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In this study, we report a preanalytical challenge noted in our laboratory on plasma samples from a critically ill COVID-19 patient treated with hydroxychloroquine. This is significant because, in critically ill COVID-19 patients on hydroxychloroquine, plasma samples can have a high measured haemolysis index in the absence of haemolysis, with the impact on reporting the results for potassium and other analytes., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

This study investigated the roles of P-selectin and Clara cell secretory protein 16 (CC16) levels in the pathogenesis of severe adenovirus (ADV) pneumonia in children and evaluated their ability to predict disease. Fifty-one children (age, 1-5 years) with ADV pneumonia who were admitted to Xiamen Children's Hospital were included in this study and divided into the mild group (24 patients) and severe group (27 patients). A control group comprising healthy children of the same age who underwent routine physical examinations during the same period (30 patients) was also included. The univariate analysis demonstrated that the levels of the white blood cell count and C-reactive protein, procalcitonin, d-dimer, and P-selectin were increased in a severe group compared with a mild group, while CC16 levels were significantly decreased (p < 0.05). The logistic regression analysis revealed that P-selectin and CC16 levels were independent risk factors for severe ADV pneumonia in children. The areas under the ROC curves suggested that P-selectin and CC16 exhibited high predictive value for severe ADV pneumonia. P-selectin values more than 898.58 pg/mL and CC16 values less than 11.355 ng/mL predicted severe ADV pneumonia. P-selectin and CC16 levels are correlated with the severity of ADV pneumonia in children., (© 2024 Wiley Periodicals LLC.)

Background: Coronavirus disease (COVID-19) induces inflammation, coagulopathy following platelet and monocyte activation, and fibrinolysis, resulting in elevated D-dimer levels. Activated platelets and monocytes produce microvesicles (MVs). We analyzed the differences in platelet and monocyte MV counts in mild, moderate, and severe COVID-19, as well as their correlation with D-dimer levels., Methods: In this cross-sectional study, blood specimens were collected from 90 COVID-19 patients and analyzed for D-dimers using SYSMEX CS-2500. Platelet MVs (PMVs; PMVCD42b + and PMVCD41a + ), monocyte MVs (MMVs; MMVCD14 + ), and phosphatidylserine-binding annexin V (PS, AnnV + ) were analyzed using a BD FACSCalibur instrument., Results: PMV and MMV counts were significantly increased in COVID-19 patients. AnnV + PMVCD42b + and AnnV + PMVCD41a + cell counts were higher in patients with severe COVID-19 than in those with moderate clinical symptoms. The median (range) of AnnV + PMVCD42b + (MV/μL) in mild, moderate, and severe COVID-19 was 1,118.3 (328.1-1,910.5), 937.4 (311.4-2,909.5), and 1,298.8 (458.2-9,703.5), respectively ( P =0.009). The median (range) for AnnV + PMVCD41a + (MV/μL) in mild, moderate, and severe disease was 885.5 (346.3-1,682.7), 663.5 (233.8-2,081.5), and 1,146.3 (333.3-10,296.6), respectively ( P =0.007). D-dimer levels (ng/mL) weak correlated with AnnV + PMVCD41a + ( P =0.047, r=0.258)., Conclusions: PMV PMVCD42b + and PMVCD41a + counts were significantly increased in patients with severe clinical symptoms, and PMVCD41a + counts correlated with D-dimer levels. Therefore, MV counts can be used as a potential biomarker of COVID-19 severity.

Purpose: Patients with bacterial, fungal, and viral community-acquired pneumonia (CAP) were studied to determine their metabolic profiles., Methods: Loop-mediated isothermal amplification technology and nucleic acid sequence-dependent amplification combined with microfluidic chip technology were applied to screen multiple pathogens from respiratory tract samples. Eighteen patients with single bacterial infection (B-CAP), fifteen with single virus infection (V-CAP), twenty with single fungal infection (F-CAP), and twenty controls were enrolled. UHPLC-MS/MS analysis of untargeted serum samples for metabolic profiles. Multiple linear regression and Spearman's rank correlation analysis were used to determine associations between metabolites and clinical parameters. The sensitivity and specificity of the screened metabolites were also examined, along with their area under the curve., Results: The metabolic signatures of patients with CAP infected by bacteria, viruses, and fungi were markedly different from those of controls. The abundances of 45, 56, and 79 metabolites were significantly unbalanced. Among these differential metabolites, 11, 13, and 29 were unique to the B-CAP, V-CAP, and F-CAP groups, respectively. Bacterial infections were the only known causes of disturbances in the pentose and glucuronate and aldarate and ascorbate metabolism interconversions metabolic pathway., Conclusions: Serum metabolomic techniques based on UHPLC-MS/MS may identify differences between individuals with CAP who have been infected by various pathogens, and they can also build a metabolite signature for early detection of the origin of infection and prompt care.

