Tag: acute covid

Predictive models of long COVID

Abstract:

Background: The cause and symptoms of long COVID are poorly understood. It is challenging to predict whether a given COVID-19 patient will develop long COVID in the future.

Methods: We used electronic health record (EHR) data from the National COVID Cohort Collaborative to predict the incidence of long COVID. We trained two machine learning (ML) models – logistic regression (LR) and random forest (RF). Features used to train predictors included symptoms and drugs ordered during acute infection, measures of COVID-19 treatment, pre-COVID comorbidities, and demographic information. We assigned the ‘long COVID’ label to patients diagnosed with the U09.9 ICD10-CM code. The cohorts included patients with (a) EHRs reported from data partners using U09.9 ICD10-CM code and (b) at least one EHR in each feature category. We analysed three cohorts: all patients (n = 2,190,579; diagnosed with long COVID = 17,036), inpatients (149,319; 3,295), and outpatients (2,041,260; 13,741).

Findings: LR and RF models yielded median AUROC of 0.76 and 0.75, respectively. Ablation study revealed that drugs had the highest influence on the prediction task. The SHAP method identified age, gender, cough, fatigue, albuterol, obesity, diabetes, and chronic lung disease as explanatory features. Models trained on data from one N3C partner and tested on data from the other partners had average AUROC of 0.75.

Interpretation: ML-based classification using EHR information from the acute infection period is effective in predicting long COVID. SHAP methods identified important features for prediction. Cross-site analysis demonstrated the generalizability of the proposed methodology.

Source: Antony B, Blau H, Casiraghi E, Loomba JJ, Callahan TJ, Laraway BJ, Wilkins KJ, Antonescu CC, Valentini G, Williams AE, Robinson PN, Reese JT, Murali TM; N3C consortium. Predictive models of long COVID. EBioMedicine. 2023 Oct;96:104777. doi: 10.1016/j.ebiom.2023.104777. Epub 2023 Sep 4. PMID: 37672869; PMCID: PMC10494314. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10494314/ (Full text)

Pulmonary embolism in patients in acute COVID-19, long-COVID and post-COVID syndrome

Abstract:

COVID-19 is a disease caused by the SARS-CoV-2 virus, which, after entering a living organism, uses the ACE-2 protein as a receptor and several other proteins as cofactors of infection. Disease symptomatology is extensive, involving mostly predominant respiratory symptoms, as well as those of the nervous, gastrointestinal, circulatory and other systems. Incidence of COVID-19 also results in markedly different laboratory findings on the hemostatic system with the predominant feature of increased D-dimer levels.

In the pathogenesis of thromboembolic complications in COVID-19, all elements of Virchow’s triad are involved: endothelial damage, coagulation disorders and blood flow disorders. Coagulopathy increases with the severity of the clinical course of COVID-19.

One of the causes of mortality associated with COVID-19 is pulmonary embolism. SARS-CoV-2 infection increases the risk of thromboembolic complications not only in the acute period of the disease. Also in the period of about a month after recovery, there is an increased risk of venous thrombosis and consequently, life-threatening pulmonary embolism.

The classic biomarker of pulmonary embolism in the general population is D-dimers. Among imaging studies, the gold standard for diagnosing this disease is computed tomography of the pulmonary arteries (CTPA). Other useful diagnostic tests are ventilation-perfusion lung scintigraphy (VQ Scans) or echocardiography. Currently reviewed guidelines and recommendations recommend extensive thromboprophylaxis in COVID-19 patients in both acute and chronic phases of the disease.

Source: Tomczyk P, Tomczyk D. Pulmonary embolism in patients in acute COVID-19, long-COVID and post-COVID syndrome. Przegl Epidemiol. 2023;77(2):172-184. doi: 10.32394/pe.77.17. PMID: 37846660. https://pubmed.ncbi.nlm.nih.gov/37846660/

Monocytes subpopulations pattern in the acute respiratory syndrome coronavirus 2 virus infection and after long COVID-19

Abstract:

Introduction and objective: The present study sought to characterize the pattern of monocyte subpopulations in patients during the course of the infections caused by SARS-CoV-2 virus or who presented long COVID-19 syndrome compared to monocytes from patients with zika virus (Zika) or chikungunya virus (CHIKV).

Casuistry: Study with 89 peripheral blood samples from patients, who underwent hemogram and serology (IgG and IgM) for detection of Zika (Control Group 1, n = 18) or CHIKV (Control Group 2, n = 9), and from patients who underwent hemogram and reverse transcription polymerase chain reaction for detection of SARS-CoV-2 at the acute phase of the disease (Group 3, n = 19); and of patients who presented long COVID-19 syndrome (Group 4, n = 43). The monocyte and subpopulations counts were performed by flow cytometry.

