A Differential Signature of Circulating miRNAs and Cytokines Between COVID-19 and Community-Acquired Pneumonia Uncovers Novel Physiopathological Mechanisms of COVID-19.
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SUBMITTER: Martinez-Fleta P
PROVIDER: S-EPMC8787267 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abstract Background Coronavirus disease 2019 (COVID-19) results from SARS-CoV-2-induced hyperinflammatory immune response, orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF increases interleukin-6 (IL-6) levels, ultimately leading to increased C-reactive protein (CRP). The LIVE-AIR trial demonstrated that lenzilumab, the GM-CSF neutralizing antibody, improved the likelihood of survival without invasive mechanical ventilation (IMV) in hospitalized COVID-19 patients requiring supplemental oxygen but not IMV. This sub-analysis correlated levels of cytokines before and after lenzilumab treatment. Methods LIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial (NCT04351152). Patients hospitalized with COVID-19 pneumonia, requiring only supplemental oxygen, were randomized to receive lenzilumab (1800 mg in three equally divided doses of 600 mg, q8h) or placebo IV infusion, in addition to standard of care which included remdesivir and corticosteroids. Blood taken at baseline (BL) and subsequent to treatment through day 10 (D10) were obtained and analyzed by high sensitivity enzyme immunoassay for GM-CSF, IL-6, and CRP. Results Baseline IL-6 levels (Loge-transformed for all cytokines and biomarkers) were linearly correlated with higher baseline GM-CSF levels (slope=0.60, p< 0.001). Baseline CRP levels were linearly correlated with higher baseline IL-6 levels (slope=0.29, p < 0.001). GM-CSF levels decreased with lenzilumab treatment on day 1 (D1) which persisted through D10 (Table). In contrast, GM-CSF increased with placebo treatment. IL-6 levels decreased only with lenzilumab treatment. CRP following lenzilumab or placebo treatment decreased on D1 to similar levels and further decreased on D10 only with lenzilumab treatment. Cytokine Levels Associated with Lenzilumab Treatment Conclusion Lenzilumab decreased GM-CSF as well as downstream cytokines and systemic biomarkers of inflammation during the hyperinflammatory immune response of COVD-19. Disclosures Dale Chappell, MD, MBA, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Adrian Kilcoyne, MD, Humanigen, Inc: Employee Frank Cerasoli, PhD, Humanigen, Inc: Advisor/Consultant John Lukas, PhD, Humanigen, Inc: Advisor/Consultant Cameron Durrant, MD, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Zelalem Temesgen, MD, Gilead: unrestricted educational grant (to the institution)|Humanigen, Inc: Grant/Research Support|Merck: unrestricted educational grant (to the institution)|ViiV: Advisor/Consultant Christopher Polk, MD, Gilead: Advisor/Consultant Jason Baker, MD, Gilead: Grant/Research Support|Humanigen, Inc: Grant/Research Support Vincent Marconi, MD, Gilead: Grant/Research Support.
| S-EPMC9752421 | biostudies-literature
Project description:Community-acquired pneumonia (CAP) is the leading cause of infectious death in the world. Immune dysregulation during acute lung infection plays a role in lung injury and the systemic inflammatory response. Cytokines seem to be major players in severe lung infection cases. Here, we present a review of published papers in the last 3 years regarding this topic. The cytokine response during pneumonia is different in bacterial vs viral infections; some of these cytokines correlate with clinical severity scales such as CURB65 or SOFA. Treatment focused in the cytokine environment is an interesting area that could impact the prognosis of CAP. Some of the agents that have been studied as co-adjuvant therapy are corticosteroids, macrolides, and linezolid, but anyone of those have shown a clear or proven efficacy or have been recommended as a part of the standard of care for CAP. More studies designed to define the role of immunomodulatory agents, such as co-adjuvant therapy in pneumonia, are needed.