In intensive care units, COVID-19 viral pneumonia patients (VPP) present symptoms similar to those of other patients with Nonviral infection (NV-ICU). To better manage VPP, it is therefore interesting to better understand the molecular pathophysiology of viral pneumonia and to search for biomarkers that may clarify the diagnosis. The secretome being a set of proteins secreted by cells in response to stimuli represents an opportunity to discover new biomarkers. The objective of this study is to identify the secretomic signatures of VPP with those of NV-ICU. Plasma samples and clinical data from NV-ICU (n = 104), VPP (n = 30) or healthy donors (HD, n = 20) were collected at Nantes Hospital (France) upon admission. Samples were enriched for the low-abundant proteins and analyzed using nontarget mass spectrometry. Specifically deregulated proteins (DEP) in VPP versus NV-ICU were selected. Combinations of 2 to 4 DEPs were established. The differences in secretome profiles of the VPP and NV-ICU groups were highlighted. Forty-one DEPs were specifically identified in VPP compared to NV-ICU. We describe five of the best combinations of 3 proteins (complement component C9, Ficolin-3, Galectin-3-binding protein, Fibrinogen alpha, gamma and beta chain, Proteoglycan 4, Coagulation factor IX and Cdc42 effector protein 4) that show a characteristic receptor function curve with an area under the curve of 95.0%. This study identifies five combinations of candidate biomarkers in VPP compared to NV-ICU that may help distinguish the underlying causal molecular alterations., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes., Methods: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery., Findings: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors., Interpretation: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment., Funding: US National Institutes of Health., Competing Interests: Declaration of interests ALG reports receiving institutional funding from Novavax, institutional partnership with AstraZeneca, and being personally named as inventor on a patent used by AstraZeneca. DDM reports receiving grants from the Danish National Research Foundation. DL reports participation in a study funded by Gilead with no salary support. EM reports payments to his institution received from SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Chemic Labs and KODA Therapeutics, and Cidara, and payment for participating in an advisory board for Basilea. KW reports honorarium for Acute Respiratory Distress Syndrome (ARDS) International Conference in 2023, and travel support from University of California San Francisco. MAM reports institutional funding by the US Department of Defence, Roche-Genetech, and Quantum Health, and personal consulting fees from Gilead, Novartis, and Johnson & Johnson. MKJ reports grants received from Regeneron, Laurent, and Gilead, honoraria from Gilead, and a leadership role with the HIV Medicine Association Board of Directors. PC reports consulting fees from Eli Lilly and Regeneron. All other authors declare no competing interests. All authors were not precluded from accessing data in the study., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study aimed to investigate the expression and significance of serum procalcitonin (PCT), leukotriene B4 (LTB4), Serum amyloid A (SAA), and C-reactive protein (CRP) in children with different types of pneumonia caused by different pathogenic infections. One hundred and one children with pneumonia admitted to The Fifth People Hospital of Zhuhai from July 2019 to June 2020 were enrolled and divided into 38 cases in the bacterial group, 30 cases in the mycoplasma group, and 33 cases in the virus group according to the different types of pathogens. The patients were divided into 42 cases in the noncritical group, 33 cases in the critical group, and 26 cases in the very critical group according to the pediatric clinical illness score (PCIS), and 30 healthy children were selected as the control group during the same period. Comparison of serum PCT, SAA: bacterial group > mycoplasma group > viral group > control group with significant differences (P < .05). Receiver operator characteristic (ROC) analysis showed that the area under the curves (AUCs) of serum PCT, LTB4, SAA, and CRP for the diagnosis of bacterial pneumonia were 1.000, 0.531, 0.969, and 0.833, respectively, and the AUCs for the diagnosis of mycoplasma pneumonia were 0.653, 0.609, 0.547, and 0.652, respectively, and the AUCs for the diagnosis of viral pneumonia were 0.888, 0.570, 0.955, and 1.000, respectively. Comparison of serum PCT, LTB4, SAA: very critical group > critical group > noncritical group > control group, with significant differences (P < .05). Serum PCT, LTB4, and SAA were negatively correlated with PCIS score by Pearson analysis (P < .05). Serum PCT and SAA showed diagnostic value for bacterial pneumonia, and serum SAA and CRP showed diagnostic value for viral pneumonia; serum PCT, LTB4, and SAA correlate with severity of disease and show higher expression with worsening of the condition., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background & objectives Krebs von den Lungen-6 (KL-6) is primarily expressed by the damaged type II pneumocytes. In this context, the relationship of KL-6 with blood gas analysis (BGA) parameters and Brixia score is still limitedly discussed. This study aims to analyze the correlation of KL-6, BGA and Brixia scores to the severity and mortality of COVID-19. Methods A cross-sectional study was conducted in adult COVID-19 positive individuals at Universitas Airlangga Hospital, Surabaya, East Java, Indonesia, from March to August 2021. KL-6, BGA, and Brixia scores were compared according to severity (severe vs. non-severe) and mortality (non-survivor vs. survivor). The receiver operating characteristic (ROC) analysis was also performed to define the optimal cut-off, sensitivity, as well as the specificity of KL-6, BGA and Brixia scores to determine the COVID-19 severity and mortality. Results Total 35 severe and 20 non-severe COVID-19 positive individuals were enrolled in this study. Of those, there were 22 non-survivors. No significant difference in serum KL-6 levels was observed in the severity and mortality groups. KL-6 and HCO3- had positive correlation in the severe group (r=0.37). KL-6 and Brixia scores showed a significant negative correlation among COVID-19 positive individuals (r=-0.283; P=0.036). KL-6 and Brixia scores together served as the best severity markers in the current study [AUC 0.809 (0.697-0.920); Sn/Sp=0.686/0.900)], followed by KL-6 and P/F ratio [AUC 0.800 (0.637-0.963); Sn/Sp=0.971/0.750]. Interpretation & conclusions The findings of this study suggest that KL-6 has the potential to be a useful adjunct laboratory parameter to the BGA and Brixia score representing COVID-19 severity and mortality.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represented a disruptive pathology that emerged in late 2019 with profound implications ranging from individual health to health systems and world economy. Our study aimed to evaluate clinical, biochemical and computerized tomography (CT) parameters values in determining the severity of pulmonary embolism (PE) associated with COVID-19., Methods: We performed an observational cohort study evaluating demographic, clinical, biochemical, coagulation markers, as well as CT imaging parameters., Results: In our study on 186 patients with COVID-19, we found that 31 patients (16,66%) had pulmonary embolism. Significant correlations for the patients with PE were detected in C-reactive protein, lactate dehydrogenase, serum ferritin, IL-6, serum myoglobin, NT-proBNP, D-dimers, serum proteins, transaminases as well as white cell blood counts. Patients with pulmonary embolism had a more severe lung involvement, with thrombi distribution mainly involving the lower lobes., Conclusion: Early identification of PE is an important step for timely and efficient treatment in the intensive care management of COVID-19 patients. Our study showed that high plasmatic values of lactate dehydrogenase, ferritin, IL-6, white blood cells and D-dimers and low proteins serum levels are strongly linked with COVID-19-associated pulmonary embolism., (© 2024 Eduard Dumea et al., published by Sciendo.)