Results: No significant difference was observed in the total number of monocytes between the groups. The classical (CD14++CD16–) and intermediate (CD14+CD16+) monocytes counts were increased in patients with acute infection or with long COVID-19 syndrome. The monocytes subpopulations counts were lower in patients with infection Zika or CHIKV.

Conclusion: Increase in the monocyte subpopulations in patients with acute infection or with long COVID-19 syndrome may be an important finding of differentiated from the infection Zika or CHIKV.

Source: Pereira VIC, de Brito Junior LC, Falcão LFM, da Costa Vasconcelos PF, Quaresma JAS, Berg AVVD, Paixão APS, Ferreira RIS, Diks IBC. Monocytes subpopulations pattern in the acute respiratory syndrome coronavirus 2 virus infection and after long COVID-19. Int Immunopharmacol. 2023 Oct 5;124(Pt B):110994. doi: 10.1016/j.intimp.2023.110994. Epub ahead of print. PMID: 37804653. https://www.sciencedirect.com/science/article/abs/pii/S156757692301319X

Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome from Early Symptoms of COVID-19 Infection

Abstract:

It is still unclear why certain individuals after viral infections continue to have severe symptoms. We investigated if predicting myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) development after contracting COVID-19 is possible by analyzing symptoms from the first two weeks of COVID-19 infection.
Using participant responses to the 54-item DePaul Symptom Questionnaire, we built predictive models based on a random forest algorithm using the participants’ symptoms from the initial weeks of COVID-19 infection to predict if the participants would go on to meet the criteria for ME/CFS approximately 6 months later.
Early symptoms, particularly those assessing post-exertional malaise, did predict the development of ME/CFS, reaching an accuracy of 94.6%. We then investigated a minimal set of eight symptom features that could accurately predict ME/CFS. The feature reduced models reached an accuracy of 93.5%. Our findings indicated that several IOM diagnostic criteria for ME/CFS occurring during the initial weeks after COVID-19 infection predicted Long COVID and the diagnosis of ME/CFS after 6 months.
Source: Hua C, Schwabe J, Jason LA, Furst J, Raicu D. Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome from Early Symptoms of COVID-19 Infection. Psych. 2023; 5(4):1101-1108. https://doi.org/10.3390/psych5040073 https://www.mdpi.com/2624-8611/5/4/73

Understanding the neurological implications of acute and long COVID using brain organoids

Abstract:

As early as in the acute phase of the coronavirus disease 2019 (COVID-19) pandemic, the research community voiced concerns about the long-term implications of infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like many other viruses, can trigger chronic disorders that last months or even years.

Long COVID, the chronic and persistent disorder lasting more than 12 weeks after the primary infection with SARS-CoV-2, involves a variable number of neurological manifestations, ranging from mild to severe and even fatal. In vitro and in vivo modeling suggest that SARS-CoV-2 infection drives changes within neurons, glia and the brain vasculature.

In this Review, we summarize the current understanding of the neuropathology of acute and long COVID, with particular emphasis on the knowledge derived from brain organoid models. We highlight the advantages and main limitations of brain organoids, leveraging their human-derived origin, their similarity in cellular and tissue architecture to human tissues, and their potential to decipher the pathophysiology of long COVID.

Source: García-González L, Martí-Sarrias A, Puertas MC, Bayón-Gil Á, Resa-Infante P, Martinez-Picado J, Navarro A, Acosta S. Understanding the neurological implications of acute and long COVID using brain organoids. Dis Model Mech. 2023 Jul 1;16(7):dmm050049. doi: 10.1242/dmm.050049. Epub 2023 Jul 17. PMID: 37458167. https://journals.biologists.com/dmm/article/16/7/dmm050049/323961/Understanding-the-neurological-implications-of  (Full text)

Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases

Abstract:

Thromboembolic complications and excessive inflammation are frequent in severe COVID-19, potentially leading to long COVID. In non-COVID studies, we and others demonstrated that circulating Reelin promotes leukocyte infiltration and thrombosis. Thus, we hypothesized that Reelin participates in endothelial dysfunction and hyperinflammation during COVID-19.

We showed that Reelin was increased in COVID-19 patients and correlated with the disease activity. In the severe COVID-19 group, we observed a hyperinflammatory state, as judged by increased concentration of cytokines (IL-1α, IL-4, IL-6, IL-10 and IL-17A), chemokines (IP-10 and MIP-1β), and adhesion markers (E-selectin and ICAM-1).

