Non-survivors Of COVID-19 Research Articles

Characteristics of cytokines/chemokines associated with disease severity and adverse prognosis in COVID-19 patients.

Cytokines and chemokines as crucial participants in innate immune response play significant roles during SARS-CoV-2 infection, yet excessive immune response exacerbates the severity of COVID-19. This study aims to investigate the involvement of which cytokines/chemokines in the cytokine storm of COVID-19, as well as the changes in cytokine/chemokine levels during the course of COVID-19, simultaneously exploring the diagnostic and prognostic value of the relevant cytokines/chemokines for COVID-19. Flow cytometry was employed to detect the levels of cytokines and chemokines in the serum of 50 COVID-19 patients. Compared with severe COVID-19 patients, the levels of cytokines IL-6, IL-8, IL-10, sCD25, and chemokines IP-10 and MIG in the peripheral blood of non-severe patients were significantly reduced, while only IL-6, IL-10, and IP-10 levels were significantly decreased compared to non-survivors of COVID-19. Meanwhile, serum concentrations of IP-10, MCP-1, sTREM-1, IL-10, and the neutrophil-to-lymphocyte ratio (NLR) in peripheral blood could distinguish between COVID-19 survivors and non-survivors and were significantly associated with mortality. Among them, the concentration of IP-10 was shown to be the most powerful indicator for predicting adverse outcomes in COVID-19 patients (AUC: 0.715); however, its combined detection with the conventional inflammatory marker NLR did not improve the predictive value for adverse outcomes in COVID-19 patients. Additionally, serum IP-10 levels were negatively correlated with peripheral blood NK cell count and total lymphocyte count, while sTREM-1 levels were positively correlated with peripheral blood CD4+ T cell count and CD3+ T cell count. Meanwhile, IL-8 levels were positively correlated with total lymphocyte count in peripheral blood. Finally, the serum levels of cytokines/chemokines in non-survivors of COVID-19 increased significantly before death, while in survivors, they returned to normal levels before discharge. Severely ill and non-surviving COVID-19 patients exhibit compromised immune function, with significantly higher levels of inflammation, cytokine/chemokine storms, and immune dysregulation compared to non-severe patients. Serum concentrations of IP-10, MCP-1, sTREM-1, and IL-10 levels can serve as biomarkers to predict adverse outcomes in COVID-19.

Lung Epithelium Releases Growth Differentiation Factor 15 in Response to Pathogen-mediated Injury.

GDF15 (growth differentiation factor 15) is a stress cytokine with several proposed roles, including support of stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury are unclear. We quantified GDF15 in lower respiratory tract biospecimens and plasma from patients with acute respiratory failure. Publicly available data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reanalyzed. We used mouse models of hemorrhagic acute lung injury mediated by Pseudomonas aeruginosa exoproducts in wild-type mice and mice genetically deficient for Gdf15 or its putative receptor, Gfral. In critically ill humans, plasma levels of GDF15 correlated with lower respiratory tract levels and were higher in nonsurvivors. SARS-CoV-2 infection induced GDF15 expression in human lung epithelium, and lower respiratory tract GDF15 levels were higher in coronavirus disease (COVID-19) nonsurvivors. In mice, intratracheal P. aeruginosa type II secretion system exoproducts were sufficient to induce airspace and plasma release of GDF15, which was attenuated with epithelial-specific deletion of Gdf15. Mice with global Gdf15 deficiency had decreased airspace hemorrhage, an attenuated cytokine profile, and an altered lung transcriptional profile during injury induced by P. aeruginosa type II secretion system exoproducts, which was not recapitulated in mice deficient for Gfral. Airspace GDF15 reconstitution did not significantly modulate key lung cytokine levels but increased circulating erythrocyte counts. Lung epithelium releases GDF15 during pathogen injury, which is associated with plasma levels in humans and mice and can increase erythrocyte counts in mice, suggesting a novel lung-blood communication pathway.

Serum Insulin-like Growth Factor-Binding Protein-2 as a Prognostic Factor for COVID-19 Severity.