The levels of endothelins were assessed in menopausal women with arterial hypertension (AH) and type 2 diabetes mellitus (T2DM) in the acute phase of the moderate COVID-19. Women under observation (age 45-69 years) were divided into two groups. Control group consisted of women (n=16) who did not have COVID-19, were not vaccinated, and had no antibodies to SARS-CoV-2 (IgG). The main group included women (n=63) in the acute phase of the moderate COVID-19 accompanied by pneumonia. According to the clinical and anamnestic data analysis, the main group was divided into subgroups: without AH and T2DM (n=21); with AH and without T2DM (n=32); and with AH and T2DM (n=10). The parameters of clinical blood analysis, as well as endothelin-1, endothelin-2, and endothelin-3 levels were assessed. In women with a moderate COVID-19, the endothelin-1 and endothelin-2 levels were increased compared to the control regardless of AH and T2DM status. We found no statistically significant differences in the studied parameters of endothelial dysfunction between the subgroups of menopausal women in the acute phase of the moderate COVID-19., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Ferritin, the central iron storage protein, has attracted attention as a biomarker of severe COVID-19. Few studies have investigated regulators of iron metabolism in the context of COVID-19. The aim was to evaluate biomarkers for iron metabolism in the acute phase response to community-acquired pneumonia (CAP) caused by SARS-CoV-2 compared with CAP caused by bacteria or influenza virus in hospitalized patients. A cross-sectional study of 164 patients from the Surviving Pneumonia Cohort recruited between January 8, 2019 and May 26, 2020. Blood samples were collected at admission and analyzed for levels of C-reactive protein (CRP), ferritin, soluble transferrin receptor, erythroferrone, and hepcidin. Median (IQR) hepcidin was higher in SARS-CoV-2 with 143.8 (100.7-180.7) ng/mL compared with bacterial and influenza infection with 78.8 (40.1-125.4) and 53.5 (25.2-125.8) ng/mL, respectively. The median ferritin level was more than 2-fold higher in patients with SARS-CoV-2 compared with the other etiologies (p < 0.001). Patients with SARS-CoV-2 had lower levels of erythroferrone and CRP compared with those infected with bacteria. Higher levels of hepcidin and lower levels of erythroferrone despite lower CRP levels among patients with SARS-CoV-2 compared with those infected with bacteria indicate alterations in iron metabolism in patients with SARS-CoV-2 infection., (© 2022 APMIS. Published by John Wiley & Sons Ltd.)

Background: Haematological markers such as absolute lymphopenia have been associated with severe COVID-19 infection. However, in the literature to date, the cohorts described have typically included patients who were moderate to severely unwell with pneumonia and who required intensive care stay. It is uncertain if these markers apply to a population with less severe illness. We sought to describe the haematological profile of patients with mild disease with COVID-19 admitted to a single centre in Singapore., Methods: We examined 554 consecutive PCR positive SARS-COV-2 patients admitted to a single tertiary healthcare institution from Feb 2020 to April 2020. In all patients a full blood count was obtained within 24 h of presentation., Results: Patients with pneumonia had higher neutrophil percentages (66.5 ± 11.6 vs 55.2 ± 12.6%, p  < 0.001), lower absolute lymphocyte count (1.5 ± 1.1 vs 1.9 ± 2.1 x109/L, p  < 0.011) and absolute eosinophil count (0.2 ± 0.9 vs 0.7 ± 1.8 × 109/L, p  = 0.002). Platelet counts (210 ± 56 vs 230 ± 61, p  = 0.020) were slightly lower in the group with pneumonia. We did not demonstrate significant differences in the neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio in patients with or without pneumonia. Sixty-eight patients (12.3%) had peripheral eosinophilia. This was more common in migrant workers living in dormitories., Conclusion: Neutrophilia and lymphopenia were found to be markers associated with severe COVID-19 illness. We did not find that combined haematological parameters: neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio, had any association with disease severity in our cohort of patients with mild-moderate disease. Migrant workers living in dormitories had eosinophilia which may reflect concurrent chronic parasitic infection.