| S-EPMC7088528 | biostudies-literature
Project description:Purpose: To discuss the different characteristics of clinical, laboratory and chest computed tomography (CT) between coronavirus disease 2019 (COVID-19) and community-acquired pneumonia (CAP) in pediatric patients. Methods: We retrospectively retrieved data of inpatients with COVID-19 from January 21st to March 14th, 2020, and CAP from November 1st, 2019 to December 31st, 2019 in Wuhan Children's Hospital. We divided CAP into mycoplasma pneumonia and other viral pneumonia. We analyzed clinical and radiological features from those patients, and compared the differences among COVID-19, mycoplasma pneumonia and other viral pneumonia. Results: Eighty COVID-19 inpatients from January 21st to March 14th, 2020, as well as 95 inpatients with mycoplasma pneumonia and 50 inpatients with other viral pneumonia from November 1st, 2019 to December 31st, 2019 were included in our study. All patients were confirmed with RT-PCR. The clinical symptoms were similar in the three groups. Except fever and cough, diarrhea (6/80, 7.5%), tachypnea (2/80, 2.5%), and fatigue (6/80, 7.5%) were less common in COVID-19 patients. Compared to mycoplasma pneumonia and other viral pneumonia inpatients, COVID-19 patients present remarkably increased alanine aminotransferase (69/80, 86.3%). The typical CT feature of COVID-19 is ground-glass opacity, and it was more common in COVID-19 patients (32/80, 40%). Conclusion: The COVID-19 shared similar onsets with CAP. Even though the ground-glass opacity and elevated level of ALT were frequent in COVID-19, the better way for treatment and management of this disease is quickly and accurately identifying the pathogen.
| S-EPMC7676900 | biostudies-literature
Project description:Mechanisms of neutrophil involvement in severe COVID-19 remain incompletely understood. Here we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls, and perform bulk RNA-sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between 6 distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated SARS-CoV-2-specific IgG1-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.
2022-08-28 | GSE212041 | GEO
Project description:The exact immunopathophysiology of COVID-19 remains clouded by methodological heterogeneity and a lack of relevant disease controls. The absence of single-cell investigations into the broader population of patients with community-acquired pneumonia (CAP) renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in PBMCs from a strictly matched cohort of eight patients with COVID-19, eight patients with CAP, and four non-infectious control subjects. With this balanced, multi-omic approach we describe diverging transcriptional and phenotypic patterns in T cell, NK cell and monocyte populations between patients with CAP caused by either SARS-CoV-2, Influenza A or other pathogens, and thereby expand our understanding of the peripheral immune response in different forms of CAP.
2021-08-31 | GSE164948 | GEO
Project description:The study was undertaken to evaluate the performance of Unyvero Hospitalized Pneumonia (HPN) panel application, a multiplex PCR-based method for the detection of bacterial pathogens from lower respiratory tract (LRT) samples, obtained from COVID-19 patients with suspected secondary hospital-acquired pneumonia. Residual LRT samples obtained from critically ill COVID-19 patients with predetermined microbiological culture results were tested using the Unyvero HPN Application. Performance evaluation of the HPN Application was carried out using the standard-of-care (SoC) microbiological culture findings as the reference method. Eighty-three LRT samples were used in the evaluation. The HPN Application had a full concordance with SoC findings in 59/83 (71%) samples. The new method detected additional bacterial species in 21 (25%) and failed at detecting a bacterial species present in lower respiratory culture in 3 (3.6%) samples. Overall the sensitivity, specificity, positive, and negative predictive values of the HPN Application were 95.1% (95%CI 96.5-98.3%), 98.3% (95% CI 97.5-98.9%), 71.6% (95% CI 61.0-80.3%), and 99.8% (95% CI 99.3-99.9%), respectively. In conclusion, the HPN Application demonstrated higher diagnostic yield in comparison with the culture and generated results within 5 h.
| S-EPMC7930892 | biostudies-literature
Project description:Background: Corona virus disease (COVID-19) is an infectious respiratory disease that has spread rapidly across the world. Many studies have already evaluated the clinical features of COVID-19, but how it compares with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative community-acquired pneumonia (SN-CAP) is still unclear. Moreover, COVID-19 mortality is correlated with disease severity, but indicators for severity grading have not been specified. We aimed to analyze the clinical characteristics of COVID-19 in comparison with SN-CAP and find indicators for disease severity in COVID-19. Methods: Patients diagnosed with COVID-19 and SN-CAP were enrolled. Clinical, radiological, and laboratory data were analyzed. Results: The numbers of COVID-19 and SN-CAP patients enrolled were 304 and 138, respectively. The age of the patients was not significantly different between the groups. Compared with SN-CAP, COVID-19 patients had more symptoms of fever and dyspnea; and showed significant difference in blood count results. Computed tomography (CT) imaging of COVID-19 patients showed patchy ground-glass opacities that correlated with disease severity, whereas the CT imaging of SN-CAP patients showed patchy high-density shadows. COVID-19 patients were classified into moderate, severe, and critically severe groups. The severe and critically severe groups had elevated levels of white blood cells (WBC), neutrophils, platelets, C-reaction protein (CRP), lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), troponin-I, creatinine, and blood urea nitrogen (BUN). However, they had decreased levels of lymphocytes, lymphocyte ratio, and albumin. Compared with the younger patients, the older COVID-19 individuals had more chronic diseases and significantly elevated levels of WBC, neutrophil, and CRP levels. Conclusion: SN-CAP showed more inflammatory reaction than COVID-19. Old people with chronic diseases are more susceptible to COVID-19 and have a high likelihood of developing severe and critically severe infection. Levels of WBC, lymphocytes, neutrophils, CRP, NLR, PLR, troponin-I, creatinine, and BUN are important indicators for severity grading in COVID-19.