Insulin-like growth factor-binding protein (IGFBP)-2 is a regulator of anabolic pathways, which become inactivated in severe illness. Here, we measured the serum IGFBP-2 levels of COVID-19 patients with moderate and severe disease as well as healthy controls to identify the associations of serum IGFBP-2 levels with disease severity. Patients with severe COVID-19 had higher serum IGFBP-2 levels than those with moderate disease and healthy controls, who had similar levels. Non-survivors of COVID-19 tended to have elevated serum IGFBP-2 levels compared to survivors. Increased serum IGFBP-2 levels were observed in patients requiring dialysis and vasopressor therapy. Serum IGFBP-2 was positively correlated with procalcitonin in both patient groups. Bacterial co-infection in severe COVID-19 patients did not influence serum IGFBP-2 levels. Patients with liver cirrhosis and obesity, showing increased and decreased serum IGFBP-2 levels, respectively, were excluded from the study. The present analysis showed that higher serum IGFBP-2 levels are associated with increased disease severity in COVID-19 patients. The similarity in serum IGFBP-2 levels between patients with moderate COVID-19 and healthy controls suggests that elevated IGFBP-2 is associated with critical illness rather than SARS-CoV-2 infection itself.

Elevated level of serum human epididymis protein 4 (HE4) predicts disease severity and mortality in COVID-19 pneumonia

BackgroundWe retrospectively analyzed serum level of human epididymis protein 4 (HE4) as a pulmonary inflammatory biomarker in patients with COVID-19 pneumonia in association with disease severity and outcome.MethodsNinety-nine (40 critically ill, 40 severe and 19 mild) COVID-19 patients and as controls 25 age- and sex-matched non-COVID-19 bacterial sepsis subjects were included. Serum HE4 was measured by an immunoassay (Architect® i1000SR, Abbott) in the baseline samples of all study participants obtained at intensive care unit (ICU) admission or during outpatient clinic visit and follow-up sera were available in case of 30 COVID-19 subjects with life-threating conditions. Associations were studied between serum HE4, routinely available laboratory parameters, clinical characteristics, and disease progression.ResultsBaseline HE4 level was significantly higher (P < 0.0001) in critically ill (524.7 [300.1–1153.0] pmol/L) than severe COVID-19 subjects (157.4 [85.2-336.9] pmol/L) and in mild SARS-CoV-2 infection (46.7 [39.1–57.2] pmol/L). Similarly increased HE4 concentrations were found in bacterial sepsis (1118.0 [418.3–1953.0] pmol/L, P = 0.056) compared to critically ill COVID-19 individuals. Serum HE4 levels significantly correlated with age, SOFA-score, inflammation-dependent biomarkers, and the degree of lung manifestation evaluated by chest CT examination in ICU COVID-19 individuals. Based on ROC-AUC curve analysis, baseline HE4 independently indicated the severity of COVID-19 with an AUC value of 0.816 (95% CI [0.723–0.908]; P < 0.0001), while binary logistic regression test found HE4 as an independent prognostic parameter for death (OR: 10.618 [2.331–48.354]; P = 0.002). Furthermore, COVID-19 non-survivors showed much higher baseline HE4 levels without a substantial change under treatment vs. survivors (P < 0.0001). Finally, pre-treatment HE4 level of ≥ 331.7 pmol/L effectively predicted a larger risk for mortality (Log-Rank P < 0.0001) due to severe COVID-19 pneumonia.ConclusionElevated serum HE4 level at ICU admission highly correlates with COVID-19 severity and predicts disease outcome.

Metatranscriptome of human lung microbial communities in a cohort of mechanically ventilated COVID-19 Omicron patients

The Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infected a substantial proportion of Chinese population, and understanding the factors underlying the severity of the disease and fatality is valuable for future prevention and clinical treatment. We recruited 64 patients with invasive ventilation for COVID-19 and performed metatranscriptomic sequencing to profile host transcriptomic profiles, plus viral, bacterial, and fungal content, as well as virulence factors and examined their relationships to 28-day mortality were examined. In addition, the bronchoalveolar lavage fluid (BALF) samples from invasive ventilated hospital/community-acquired pneumonia patients (HAP/CAP) sampled in 2019 were included for comparison. Genomic analysis revealed that all Omicron strains belong to BA.5 and BF.7 sub-lineages, with no difference in 28-day mortality between them. Compared to HAP/CAP cohort, invasive ventilated COVID-19 patients have distinct host transcriptomic and microbial signatures in the lower respiratory tract; and in the COVID-19 non-survivors, we found significantly lower gene expressions in pathways related viral processes and positive regulation of protein localization to plasma membrane, higher abundance of opportunistic pathogens including bacterial Alloprevotella, Caulobacter, Escherichia-Shigella, Ralstonia and fungal Aspergillus sydowii and Penicillium rubens. Correlational analysis further revealed significant associations between host immune responses and microbial compositions, besides synergy within viral, bacterial, and fungal pathogens. Our study presents the relationships of lower respiratory tract microbiome and transcriptome in invasive ventilated COVID-19 patients, providing the basis for future clinical treatment and reduction of fatality.