Objectives: This study aimed to explore clinical indexes for management of severe/critically ill patients with COVID-19, influenza A H7N9, and H1N1 pneumonia by comparing hematological and radiological characteristics., Methods: Severe/critically ill patients with COVID-19, H7N9, and H1N1 pneumonia were retrospectively enrolled. The demographic data, clinical manifestations, hematological parameters, and radiological characteristics were compared., Results: In this study, 16 cases of COVID-19, 10 cases of H7N9, and 13 cases of H1N1 who met severe/critically ill criteria were included. Compared with COVID-19, H7N9 and H1N1 groups had more chronic diseases (80% and 92.3% vs. 25%, p < 0.05), higher APACHE Ⅱ scores (16.00 ± 8.63 and 15.08 ± 6.24, vs. 5.50 ± 2.58, p < 0.05), higher mortality rates (40% and 46.2% vs. 0%, p < 0.05), significant lymphocytopenia (0.59 ± 0.31 × 10 9 /L and 0.56 ± 0.35 × 10 9 /L vs. 0.97 ± 0.33 × 10 9 /L, p < 0.05), and elevated neutrophil-to-lymphocyte ratio (NLR; 14.67 ± 6.10 and 14.64 ± 10.36 vs. 6.29 ± 3.72, p < 0.05). Compared with the H7N9 group, ground-glass opacity (GGO) on chest CT was common in the COVID-19 group (p = 0.028), while pleural effusion was rare (p = 0.001)., Conclusions: The NLR can be used as a clinical parameter for the predication of risk stratification and outcome in COVID-19 and influenza A pneumonia. Manifestations of pleural effusion or GGO in chest CT may be helpful for the identification of different viral pneumonia., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Hyperglycaemia has emerged as an important risk factor for death in coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the association between blood glucose (BG) levels and in-hospital mortality in non-critically patients hospitalized with COVID-19., Methods: This is a retrospective multi-centre study involving patients hospitalized in Spain. Patients were categorized into three groups according to admission BG levels: <140 mg/dL, 140-180 mg/dL and >180 mg/dL. The primary endpoint was all-cause in-hospital mortality., Results: Of the 11,312 patients, only 2128 (18.9%) had diabetes and 2289 (20.4%) died during hospitalization. The in-hospital mortality rates were 15.7% (<140 mg/dL), 33.7% (140-180 mg) and 41.1% (>180 mg/dL), p <.001. The cumulative probability of mortality was significantly higher in patients with hyperglycaemia compared to patients with normoglycaemia (log rank, p <.001), independently of pre-existing diabetes. Hyperglycaemia (after adjusting for age, diabetes, hypertension and other confounding factors) was an independent risk factor of mortality (BG >180 mg/dL: HR 1.50; 95% confidence interval (CI): 1.31-1.73) (BG 140-180 mg/dL; HR 1.48; 95%CI: 1.29-1.70). Hyperglycaemia was also associated with requirement for mechanical ventilation, intensive care unit (ICU) admission and mortality., Conclusions: Admission hyperglycaemia is a strong predictor of all-cause mortality in non-critically hospitalized COVID-19 patients regardless of prior history of diabetes. KEY MESSAGE Admission hyperglycaemia is a stronger and independent risk factor for mortality in COVID-19. Screening for hyperglycaemia, in patients without diabetes, and early treatment of hyperglycaemia should be mandatory in the management of patients hospitalized with COVID-19. Admission hyperglycaemia should not be overlooked in all patients regardless prior history of diabetes.

Background/aim: Biochemical markers are needed to show lung involvement in COVID-19 disease. Galectin-3 is known to play a key role in the inflammation and fibrosis process. We aimed to evaluate the predictive role of galectin-3 levels for pneumonia in patients with COVID-19., Materials and Methods: Total of 176 patients with COVID-19, confirmed with reverse transcriptase polymerase chain reaction, admitted to the Erzurum Regional Training and Research Hospital was analyzed. The study was designed as a cross sectional. The baseline data of laboratory examinations, including galectin-3 were collected at the time of diagnosis. CT images evaluated by a single radiologist according to the recommendation of the Radiological Society of North America Expert Consensus Document for pulmonary involvement. The severity of COVID-19 pneumonia was assessed using the total severity score., Results: The mean galectin-3 level in patients with typical pneumonia was found to be significantly higher than those patients with atypical (p < 0.01) and indeterminate appearance (p < 0.01) and patients without pneumonia (p < 0.01). The severity of lung involvement was significantly associated with Galectin-3 levels (p < 0.01 r: 0.76). Stepwise logistic regression model showed that the levels of ferritin (odds ratio [OR] = 0.05, p: 0.08) and galectin-3 (OR = 0.1, p < 0.01) were significantly and independently associated with typical pneumoniain COVID-19 patients. When COVID-19 patients were evaluated in terms of typical pneumonia, we determined a cut-off value of 18.9 ng/mL for galectin-3 via ROC analysis (87% sensitivity; 73% specificity; area under curve (AUC): 0.89; p < 0.001)., Conclusion: Galectin-3 was found as a diagnostic tool for COVID-19 associated typical pneumonia and as an indicator of both pneumonia and its severity., Competing Interests: The authors do not report any conflict of interest., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease is rare but may occur in high-risk settings, often manifesting as a pulmonary infection. To date HCMV has not been investigated in malignant pleural mesothelioma (MPM). In a consecutive case series of 144 MPM patients we evaluated two biomarkers of HCMV: IgG serostatus (defined as positive and negative) and DNAemia (>100 copies/mL of cell free HCMV DNA in serum). Approximately half of the MPM patient population was HCMV IgG seropositive (51%). HCMV DNAemia was highly prevalent (79%) in MPM and independent of IgG serostatus. DNAemia levels consistent with high level current infection (>1000 copies/mL serum) were present in 41% of patients. Neither IgG serostatus nor DNAemia were associated with patient survival. In tissues, we observed that HCMV DNA was present in 48% of tumors (n = 40) and only 29% of normal pleural tissue obtained from individuals without malignancy (n = 21). Our results suggest nearly half of MPM patients have a high level current HCMV infection at the time of treatment and that pleural tissue may be a reservoir for latent HCMV infection. These findings warrant further investigation to determine the full spectrum of pulmonary infections in MPM patients, and whether treatment for high level current HCMV infection may improve patient outcomes., Competing Interests: The authors have declared no competing interests exist.