| S-EPMC7309449 | biostudies-literature
Project description:BackgroundSome patients previously presenting with COVID-19 have been reported to develop persistent COVID-19 symptoms. While this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the incidence and factors associated with the characteristics of persistent COVID-19. On the other hand, these patients very often have intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence on poor health post-COVID 19 syndrome in ICU-discharged patients.MethodsThis prospective, multicentre, and observational study was carrid out across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge.ResultsA total of 1255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP). Patients requiring invasive mechanical ventilation had more persistent post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, development of ICUAP, and ARDS were independent factors for persistent poor health post-COVID-19.ConclusionsPersistent post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay, development of ICUAP, and ARDS all comprised independent factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-COVID-19.
| S-EPMC8746263 | biostudies-literature
Project description:Even with over 80% of the population being vaccinated against COVID-19, the disease continues to claim victims. Therefore, it is crucial to have a secure Computer-Aided Diagnostic system that can assist in identifying COVID-19 and determining the necessary level of care. This is especially important in the Intensive Care Unit to monitor disease progression or regression in the fight against this epidemic. To accomplish this, we merged public datasets from the literature to train lung and lesion segmentation models with five different distributions. We then trained eight CNN models for COVID-19 and Common-Acquired Pneumonia classification. If the examination was classified as COVID-19, we quantified the lesions and assessed the severity of the full CT scan. To validate the system, we used Resnetxt101 Unet++ and Mobilenet Unet for lung and lesion segmentation, respectively, achieving accuracy of 98.05%, F1-score of 98.70%, precision of 98.7%, recall of 98.7%, and specificity of 96.05%. This was accomplished in just 19.70 s per full CT scan, with external validation on the SPGC dataset. Finally, when classifying these detected lesions, we used Densenet201 and achieved accuracy of 90.47%, F1-score of 93.85%, precision of 88.42%, recall of 100.0%, and specificity of 65.07%. The results demonstrate that our pipeline can correctly detect and segment lesions due to COVID-19 and Common-Acquired Pneumonia in CT scans. It can differentiate these two classes from normal exams, indicating that our system is efficient and effective in identifying the disease and assessing the severity of the condition.
| S-EPMC10215490 | biostudies-literature
Project description:Rationale: COVID-19 displays distinct characteristics that suggest a unique pathogenesis. The objective of this study was to compare biomarkers of coagulopathy and outcomes in COVID-19 and non-COVID-19 patients with severe pneumonia. Methods: Thirty-six non-COVID-19 and 27 COVID-19 non-immunocompromised patients with severe pneumonia were prospectively enrolled, most requiring intensive care. Clinical and biological characteristics (including plasma biomarkers of coagulopathy) were compared. Results: At similar baseline severity, COVID-19 patients required mechanical ventilation (MV) for significantly longer than non-COVID-19 patients (p = 0.0049) and more frequently developed venous thrombotic complications (p = 0.031). COVID-19 patients had significantly higher plasma concentrations of soluble VCAM1 (sVCAM1) (5,739 ± 3,293 vs. 3,700 ± 2,124 ng/ml; p = 0.009), but lower levels of D-dimers, vWF-A2, sICAM1, sTREM1, VEGF, and P-selectin, compared to non-COVID-19 patients. Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariable regression analysis confirmed that sVCAM1 rising levels were independently associated with a longer duration of MV. Finally, we identified close correlations between sVCAM1 and some features of COVID-19 immune dysregulation (ie. CXCL10, GM-CSF, and IL-10). Conclusion: We identified specific features of the coagulopathy signature in severe COVID-19 patients, with higher plasma sVCAM1 levels, that were independently associated with the longer duration of mechanical ventilation. Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT03505281.
| S-EPMC8371474 | biostudies-literature