Reelin level was correlated with IL-1α, IL-4, IP-10, MIP-1β, and ICAM-1, suggesting a specific role for Reelin in COVID-19 progression. Furthermore, Reelin and all of the inflammatory markers aforementioned returned to normal in a long COVID cohort, showing that the hyperinflammatory state was resolved. Finally, we tested Reelin inhibition with the anti-Reelin antibody CR-50 in hACE2 transgenic mice infected with SARS-CoV-2. CR-50 prophylactic treatment decreased mortality and disease severity in this model.

These results demonstrate a direct proinflammatory function for Reelin in COVID-19 and identify it as a drug target. This work opens translational clinical applications in severe SARS-CoV-2 infection and beyond in auto-inflammatory diseases.

Source: Calvier L, Drelich A, Hsu J, Tseng CT, Mina Y, Nath A, Kounnas MZ, Herz J. Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases. Front Immunol. 2023 Jun 27;14:1185748. doi: 10.3389/fimmu.2023.1185748. PMID: 37441066; PMCID: PMC10333573. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333573/ (Full text)

The association between the number of symptoms and the severity of Post-COVID-Fatigue after SARS-CoV-2 infection treated in an outpatient setting

Abstract:

Background: Post-COVID-Fatigue (PCF) is one of the most reported symptoms following SARS-CoV-2 infection. Currently, research on persistent symptoms focuses mainly on severe infections, while outpatients are rarely included in observations.

Objective: To investigate whether the severity of PCF is related to the number of acute and persistent symptoms due to mild-to-moderate COVID-19 and to compare the most common symptoms during acute infection with the persistent symptoms in PCF patients.

Methods: A total of 425 participants were examined after COVID-19 treated as an outpatient (median 249 days [IQR: 135; 322] after acute disease) at the site of University Hospital Augsburg, Germany. The Fatigue Assessment Scale (FAS) was used to quantify the severity of PCF. The number of symptoms (maximum 41) during acute infection and persistent symptoms (during the last 14 days before examination) were added up to sum scores. Multivariable linear regression models were used to show the association between the number of symptoms and PCF.

Results: Of the 425 participants, 37% (n = 157) developed PCF; most were women (70%). The median number of symptoms was significantly higher in the PCF group than in the non-PCF group at both time points. In multivariable linear regression models, both sum scores were associated with PCF (acute symptoms: β-estimate per additional symptom [95%-CI]: 0.48 [0.39; 0.57], p < 0.0001); persistent symptoms: β-estimate per additional symptom [95%-CI]: 1.18 [1.02; 1.34], p < 0.0001). The acute symptoms strongest associated with PCF severity were difficulty concentrating, memory problems, dyspnea or shortness of breath on exertion, palpitations, and problems with movement coordination.

Conclusion: Each additional symptom that occurs in COVID-19 increases the likelihood of suffering a higher severity of PCF. Further research is needed to identify the aetiology of PCF.

Source: Schmidbauer L, Kirchberger I, Goßlau Y, Warm TD, Hyhlik-Dürr A, Linseisen J, Meisinger C. The association between the number of symptoms and the severity of Post-COVID-Fatigue after SARS-CoV-2 infection treated in an outpatient setting. J Neurol. 2023 May 23:1–9. doi: 10.1007/s00415-023-11752-9. Epub ahead of print. PMID: 37219607; PMCID: PMC10204671. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204671/ (Full text)

Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues

Introduction: Pulmonary and extrapulmonary manifestations have been described after infection with SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). The virus is known to persist in multiple organs due to its tropism for several tissues. However, previous reports were unable to provide definitive information about whether the virus is viable and transmissible. It has been hypothesized that the persisting reservoirs of SARS-CoV-2 in tissues could be one of the multiple potentially overlapping causes of long COVID.

Methods: In the present study, we investigated autopsy materials obtained from 21 cadaveric donors with documented first infection or reinfection at the time of death. The cases studied included recipients of different formulations of COVID-19 vaccines. The aim was to find the presence of SARS-CoV-2 in the lungs, heart, liver, kidneys, and intestines. We used two technical approaches: the detection and quantification of viral genomic RNA using RT-qPCR, and virus infectivity using permissive in vitro Vero E6 culture.

Results: All tissues analyzed showed the presence of SARS-CoV-2 genomic RNA but at dissimilar levels ranging from 1.01 × 102 copies/mL to 1.14 × 108 copies/mL, even among those cases who had been COVID-19 vaccinated. Importantly, different amounts of replication-competent virus were detected in the culture media from the studied tissues. The highest viral load were measured in the lung (≈1.4 × 106 copies/mL) and heart (≈1.9 × 106 copies/mL) samples. Additionally, based on partial Spike gene sequences, SARS-CoV-2 characterization revealed the presence of multiple Omicron sub-variants exhibiting a high level of nucleotide and amino acid identity among them.