EVIDENCE FROM FATAL COVID-19 FOR TARGETING THE BRADYKININ METABOLISM-A SINGLE-CENTER COHORT STUDY.

Background: Severe progression of COVID-19 to critical illness, with pulmonary failure, multiple organ failure, and death, is driven by systemic inflammatory responses with overproduction of inflammatory cytokines. In the past years, the potential role of bradykinin, leading to inappropriate immune responses in the pathogenesis of COVID-19, has been raised in a so-called bradykinin storm. However, clinical investigations of bradykinin, its metabolite des-Arg 9 -bradykinin, or substance P, are rare or completely lacking during intensive care of COVID-19 patients. A prospective prolonged cohort study was conducted, including 44 COVID-19 patients (09/2020-02/2021, prevalent wildtype SARS-CoV-2) from the intensive care unit. Plasma levels of bradykinin, des-Arg 9 -bradykinin, and substance P were measured daily by ELISA in survivors (n = 21) and nonsurvivors (n = 23) of COVID-19 from admission until discharge or death. Results: We found significantly higher plasma levels of des-Arg 9 -bradykinin in survivors and nonsurvivors of COVID-19 compared with healthy controls. In addition, plasma des-Arg 9 -bradykinin levels were higher ( P < 0.001, effect size = 0.79) in nonsurvivors compared with survivors of COVID-19 and correlated significantly with disease worsening, and clinical parameters of inflammation, like leukocyte count, IL-6 or lactate dehydrogenase, and outcome. Consequently, compared with healthy controls, bradykinin and substance P plasma levels were significantly reduced in survivors and nonsurvivors of COVID-19. Furthermore, plasma substance P levels were significantly reduced ( P < 0.001, effect size = 0.7) in nonsurvivors compared with survivors of COVID-19, whereas plasma bradykinin levels did not significantly differ between survivors and nonsurvivors of COVID-19. Conclusion: Our data demonstrates that des-Arg 9 -bradykinin is significantly elevated in COVID-19 intensive care unit patients and is associated with disease severity, clinical inflammatory parameters, and survival. These results indicate that des-Arg 9 -bradykinin, not bradykinin, is one of the pivotal peptides of concern for the lethal COVID-19 aggravation and outcome. Further investigations are necessary to evaluate whether des-Arg 9 -bradykinin exhibits potent blood biomarker properties in COVID-19 and offer new treatment approaches.

Clinico-epidemiological profile of non-survivors of COVID-19 during the last two waves in a tertiary care hospital of North India: A retrospective descriptive study

Background: SARS-CoV-causing COVID-19 resulted in mortality, and the clinic-epidemiological profile at the time of admission of patients who died later could provide an insight into pathophysiological consequences due to infection. Method: Retrospective observational study of 64 RTPCR-confirmed COVID-19 non-survivors was conducted from April - June 2021 and January February 2022. Data were analyzed, and a P value&lt;0.05 was taken as significant. Results: 60.94% and 39.06 % were males and females, and 26.57% &amp; 73.43 % of patients had moderate and severe disease, respectively. Fever, cough, and dyspnea were the most common presenting symptoms. 78.12% and 21.88% had pre-existing (diabetes and hypertension were most common) and no co-morbidities, respectively. 65.62 &amp; 17.19 % of patients had bilateral and unilateral ground glass opacities, respectively. Thrombocytopenia, lymphopenia, neutrophilia, elevated monocytes, and neutrophil-lymphocyte ratio (NLR) of 7.52 were hematological findings. D dimer was elevated. ABG showed low PaO2 and SPO2 %. ALT and AST were elevated. Tachycardia was also present. Compared to the first wave, no significant association of gender with severity was found. However, the percentage of male patients was higher. The association of the duration of stay and co-morbidity with disease severity was significant in both the first and subsequent waves of COVID-19. Conclusion: Co-morbidity, disease severity, and radiological lung opacities play a role in the outcome of COVID-19. The associated findings are hematological, renal, liver, cardiovascular, and arterial blood gas derangements.

Biochemical Analysis of Ferritin and D-dimer in COVID-19 Survivors and Non-survivors.