Introduction: The SARS-CoV-2 virus affects many organs, especially the lungs, with widespread inflammation. We aimed to compare the endogenous oxidative damage markers of coenzyme Q10, nicotinamide dinucleotide oxidase 4, malondialdehyde, and ischemia-modified albumin levels in patients with pneumonia caused by SARS-CoV-2 and in an healthy control group. We also aimed to compare these parameters between patients with severe and non-severe pulmonary involvement., Methods: The study included 58 adult patients with SARS-CoV-2 pneumonia and 30 healthy volunteers. CoQ10 and MDA levels were determined by high-pressure liquid chromatography. NOX4 and IMA levels were determined by ELISA assay and colorimetric method., Results: Higher levels of CoQ10, MDA, NOX4, and IMA and lower levels of COQ10H were observed in patients with SARS-CoV-2 pneumonia than in the control group. MDA, IMA, NOX4, and CoQ10 levels were significantly higher in patients with severe pulmonary involvement than in patients with non-severe pulmonary involvement, but no significant difference was observed in CoQ10H levels. CoQ10 levels were significantly and positively correlated with both ferritin and CRP levels., Conclusion: SARS-CoV-2 pneumonia is significantly associated with increased endogenous oxidative damage. Oxidative damage seems to be associated with pulmonary involvement severity., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Early detection of severe forms of COVID-19 is absolutely essential for timely triage of patients. We longitudinally followed-up two well-characterized patient groups, hospitalized moderate to severe (n = 26), and ambulatory mild COVID-19 patients (n = 16) at home quarantine. Human D-dimer, C-reactive protein (CRP), ferritin, cardiac troponin I, interleukin-6 (IL-6) levels were measured on day 1, day 7, day 14 and day 28. All hospitalized patients were SARS-CoV-2 positive on admission, while all ambulatory patients were SARS-CoV-2 positive at recruitment. Hospitalized patients had higher D-dimer, CRP and ferritin, cardiac troponin I and IL-6 levels than ambulatory patients (p < 0.001, p < 0.001, p = 0.016, p = 0.035, p = 0.002 respectively). Hospitalized patients experienced significant decreases in CRP, ferritin and IL-6 levels from admission to recovery (p < 0.001, p = 0.025, and p = 0.001 respectively). Cardiac troponin I levels were high during the acute phase in both hospitalized and ambulatory patients, indicating a potential myocardial injury. In summary, D-dimer, CRP, ferritin, cardiac troponin I, IL-6 are predictive laboratory markers and can largely determine the clinical course of COVID-19, in particular the prognosis of critically ill COVID-19 patients., (© 2021. The Author(s).)

Background: To explore the long-term trajectories considering pneumonia volumes and lymphocyte counts with individual data in COVID-19., Methods: A cohort of 257 convalescent COVID-19 patients (131 male and 126 females) were included. Group-based multi-trajectory modelling was applied to identify different trajectories in terms of pneumonia lesion percentage and lymphocyte counts covering the time from onset to post-discharge follow-ups. We studied the basic characteristics and disease severity associated with the trajectories., Results: We characterised four distinct trajectory subgroups. (1) Group 1 (13.9%), pneumonia increased until a peak lesion percentage of 1.9% (IQR 0.7-4.4) before absorption. The slightly decreased lymphocyte rapidly recovered to the top half of the normal range. (2) Group 2 (44.7%), the peak lesion percentage was 7.2% (IQR 3.2-12.7). The abnormal lymphocyte count restored to normal soon. (3) Group 3 (26.0%), the peak lesion percentage reached 14.2% (IQR 8.5-19.8). The lymphocytes continuously dropped to 0.75 × 10 9 /L after one day post-onset before slowly recovering. (4) Group 4 (15.4%), the peak lesion percentage reached 41.4% (IQR 34.8-47.9), much higher than other groups. Lymphopenia was aggravated until the lymphocytes declined to 0.80 × 10 9 /L on the fourth day and slowly recovered later. Patients in the higher order groups were older and more likely to have hypertension and diabetes (all P values < 0.05), and have more severe disease., Conclusions: Our findings provide new insights to understand the heterogeneous natural courses of COVID-19 patients and the associations of distinct trajectories with disease severity, which is essential to improve the early risk assessment, patient monitoring, and follow-up schedule., (© 2021. The Author(s).)

Recent publications on the probable role of heparin-binding protein (HBP) as a biomarker in sepsis prompted us to investigate its diagnostic and prognostic performance in severe COVID-19. HBP and IL-6 were measured by immunoassays at admission and on day 7 in 178 patients with pneumonia by SARS-CoV-2. Patients were classified into non-sepsis and sepsis as per the Sepsis-3 definitions and were followed up for the development of severe respiratory failure (SRF) and for outcome. Results were confirmed by multivariate analyses. HBP was significantly higher in patients classified as having sepsis and was negatively associated with the oxygenation ratio and positively associated with creatinine and lactate. Logistic regression analysis evidenced admission HBP more than 18 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for the development of SRP. Their integration prognosticated SRF with respective sensitivity, specificity, positive predictive value, and negative predictive 59.1%, 96.3%, 83.9%, and 87.8%. Cox regression analysis evidenced admission HBP more than 35 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for 28-day mortality. Their integration prognosticated 28-day mortality with respective sensitivity, specificity, positive predictive value, and negative predictive value 69.2%, 92.7%, 42.9%, and 97.5%. HBP remained unchanged over-time course. A prediction score of the disposition of patients with COVID-19 is proposed taking into consideration admission levels of IL-6 and HBP. Using different cut-offs, the score may predict the likelihood for SRF and for 28-day outcome.

Competing Interests: Competing interests: We have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare.