Discussion: These findings highlight that SARS-CoV-2 can spread to multiple tissue locations such as the lungs, heart, liver, kidneys, and intestines, both after primary infection and after reinfections with the Omicron variant, contributing to extending knowledge about the pathogenesis of acute infection and understanding the sequelae of clinical manifestations that are observed during post-acute COVID-19.

Source: Santiago Maffia-Bizzozero, Cintia Cevallos, Federico Remes Lenicov, Rosa Nicole Freiberger, Cinthya Alicia Marcela Lopez, Alex Guano Toaquiza, Franco Sviercz, Patricio Jarmoluk, Cristina Bustos, Adriana Claudia D’Addario, Jorge Quarleri, and M. Victoria Delpino. Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues. Front. Microbiol., 22 May 2023. https://www.frontiersin.org/articles/10.3389/fmicb.2023.1192832/full (Full text)

Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms

Abstract:

It is well known the potential of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection to induce post-acute sequelae, a condition called Long COVID. This syndrome includes several symptoms, but the central nervous system (CNS) main one is neurocognitive dysfunction. Recently it has been demonstrated the relevance of plasma levels of neurofilament light chain (pNfL), as a biomarker of early involvement of the CNS in COVID-19.

The aim of this study was to investigate the relationship between pNfL in patients with post-acute neurocognitive symptoms and the potential of NfL as a prognostic biomarker in these cases. A group of 63 long COVID patients ranging from 18 to 59 years-old were evaluated, submitted to a neurocognitive battery assessment, and subdivided in different groups, according to results. Plasma samples were collected during the long COVID assessment and used for measurement of pNfL with the Single molecule array (SIMOA) assays. Levels of pNfL were significantly higher in long COVID patients with neurocognitive symptoms when compared to HC (p = 0.0031).

Long COVID patients with cognitive impairment and fatigue symptoms presented higher pNfL levels when compared to long COVID patients without these symptoms, individually and combined (p = 0.0263, p = 0.0480, and 0.0142, respectively). Correlation analysis showed that levels of cognitive lost and exacerbation of fatigue in the neurocognitive evaluation had a significative correlation with higher pNfL levels (p = 0.0219 and 0.0255, respectively). Previous reports suggested that pNfL levels are related with higher risk of severity and predict lethality of COVID-19.

Our findings demonstrate that SARS-CoV-2 infection seems to have a long-term impact on the brain, even in patients who presented mild acute disease. NfL measurements might be useful to identify CNS involvement in long COVID associated with neurocognitive symptoms and to identify who will need continuous monitoring and treatment support.

Source: Gutman E, Salvio A, Fernandes R, et al. Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms. Research Square; 2023. DOI: 10.21203/rs.3.rs-2921879/v1. https://www.researchsquare.com/article/rs-2921879/v1 (Full text)

Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19

Abstract:

A growing number of patients with SARS-CoV-2 infections experience long-lasting symptoms. Even patients who suffered from a mild acute infection show a variety of persisting and debilitating neurocognitive, respiratory, or cardiac symptoms (Long-Covid syndrome), consequently leading to limitations in everyday life. Because data on health-related quality of life (HRQoL) is scarce, we aimed to characterize the impact of Long-Covid symptoms after a mild or moderate acute infection on HRQoL.

In this observational study, outpatients seeking counseling in the interdisciplinary Post-Covid consultation of the University Hospital Zurich with symptoms persisting for more than 4 weeks were included. Patients who received an alternative diagnosis or suffered from a severe acute Covid-19 infection were excluded. St. George’s Respiratory Questionnaire (SGRQ), Euroquol-5D-5L (EQ-5D-5L), and the Short form 36 (SF-36) were distributed to assess HRQoL. 112 patients were included, 86 (76.8%) were female, median (IQR) age was 43 (32.0, 52.5) years with 126 (91, 180) days of symptoms.

Patients suffered frequently from fatigue (81%), concentration difficulties (60%), and dyspnea (60%). Patients mostly stated impairment in performing usual activities and having pain/discomfort or anxiety out of the EQ-5D-5L. EQ index value and SGRQ activity score component were significantly lower in females. SF-36 scores showed remarkably lower scores in the physical health domain compared to the Swiss general population before and during the COVID-19 pandemic.

Long-Covid syndrome has a substantial impact on HRQoL. Long-term surveillance of patients must provide clarity on the duration of impairments in physical and mental health.

Trial registration: The study is registered on www.ClinicalTrials.gov , NCT04793269.

Source: Malesevic S, Sievi NA, Baumgartner P, Roser K, Sommer G, Schmidt D, Vallelian F, Jelcic I, Clarenbach CF, Kohler M. Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19. Sci Rep. 2023 May 12;13(1):7717. doi: 10.1038/s41598-023-34678-8. PMID: 37173355; PMCID: PMC10175927. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175927/ (Full text)