Background COVID-19 is a major cause of illness and mortality. The management of COVID-19-related illnesses might change if variables connected to their severity and the requirement for ICU admission could be found. The severity of COVID-19 might be efficiently predicted with several laboratory measures, such as ferritin levels and D-dimer analysis. Objectives This study aimed to evaluate the association between serum D-dimer and ferritin levels and their effects on mortality in patients with COVID-19. Methods This retrospective observational study included all patients with positive real-time polymerase chain reaction (RT-PCR) results for COVID-19 who were hospitalized in the Ministry of Health South Al-Qunfudah General Hospital between March and September 30, 2020. Their laboratory parameters, serum D-dimer, and ferritin levels were evaluated. IBMSPSSStatistics for Windows, Version 26.0 (released 2019; IBM Corp., Armonk, New York, United States) was used to analyze the data. Results A total of 318 COVID-19 patients were analyzed; 56.9% (n=181) were male and 43.1% (n=137) were female. Of these, 78.6% (n=250) survived, including 58% of men and 42% of women. The mean D-dimer was 2.1 mcg/mL (SD=3.16) and the mean ferritin was 698.59 ng/mL (SD=603.11). Non-recovered patients were substantially older (66.16 years old) and had higher D-dimer (5.46) mcg/mL and ferritin levels (992.96) ng/mL. Intubation length and gender did not affect survival. Of the non-survivors, 95.6% (n=239) were admitted to the ICU, and 50% (n=34) required mechanical ventilation. Conclusions COVID-19 infection mortality dramatically increased with older age and increased mean ferritin and plasma D-dimer values, which were significantly higher in COVID-19 non-survivors than in survivors. Therefore, assessing and monitoring these laboratory markers in the early stages of the disease may have a significant impact on preventing disease progression and death.

Initial clinical, laboratory and radiological features of SARS-CoV-2-infected patients and their impact on the course of the disease.

On March 11, 2020, coronavirus disease (COVID-19) was declared a global threat by the World Health Organization (WHO). It quickly became apparent that reducing inpatient mortality rates and early phase prediction of possible deterioration or severe disease course relied on finding more specific biomarkers. This retrospective study assessed initial clinical, laboratory and radiological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients and explored their impact on mortality and the course of the disease. Such efforts aimed to facilitate the identification of high-risk patients and to improve the formulation of treatment plans for these individuals. The cohort comprised 111 consecutive adult inpatients diagnosed with COVID-19 and hospitalized in the Internal Medicine Ward of the University Clinical Center of prof. K. Gibiński of the Medical University of Silesia in Katowice, Poland, a COVID-19 Treatment Unit, between November 16, 2020 and February 15, 2021. All available clinical, laboratory and radiological findings were extracted from electronic records and assessed as possible risk factors for poor prognosis. Clinicasl and radiological features with higher frequency in COVID-19 non-survivors included older age, history of smoking, concomitant cardiovascular diseases, low oxygen saturation (SpO2), and high infection risk assessed on admission as well as high opacity score, percentage of opacity and percentage of high opacity in computed tomography. Non-survivors had decreased serum lymphocytes, monocytes, calcium, magnesium, and hemoglobin oxygen saturation. They also had increased red cell distribution width (RDW), C-reactive protein (CRP), procalcitonin, alkaline phosphatase (ALP), creatinine, blood urea nitrogen (BUN), D-dimer, troponin, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, as well as a base deficit. This retrospective study identified several markers associated with a fatal course of COVID-19. The early assessment of SARS-CoV-2-infected inpatients should consider these markers.

Cellular Immune Profiling of Lung and Blood Compartments in Patients with SARS-CoV-2 Infection.

SARS-CoV-2 related immunopathology may be the driving cause underlying severe COVID-19. Through an immunophenotyping analysis on paired bronchoalveolar lavage fluid (BALF) and blood samples collected from mechanically ventilated patients with COVID-19-associated Acute Respiratory Distress Syndrome (CARDS), this study aimed to evaluate the cellular immune responses in survivors and non-survivors of COVID-19. A total of 36 paired clinical samples of bronchoalveolar lavage fluid (BALF) mononuclear cells (BALF-MC) and peripheral blood mononuclear cells (PBMC) were collected from 18 SARS-CoV-2-infected subjects admitted to the intensive care unit (ICU) of the Policlinico Umberto I, Sapienza University Hospital in Rome (Italy) for severe interstitial pneumonia. The frequencies of monocytes (total, classical, intermediate and non-classical) and Natural Killer (NK) cell subsets (total, CD56bright and CD56dim), as well as CD4+ and CD8+ T cell subsets [naïve, central memory (TCM) and effector memory (TEM)], and those expressing CD38 and/or HLADR were evaluated by multiparametric flow cytometry. Survivors with CARDS exhibited higher frequencies of classical monocytes in blood compared to non-survivors (p < 0.05), while no differences in the frequencies of the other monocytes, NK cell and T cell subsets were recorded between these two groups of patients (p > 0.05). The only exception was for peripheral naïve CD4+ T cells levels that were reduced in non-survivors (p = 0.04). An increase in the levels of CD56bright (p = 0.012) and a decrease in CD56dim (p = 0.002) NK cell frequencies was also observed in BALF-MC samples compared to PBMC in deceased COVID-19 patients. Total CD4+ and CD8+ T cell levels in the lung compartment were lower compared to blood (p = 0.002 and p < 0.01, respectively) among non-survivors. Moreover, CD38 and HLA-DR were differentially expressed by CD4+ and CD8+ T cell subsets in BALF-MC and in PBMC among SARS-CoV-2-infected patients who died from COVID-19 (p < 0.05). These results show that the immune cellular profile in blood and pulmonary compartments was similar in survivors and non-survivors of COVID-19. T lymphocyte levels were reduced, but resulted highly immune-activated in the lung compartment of patients who faced a fatal outcome.