Background: Hematological comparison of coronavirus disease (COVID-19) and other viral pneumonias can provide insights into COVID-19 treatment., Methods: In this retrospective case-control single-center study, we compared the data of 126 patients with viral pneumonia during different outbreaks [severe acute respiratory syndrome (SARS) in 2003, influenza A (H1N1) in 2009, human adenovirus type 7 in 2018, and COVID-19 in 2020]., Results: One of the COVID-19 characteristics was a continuous decline in the hemoglobin level. The neutrophil count was related to the aggravation of COVID-19 and SARS. Thrombocytopenia occurred in patients with SARS and severe COVID-19 even at the recovery stage. Lymphocytes were related to the entire course of adenovirus infection, recovery of COVID-19, and disease development of SARS., Conclusions: Dynamic changes in hematological counts could provide a reference for the pathogenesis and prognosis of pneumonia caused by respiratory viruses in clinics.

Background and Objectives: An effective treatment option is not yet available for SARS-CoV2, which causes the COVID-19 pandemic and whose effects are felt more and more every day. Ivermectin is among the drugs whose effectiveness in treatment has been investigated. In this study; it was aimed to investigate the presence of gene mutations that alter ivermectin metabolism and cause toxic effects in patients with severe COVID-19 pneumonia, and to evaluate the effectiveness and safety of ivermectin use in the treatment of patients without mutation., Materials and Methods: Patients with severe COVID19 pneumonia were included in the study, which was planned as a prospective, randomized, controlled, single-blind phase 3 study. Two groups, the study group and the control group, took part in the study. Ivermectin 200 mcg/kg/day for 5 days in the form of a solution prepared for enteral use added to the reference treatment protocol -hydroxychloroquine + favipiravir + azithromycin- of patients included in the study group. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The presence of mutations was investigated by performing sequence analysis in the mdr1/abcab1 gene with the Sanger method in patients included in the study group according to randomization. Patients with mutations were excluded from the study and ivermectin treatment was not continued. Patients were followed for 5 days after treatment. At the end of the treatment and follow-up period, clinical response and changes in laboratory parameters were evaluated., Results: A total of 66 patients, 36 in the study group and 30 in the control group were included in the study. Mutations affecting ivermectin metabolism was detected in genetic tests of six (16.7%) patients in the study group and they were excluded from the study. At the end of the 5-day follow-up period, the rate of clinical improvement was 73.3% (22/30) in the study group and was 53.3% (16/30) in the control group (p = 0.10). At the end of the study, mortality developed in 6 patients (20%) in the study group and in 9 (30%) patients in the control group (p = 0.37). At the end of the follow-up period, the average peripheral capillary oxygen saturation (SpO2) values of the study and control groups were found to be 93.5 and 93.0%, respectively. Partial pressure of oxygen (PaO2)/FiO2 ratios were determined as 236.3 ± 85.7 and 220.8 ± 127.3 in the study and control groups, respectively. While the blood lymphocyte count was higher in the study group compared to the control group (1698 ± 1438 and 1256 ± 710, respectively) at the end of the follow-up period (p = 0.24); reduction in serum C-reactive protein (CRP), ferritin and D-dimer levels was more pronounced in the study group (p = 0.02, p = 0.005 and p = 0.03, respectively)., Conclusions: According to the findings obtained, ivermectin can provide an increase in clinical recovery, improvement in prognostic laboratory parameters and a decrease in mortality rates even when used in patients with severe COVID-19. Consequently, ivermectin should be considered as an alternative drug that can be used in the treatment of COVID-19 disease or as an additional option to existing protocols.

It is difficult to distinguish coronavirus disease-2019 (COVID-19) from other viral respiratory tract infections owing to the similarities in clinical and radiological findings. This study aims to determine the clinical importance of platelet count and platelet indices in the differentiation of COVID-19 from influenza and the value of these parameters in the differential diagnosis of COVID-19. The medical records of the patients and the electronic patient monitoring system were retrospectively analyzed. Demographic characteristics, admission symptoms, laboratory findings, radiological involvement, comorbidities, and mortality of the patients were recorded. Forty-three patients diagnosed with influenza and 54 diagnosed with COVID-19 were included in the study. The average age of the COVID-19 patients was lower than that of the influenza patients (influenza: 60.5 years, COVID-19: 52.4 years; pp = 0.024),.024), and the male gender was predominant in the COVID-19 group (influenza: 42%, COVID-19: 56%). According to laboratory findings, the mean platelet volume (MPV) and MPV/platelet ratio were statistically significantly lower, whereas the eosinophil count and platelet distribution width levels were significantly higher (p < 0.05) in the COVID-19 group. It was found that the most common symptom in both groups was dyspnea and that the symptom was more prevalent among influenza patients. In the diagnosis of COVID-19, the platelet count and platelet indices are easily accessible, inexpensive, and important parameters in terms of differential diagnosis and can help in the differentiation of COVID-19 from influenza during seasonal outbreaks of the latter., (© 2020 Wiley Periodicals LLC.)

