoms (higher symptom load) could be more relevant for the development of post-COVID pain. Because inflammatory biomarkers were not directly analyzed, they may have stronger predictive strengths for the development of post-COVID pain symptoms.

Source: Fernández-de-Las-Peñas C, Ryan-Murua P, de-la-Llave-Rincón AI, Gómez-Mayordomo V, Arendt-Nielsen L, Torres-Macho J. Serological biomarkers of COVID-19 severity at hospital admission are not related to long-term post-COVID pain symptoms in hospitalized COVID-19 survivors. Pain. 2022 Nov 1;163(11):2112-2117. doi: 10.1097/j.pain.0000000000002608. Epub 2022 Feb 3. PMID: 35121694; PMCID: PMC9560903.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9560903/ (Full text)