How Does COVID-19 Affect the Heart?

Cardiac consequences occur in bothacute COVID-19and post-acute sequelae of COVID-19 (PASC). Here, we highlight the current understanding about COVID-19 cardiac effects, based upon clinical, imaging, autopsy, andmolecular studies. COVID-19 cardiac effects are heterogeneous. Multiple, concurrent cardiac histopathologic findings have been detected on autopsies ofCOVID-19 non-survivors. Microthrombi and cardiomyocyte necrosis are commonly detected. Macrophages often infiltrate the heart at high density but without fulfillinghistologic criteria for myocarditis. The high prevalences of microthrombi and inflammatory infiltrates in fatal COVID-19 raise the concern that recovered COVID-19 patients may have similar but subclinical cardiac pathology. Molecular studies suggest that SARS-CoV-2 infection of cardiac pericytes, dysregulated immunothrombosis, and pro-inflammatory and anti-fibrinolytic responses underlie COVID-19 cardiac pathology. The extent and nature by which mild COVID-19 affects the heart is unknown. Imaging and epidemiologic studies of recovered COVID-19 patients suggest that even mild illness confers increased risks of cardiac inflammation, cardiovascular disorders, and cardiovascular death. The mechanistic details of COVID-19 cardiac pathophysiology remain under active investigation. The ongoing evolution of SARS-CoV-2 variants and vast numbers of recovered COVID-19 patients portend a burgeoning global cardiovascular disease burden. Our ability to prevent and treat cardiovascular disease in the future will likely depend on comprehensive understanding of COVID-19 cardiac pathophysiologic phenotypes.

Plasma Apolipoprotein Concentrations Are Highly Altered in Severe Intensive Care Unit COVID-19 Patients: Preliminary Results from the LIPICOR Cohort Study.

SARS-CoV-2 infection goes beyond acute pneumonia, as it also impacts lipid metabolism. Decreased HDL-C and LDL-C levels have been reported in patients with COVID-19. The lipid profile is a less robust biochemical marker than apolipoproteins, components of lipoproteins. However, the association of apolipoprotein levels during COVID-19 is not well described and understood. The objective of our study is to measure plasma levels of 14 apolipoproteins in patients with COVID-19 and to evaluate the relationships between apolipoprotein levels, severity factors and patient outcomes. From November to March 2021, 44 patients were recruited on admission to the intensive care unit because of COVID-19. Fourteen apolipoproteins and LCAT were measured by LC-MS/MS in plasma of 44 COVID-19 patients on admission to the ICU and 44 healthy control subjects. Absolute apolipoprotein concentrations were compared between COVID-19 patients and controls. Plasma apolipoproteins (Apo) A (I, II, IV), C(I, II), D, H, J and M and LCAT were lower in COVID-19 patients, whereas Apo E was higher. COVID-19 severity factors such as PaO2/FiO2 ratio, SO-FA score and CRP were correlated with certain apolipoproteins. Lower Apo B100 and LCAT levels were observed in non-survivors of COVID-19 versus survivors. To conclude, in this study, lipid and apolipoprotein profiles are altered in COVID-19 patients. Low Apo B100 and LCAT levels may be predictive of non-survival in COVID-19 patients.

COVID-19 in older adult residents in nursing homes: factors associated with mortality and impact on functional capacity.

