Tag: acute covid

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)

Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19

Abstract:

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach.

Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology.

Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Source: Druzak, S., Iffrig, E., Roberts, B.R. et al. Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19. Nat Commun 14, 1638 (2023). https://doi.org/10.1038/s41467-023-37269-3 (Full text)

Comparison of Symptoms in Covid-19 Acute Infection and Long Covid-19

Abstract:

Background: Relatively little is known about the clinical course of covid-19 and the differences between the symptoms of covid-19 in acute phase of infection and the symptoms of long covid-19 in people with milder outpatient illnesses.

Objective: To compare clinical characteristics of covid-19 in acute infection with long covid-19 (presence of prolonged symptoms for at least 12 weeks, lasting at least 2 months, after acute covid-19 infection, and that are not explained by an alternative diagnosis).

Methodology: Comparison of secondary data among tow previous observational, longitudinal and prospective studies: 1) patients with post-acute covid-19 syndrome from March 15, 2020 to March 31, 2021; and 2) patients with Long covid-19 from March 15, 2020 to October 31, 2022, in the same population in general medicine.

Results: 33 covid-19 in acute phase, with 138 symptoms and 27 Long covid-19 cases with 44 symptoms were included. Respiratory symptoms predominated in both groups. Symptoms in Long covid-19 cases were significantly lower in general symptoms (X2= 5.9539. p= .014), and higher in Circulatory and Genitourinary system (Fisher exact test= 0.05).

Conclusion: Both in Long covid-19 and in covid-19 acute phase respiratory symptoms predominate. But they differ in that the symptoms of long covid-19 are less general than those of covid-19 acute phase, and present more symptoms of almost all organs and systems, those of the Circulatory and Genitourinary system being significant. The symptoms of Long covid-19 vs. acute phase are more debilitating and clinically heterogeneous.

Source: Turabian, Jose. (2023). Comparison of Symptoms in Covid-19 Acute Infection and Long Covid-19. 2694-5843. 10.36266/JCMHR/170.  https://www.researchgate.net/publication/369088222_Comparison_of_Symptoms_in_Covid-19_Acute_Infection_and_Long_Covid-19 (Full text)

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases

Abstract:

Background: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2.

Methods: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein.

Results: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient’s medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein.

Conclusions: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Source: Agrawal S, Farfel JM, Arfanakis K, Al-Harthi L, Shull T, Teppen TL, Evia AM, Patel MB, Ely EW, Leurgans SE, Bennett DA, Mehta R, Schneider JA. Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases. Acta Neuropathol Commun. 2022 Dec 17;10(1):186. doi: 10.1186/s40478-022-01493-7. PMID: 36528671; PMCID: PMC9758667. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758667/ (Full text)

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome

Abstract:

The duration and severity of COVID-19 are related to age, comorbidities, and cytokine synthesis. This study evaluated the impact of these factors on patients with clinical presentations of COVID-19 in a Brazilian cohort.

A total of 317 patients diagnosed with COVID-19 were included; cases were distributed according to clinical status as severe (n=91), moderate (n=56) and mild (n=170). Of these patients, 92 had acute COVID-19 at sample collection, 90 had already recovered from COVID-19 without sequelae, and 135 had sequelae (long COVID syndrome).

In the acute COVID-19 group, patients with the severe form had higher IL-6 levels (p=0.0260). In the post-COVID-19 group, there was no significant difference in cytokine levels between groups with different clinical conditions. In the acute COVID-19 group, younger patients had higher levels of TNF-α, and patients without comorbidities had higher levels of TNF-α, IL-4 and IL-2 (p<0.05). In contrast, patients over age 60 with comorbidities had higher levels of IL-6. In the post-COVID-19 group, subjects with long COVID-19 had higher levels of IL-17 and IL-2 (p<0.05), and subjects without sequelae had higher levels of IL-10, IL-6 and IL- 4 (p<0.05).

Our results suggest that advanced age, comorbidities and elevated serum IL-6 levels are associated with severe COVID-19 and are good markers to differentiate severe from mild cases. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 and IL-10 appear to constitute a cytokine profile of long COVID-19, and these markers are potential targets for COVID-19 treatment and prevention strategies.

Source: Queiroz MAF, Neves PFMD, Lima SS, Lopes JDC, Torres MKDS, Vallinoto IMVC, Bichara CDA, Dos Santos EF, de Brito MTFM, da Silva ALS, Leite MM, da Costa FP, Viana MNDSA, Rodrigues FBB, de Sarges KML, Cantanhede MHD, da Silva R, Bichara CNC, van den Berg AVS, Veríssimo AOL, Carvalho MDS, Henriques DF, Dos Santos CP, Nunes JAL, Costa IB, Viana GMR, Carneiro FRO, Palacios VRDCM, Quaresma JAS, Brasil-Costa I, Dos Santos EJM, Falcão LFM, Vallinoto ACR. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front Cell Infect Microbiol. 2022 Jun 30;12:922422. doi: 10.3389/fcimb.2022.922422. PMID: 35846757; PMCID: PMC9279918. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279918/ (Full text)