Background: Although first responders (FRs) represent a high-risk group for exposure, little information is available regarding their risk of coronavirus disease 2019 (COVID-19) infection. The purpose of the current study was to determine the serological prevalence of past COVID-19 infection in a cohort of municipal law enforcement (LE) and firefighters (FFs)., Methods: Descriptive analysis of a de-identified data reporting Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) immunoglobulin G (IgG), or COR2G, serology results for municipal FRs. As part of the serology process, FRs were surveyed for COVID-19-like symptoms since February 2020 and asked to report any prior COVID-19 nasal swab testing. Descriptive statistics and two-sided Chi Square tests with Yates correction were used to compare groups., Results: Of 318 FRs, 225 (80.2%) underwent serology testing (LE: 163/207 [78.7%]; FF: 92/111 [82.9%]). The prevalence of positive serology for all FRs tested was 3/255 (1.2%). Two LE (1.2%) and one FF (1.1%) had positive serology (P = 1.0). Two hundred and twenty-four FRs responded to a survey regarding prior symptoms and testing. Fifty-eight (25.9%) FRs (44 LE; 14 FFs) reported the presence of COVID-19-like symptoms. Of these, only nine (15.5%) received reverse transcriptase - polymerase chain reaction (RT-PCR) testing; none were positive. Two of the three FRs with positive serology reported no COVID-19-like symptoms and none of these responders had received prior nasal RT-PCR swabs. The overall community positive RT-PCR rate was 0.36%, representing a three-fold higher rate of positive seroprevalence amongst FRs compared with the general population (P = .07)., Conclusions: Amongst a cohort of municipal FRs with low community COVID-19 prevalence, the seroprevalence of SARS-CoV-19 IgG Ab was three-fold greater than the general community. Two-thirds of positive FRs reported a lack of symptoms. Only 15.5% of FRs with COVID-19-like symptoms received RT-PCR testing. In addition to workplace control measures, increased testing availability to FRs is critical in limiting infection spread and ensuring response capability.

The emerging outbreak of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide. We prescribed some promising medication to our patients with mild to moderate pneumonia due to SARS-CoV-2, however such drugs as chloroquine, hydrossichloroquine, azithromycin, antivirals (lopinavir/ritonavir, darunavir/cobicistat) and immunomodulating agents (steroids, tocilizumab) were not confirmed as effective against SARS-CoV2. We, therefore, started to use auto-hemotherapy treated with an oxygen/ozone (O 2 /O 3 ) gaseous mixture as adjuvant therapy. In Udine University Hospital (Italy) we performed a case-control study involving hospitalized adult patients with confirmed COVID-19 with mild to moderate pneumonia. Clinical presentations are based upon clinical phenotypes identified by the Italian Society of Emergency and Urgency Medicine (SIMEU-Società Italiana di Medicina di Emergenza-Urgenza) and patients that met criteria of phenotypes 2 to 4 were treated with best available therapy (BAT), with or without O 3 -autohemotherapy. 60 patients were enrolled in the study: 30 patients treated with BAT and O 2 /O 3 mixture, as adjuvant therapy and 30 controls treated with BAT only. In the group treated with O 3 -autohemotherapy plus BAT, patients were younger but with more severe clinical phenotypes. A decrease of SIMEU clinical phenotypes was observed (2.70 ± 0.67 vs. 2.35 ± 0.88, p = 0.002) in all patients during hospitalization but this clinical improvement was statistically significant only in O 3 -treated patients (2.87 ± 0.78 vs. 2.27 ± 0.83, p < 0.001), differently to the control group (2.53 ± 0.51 vs. 2.43 ± 0.93, p = 0.522). No adverse events were observed associated with the application of O 2 /O 3 gaseous mixture. O 2 /O 3 therapy as adjuvant therapy could be useful in mild to moderate pneumonia due to SARS-CoV-2. Randomized prospective study is ongoing [Clinical Trials.gov ID: Z7C2CA5837].

A 32-year-old man with a clear and compact graft following a penetrating keratoplasty 6 years back, developed an episode of acute graft rejection, coinciding with the COVID-19 disease. Subsequent to the infection with the novel coronavirus, he developed symptoms of acute graft rejection concurrent with the development of respiratory distress and peak systemic symptoms. This was the phase of cytokine storm as evidenced by the raised inflammatory markers in his blood tests. Such a case of acute corneal graft rejection coinciding with SARS-CoV-2 infection has been reported only once in the literature and this unique association needs to be researched further., Competing Interests: None

Background: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm., Method: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26., Results: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation., Conclusion: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.