To verify if the functional capacity prior to COVID-19 infection was different between Survivor and Non-survivor older adults. Also, to verify the effect of the isolation period after COVID-19 infection on the functional capacity of the Survivors residing in nursing homes. Older adults residing in nursing homes were evaluated 30days before the COVID-19 outbreak at the site for (i) general health characteristics (obtained from medical records); (ii) gait speed, handgrip strength and 30-s sit-to-stand; (iii) sarcopenia and (iv) estimated muscle mass. Comparisons were made between Survivors and Non-survivors of COVID-19. After the isolation, the Survivors performed the assessments again. Twenty-one (81 ± 9.3years) participants tested positive for COVID-19 and participated in the study, 12 survivors. No difference was observed between Survivors and Non-survivors in any of the outcomes evaluated. However, a moderate effect size was observed for handgrip strength, with lower values for the Non-survivors group (- 16%; d = 0.53). The isolation period reduced the number of sit-to-stand repetitions with moderate effect size in the Survivors (p = 0.046, gav = 0.66). Although the null hypothesis analysis did not find significant differences between the groups, the effect size suggests that older adults residing in nursing homes who died from COVID-19 had lower handgrip strength. In the survivors, the isolation period after COVID-19 infection only negatively impacted the sit-to-stand performance.

Risk of mortality in COVID-19 patients: a meta- and network analysis

Understanding the most relevant hematological/biochemical characteristics, pre-existing health conditions and complications in survivors and non-survivor will aid in predicting COVID-19 patient mortality, as well as intensive care unit (ICU) referral and death. A literature review was conducted for COVID-19 mortality in PubMed, Scopus, and various preprint servers (bioRxiv, medRxiv and SSRN), with 97 observational studies and preprints, consisting of survivor and non-survivor sub-populations. This meta/network analysis comprised 19,014 COVID-19 patients, consisting of 14,359 survivors and 4655 non-survivors. Meta and network analyses were performed using META-MAR V2.7.0 and PAST software. The study revealed that non-survivors of COVID-19 had elevated levels of gamma-glutamyl transferase and creatinine, as well as a higher number of neutrophils. Non-survivors had fewer lymphocytes and platelets, as well as lower hemoglobin and albumin concentrations. Age, hypertension, and cerebrovascular disease were shown to be the most influential risk factors among non-survivors. The most common complication among non-survivors was heart failure, followed by septic shock and respiratory failure. Platelet counts, creatinine, aspartate aminotransferase, albumin, and blood urea nitrogen levels were all linked to ICU admission. Hemoglobin levels preferred non-ICU patients. Lower levels of hemoglobin, lymphocytes, and albumin were associated with increased mortality in ICU patients. This meta-analysis showed that inexpensive and fast biochemical and hematological tests, as well as pre-existing conditions and complications, can be used to estimate the risk of mortality in COVID-19 patients.

Remdesivir Influence on SARS-CoV-2 RNA Viral Load Kinetics in Nasopharyngeal Swab Specimens of COVID-19 Hospitalized Patients: A Real-Life Experience

There are still conflicting data on the virological effects of the SARS-CoV-2 direct antivirals used in clinical practice, in spite of the documented clinical efficacy. The aim of this monocentric retrospective study was to compare virologic and laboratory data of patients admitted due to SARS-CoV-2 infection from March to December 2020 treated with either remdesivir (R), a protease inhibitor (lopinavir or darunavir/ritonavir (PI)) or no direct antiviral drugs (NT). Viral load variation was indirectly assessed through PCR cycle threshold (Ct) values on the nasopharyngeal swab, analyzing the results from swabs obtained at ward admission and 7 (±2) days later. Overall, 253 patients were included: patients in the R group were significantly older, more frequently males with a significantly higher percentage of severe COVID-19, requiring more often intensive care admission, compared to the other groups. Ct variation over time did not differ amongst the three treatment groups and did not seem to be influenced by corticosteroid use, even after normalization of the treatment groups for disease severity. Non-survivors had lower Ct on admission and showed a significantly slower viral clearance compared to survivors. CD4 T-lymphocytes absolute count assessed at ward admission correlated with a reduced Ct variation over time. In conclusion, viral clearance appears to be slower in COVID-19 non-survivors, while it seems not to be influenced by the antiviral treatment received.

HATCH Score for Predicting Mortality in COVID-19 Patients.

We aimed to evaluate the relationship between HATCH score [hypertension, age >75 yr, previous transient ischemic attack (TIA) or stroke (doubled), chronic obstructive pulmonary disease, heart failure (doubled)] and in-hospital mortality in COVID-19 patients. Overall, 572 COVID-19 patients hospitalized between Mar 15 and Apr 15, 2020, were included in this multicenter retrospective study, in Turkey. The HATCH score of each patient was calculated. Mortality results were followed for 50 days. The patients were divided into 2 groups developing mortality (n=267) and non-mortality (n=305). Clinical outcomes were defined as in-hospital mortality improvement status. HATCH scores in non-survivors of COVID-19 were significantly higher than in survivors (P<0.001). In logistic regression analysis, HATCH score (OR: 1.253, 95% CI: 1.003-1.565; P=0.047), platelet count (OR: 0.995, 95% CI: 0.993-0.998; P<0.001), C-reactive protein level (OR: 1.010, 95% CI: 1.007-1.013, P<0.001) and estimated glomerular filtration ratio (eGFR) level (OR: 0.963, 95% CI: 0.953-0.973; P<0.001) were independent predictors of in-hospital mortality in COVID-19 patients. The HATCH score is useful in predicting in-hospital mortality in patients hospitalized with COVID-19.

Hemograms and serial hemogram-derived ratios in survivors and non-survivors of COVID-19 in Campinas, Brazil

The hemogram and hemogram-derivative ratios (HDRs) are becoming markers of the severity and mortality of COVID-19. We evaluated the hemograms and serial weekly HDRs [neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), neutrophil-platelet ratio (NPR) and systemic immune-inflammatory index (SII)] in the survivors and non-survivors of COVID-19. We retrospectively reviewed the medical notes and serial hemograms of real-time reverse-transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19 adults hospitalized from April 2020 to March 2021 from the time of diagnosis to the 3rd week of diagnosis. Of the 320 adults, 257 (80.3%) were survivors and had a lower mean age than the non-survivors (57.73 vs. 64.65 years, p < 0.001). At diagnosis, the non-survivors had lower hematocrit (p = 0.021), and lymphocyte (p = 0.002) and basophil (p = 0.049) counts and the hematocrit showed a p-value (Is this what you meant???) of 0.021); higher NLR (p < 0.001), PLR (p = 0.047), NPR (p = 0.022) and SII (p = 0.022). Using general linear models, the survivors and non-survivors showed significant variations with weekly lymphocyte count (p < 0.001), neutrophil count (p = 0.005), NLR (p = 0.009), MLR (p = 0.010) and PLR (p = 0.035). All HDRs remained higher in the non-survivors in the 2nd week and 3rd week of diagnosis and the HDRs were higher in the intubated patients than in the non-intubated patients. The NLR and SII were more efficient predictors of mortality in COVID-19 patients. This study shows that serial lymphocyte and neutrophil counts, NLR, PLR, MLR, NPR and SII could serve as good and easily accessible markers of severity and predictors of outcomes in COVID-19 patients and should be used for the monitoring of treatment response.

The Mortality Risk and Pulmonary Fibrosis Investigated by Time-Resolved Fluorescence Spectroscopy from Plasma in COVID-19 Patients.

A method of rapidly pointing out the risk of developing persistent pulmonary fibrosis from a sample of blood is extraordinarily needed for diagnosis, prediction of death, and post-infection prognosis assessment. Collagen scar formation has been found to play an important role in the lung remodeling following SARS-CoV-2 infection. For this reason, the concentration of collagen degradation products in plasma may reflect the process of lung remodeling and determine the extent of fibrosis. According to our previously published results of an in vitro study, an increase in the concentration of type III collagen degradation products in plasma resulted in a decrease in the fluorescence lifetime of plasma at a wavelength of 450 nm. The aim of this study was to use time-resolved fluorescence spectroscopy to assess pulmonary fibrosis, and to find out if the lifetime of plasma fluorescence is shortened in patients with COVID-19. The presented study is thus far the only one to explore the fluorescence lifetime of plasma in patients with COVID-19 and pulmonary fibrosis. The time-resolved spectrometer Life Spec II with the sub-nanosecond pulsed 360 nm EPLED® diode was used in order to measure the fluorescence lifetime of plasma. The survival analysis showed that COVID-19 mortality was associated with a decreased mean fluorescence lifetime of plasma. The AUC of mean fluorescence lifetime in predicting death was 0.853 (95% CI 0.735–0.972, p < 0.001) with a cut-off value of 7 ns, and with 62% sensitivity and 100% specificity. We observed a significant decrease in the mean fluorescence lifetime in COVID-19 non-survivors (p < 0.001), in bacterial pneumonia patients without COVID-19 (p < 0.001), and in patients diagnosed with idiopathic pulmonary fibrosis (p < 0.001), relative to healthy subjects. Furthermore, these results suggest that the development of pulmonary fibrosis may be a real and serious problem in former COVID-19 patients in the future. A reduction in the mean fluorescence lifetime of plasma was observed in many patients 6 months after discharge. On the basis of these data, it can be concluded that a decrease in the mean fluorescence lifetime of plasma at 450 nm may be a risk factor for mortality, and probably also for pulmonary fibrosis in hospitalized COVID-19 patients.

Phylogenetic analysis and comparative genomics of SARS-CoV-2 from survivor and non-survivor COVID-19 patients in Cordoba, Argentina

BackgroundThe SARS-CoV-2 virus is responsible for the COVID-19 pandemic. To better understand the evolution of SARS-CoV-2 early in the pandemic in the Province of Cordoba, Argentina, we performed a comparative genomic analysis of SARS-CoV-2 strains detected in survivors and non-survivors of COVID-19. We also carried out an epidemiological study to find a possible association between the symptoms and comorbidities of these patients with their clinical outcomes.ResultsA representative sampling was performed in different cities in the Province of Cordoba. Ten and nine complete SARS-CoV-2 genomes were obtained by next-generation sequencing of nasopharyngeal specimens from non-survivors and survivors, respectively. Phylogenetic and phylodynamic analyses revealed multiple introductions of the most common lineages in South America, including B.1, B.1.1.1, B.1.499, and N.3. Fifty-six mutations were identified, with 14% of those in common between the non-survivor and survivor groups. Specific SARS-CoV-2 mutations for survivors constituted 25% whereas for non-survivors they were 41% of the repertoire, indicating partial selectivity. The non-survivors’ variants showed higher diversity in 9 genes, with a majority in Nsp3, while the survivors’ variants were detected in 5 genes, with a higher incidence in the Spike protein. At least one comorbidity was present in 60% of non-survivor patients and 33% of survivors. Age 75–85 years (p = 0.018) and hospitalization (p = 0.019) were associated with non-survivor patients. Related to the most common symptoms, the prevalence of fever was similar in both groups, while dyspnea was more frequent among non-survivors and cough among survivors.ConclusionsThis study describes the association of clinical characteristics with the clinical outcomes of survivors and non-survivors of COVID-19 patients, and the specific mutations found in the genome sequences of SARS-CoV-2 in each patient group. Future research on the functional characterization of novel mutations should be performed to understand the role of these variations in SARS-CoV-2 pathogenesis and COVID-19 disease outcomes. These results add new genomic data to better understand the evolution of the SARS-CoV-2 variants that spread in Argentina during the first wave of the COVID-19 pandemic.

Dramatic Decrease of Vitamin K2 Subtype Menaquinone-7 in COVID-19 Patients.

(1) Background: Vitamin K (VK) is a fat-soluble compound with a common chemical structure, a 2-methyl-1,4-naphthoquinone ring, and a variable aliphatic side-chain. VK is involved in the synthesis of blood-clotting proteins, bone stability, anti-oxidative, and immune inflammatory-modulatory functions. Vitamin K also activates protein S, which acts as an antioxidant and anti-inflammatory. The fact that cytokine overproduction, oxidative stress, and disturbed microcirculation by thrombogenicity play a central role in severe COVID-19 prompted us to analyze this vitamin. (2) Methods: We analyzed by a validated liquid-chromatography tandem mass-spectrometry method serum vitamin K1, MK4, MK7, and VK epoxide levels in 104 healthy controls, 77 patients with non-COVID-19 pneumonia, and 135 hospitalized COVID-19 patients with potentially fatal outcomes admitted to our University Hospital between April and November 2020. We included the quotient between VK and triglyceride (TG, nmol/mmol/L) values in the analyses with respect to the TG transporter function for all VK subtypes. Additionally, we assessed anthropometric, routine laboratory, and clinical data from the laboratory and hospital information systems. (3) Results: The COVID-19 patients had significantly lower MK7 levels than non-COVID-19 pneumonia patients and healthy controls. COVID-19 and non-COVID-19 pneumonia patients had significantly lower vitamin K1 and significantly higher MK4 compared to healthy controls, but did not differ significantly from each other. Between COVID-19 non-survivors (n = 30) and survivors (n = 105) no significant differences were seen in all vitamin K subtypes, despite the fact that non-survivors had higher peak concentrations of IL-6, CRP, d-dimer, and higher oxygen needs, respectively. (4) Conclusions: The present data identified significantly decreased vitamin K1, K2 (MK7), and increased MK4 levels in patients with COVID-19 compared to healthy controls. Vitamin K2 (MK7) was lowest in COVID-19 patients irrespective of potentially fatal courses, indicating consumption of this VK subtype by COVID-19 immanent effects, most probably inflammatory and oxidative stress factors.