Rationale: Northern Italy has been particularly hit by the current Covid-19 pandemic. Italian deceased patients have a mean age of 78.5 years and only 1.2% have no comorbidities. These data started a public debate whether patients die "with" or "from" Covid-19. If on one hand the public opinion has been persuaded to believe that Covid-19 infection has poor outcomes just in elderly and/or fragile subjects, on the other hand, hospitals are admitting an increasing number of healthy young patients needing semi-intensive or intensive care units., Patient Concerns: At the end of March 2020, a 79-year-old patient (M.G.) was admitted to the emergency department of our hospital with a 5 days history of fever, dyspnea, and cough. He was known for hypertension and coronary artery disease with a previous coronary artery stenting. Both the comorbidities were carried out without complications and the patient was previously asymptomatic and in good health. At admission, he was febrile and showed signs of respiratory failure with hypoxia and hypocapnia at blood gas analysis., Diagnosis: The day after, he was tested for SARS-CoV-2 with a real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swab, which turned positive and a chest CT-Scan was consistent with the diagnosis of interstitial pneumonia., Interventions: He was treated with i.v. diuretics, paracetamol, prolonged noninvasive ventilation (CPAP), and empiric antibiotic therapy on top of his chronic treatment., Outcomes: A treatment with heparin and corticosteroids was started; however, he developed irreversible respiratory failure. Invasive ventilation was not considered appropriate due to his comorbidities, low chances of recovery, and intensive care unit overcrowding. The patient died 9 days after admission., Lessons: Health conditions that are most reported as risk factors are common cardiovascular diseases that can be managed in modern clinical practice. Through a brief illustrative clinical case, we would like to underline how Covid-19 can be per se the cause of death in patients that would otherwise have had an acceptable life expectancy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A high number of thrombotic complications have been reported in critically ill patients with coronavirus disease 2019 (COVID-19) and appear to be related to a hypercoagulable state. Evidence regarding detection, management, and monitoring of COVID-19-associated coagulopathy is still missing. We propose to describe the thrombus viscoelastic properties to investigate the mechanisms of hypercoagulability in patients with COVID-19., Methods: Thromboelastography (TEG) was performed in 24 consecutive patients admitted to a single intensive care unit for COVID-19 pneumonia, and 10 had a second TEG before being discharged alive from the intensive care unit., Results: Compared with a group of 20 healthy participants, patients with COVID-19 had significantly decreased values of reaction time, coagulation time, and lysis index and increased values of α angle, maximum amplitude, clot strength, and coagulation index. Velocity curves were consistent with increased generation of thrombin. These values persisted in surviving patients despite their good clinical course., Discussion: In patients with COVID-19, TEG demonstrates a complex and prolonged hypercoagulable state including fast initiation of coagulation and clot reinforcement, low fibrinolysis, high potential of thrombin generation, and high fibrinogen and platelet contribution. The antithrombotic strategy in patients with COVID-19 during intensive care hospitalisation and after discharge should be investigated in further studies., Competing Interests: Conflict of interest On behalf of all the authors, the corresponding author states that there is no conflict of interest., (Copyright © 2020 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Coronavirus Disease-19 (COVID-19) is associated with a high rate of thrombosis, the pathophysiology of which is not well defined. Viscoelastic testing may identify and characterise hypercoagulable states which are not apparent using conventional coagulation assays., Objectives: The objective of this study was to undertake viscoelastic evaluation of the coagulation state in critically ill adults with COVID-19-associated respiratory failure METHODS: This was a single-centre observational point prevalence cohort study of adults with COVID-19-associated respiratory failure requiring respiratory support in the intensive care unit. Coagulation status was evaluated using rotational thromboelastometry (ROTEM®) in conjunction with laboratory markers of coagulation., Results: Six patients fulfilled inclusion criteria. Each patient had one ROTEM® performed. All patients had supranormal clot amplitude at 10 min (A10) and supranormal clot firmness (maximal clot firmness) measured in at least one ROTEM® pathway, and five were supranormal on all pathways. Minimal clot lysis was present on all analyses. Fibrinogen and D-dimer were elevated and routine markers of coagulation within normal ranges in all patients., Conclusion: Patients with COVID-19-associated respiratory failure admitted to the intensive care unit exhibit a hypercoagulable state which is not appreciable on conventional tests of coagulation. Supranormal clot firmness, minimal fibrinolysis, and hyperfibrinogenaemia are key findings. Further research is required into the pathophysiology of this hypercoagulable state, as well as the harms and benefits of different anticoagulation strategies., Competing Interests: Conflict of Interest None of the authors have any interests to declare., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Background: Previous studies have demonstrated an association between adenovirus viremia and disease severity in immunocompromised children. However, few studies have focused on this association in immunocompetent children. This study explored the association between adenovirus viremia and adenovirus pneumonia severity in immunocompetent children., Methods: We performed a retrospective, observational study of immunocompetent children with adenovirus pneumonia admitted to Shenzhen Children's Hospital in Shenzhen, China. Pneumonia was classified as severe or mild based on the Chinese guideline for the classification of pneumonia severity. Serum samples from all the children included in the study were tested for adenovirus DNA with a quantitative polymerase chain reaction. Clinical manifestations, laboratory examinations, and disease severity were compared between children with severe and mild pneumonia., Results: A total of 111 immunocompetent children with adenovirus pneumonia (60 severe, 51 mild) were included. The median age was 40 months, and 64 patients were male. Five patients were admitted to the intensive care unit, and two underwent endotracheal intubation. All patients were discharged after recovery or improvement. Univariate analysis and binary logistic regression analysis showed that leukocytosis (OR = 1.1; 95% CI: 1.0 to 1.2; P = 0.033), co-infection with Mycoplasma pneumoniae (OR = 5.0; 95% CI: 2.1 to 12.3; P <  0.001), and high blood viral load (OR = 1.5; 95% CI: 1.2 to 2.0; P = 0.001) may be risk factors for severe adenovirus pneumonia., Conclusions: Leukocytosis, co-infection with Mycoplasma pneumoniae, and high blood viral load may be risk factors for severe adenovirus pneumonia in immunocompetent children. Blood viral load may predict pneumonia severity.

Background: Human adenoviruses (HAdV) infection caused pneumonia remains a major threat to global children health. Currently, diagnosis of severe HAdV pneumonia in children is hampered by the lack of specific biomarkers. Also, the severity of adenovirus pneumonia in pediatric patients is generally based on clinical features and existing biomarkers do not reliably correlate to clinical severity. Here, we asked whether local and systemic inflammatory mediators could act as biomarkers predicting severe HAdV pneumonia in children., Methods: Totally 37 common inflammatory protein levels were determined by Luminex assay in plasma and bronchoalveolar lavage (BAL) from pediatric patients who were diagnosed with HAdV pneumonia, and their correlation with the disease severity and lung lesion were assessed using statistical and bioinformatic analysis., Results: Among 37 inflammatory cytokines, the protein levels of 4 TNF superfamily (TNFSF) members and their receptors (TNF receptor superfamily, TNFRSF) [TNFSF13B, TNFSF14, sTNF-R1 and sTNF-R2] in the plasma and 7 TNFSF/TNFRSF members [TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFRSF8, sTNF-R1, and sTNF-R2] in the BAL were enhanced in patients with HAdV pneumonia compared with control subjects with airway foreign body. Moreover, the protein levels of all the tested TNFSF/TNFRSF members (except TNFSF12) were elevated in the BAL of severe group compared with non-severe HAdV pneumonia patients, while only TNFSF13B and TNFSF14 were dramatically increased in the plasma of severe cases, and positively related to the plasma CRP levels. In addition, ROC analysis indicated that TNFSF13B and TNFSF14 displayed a great potential to predict severe HAdV pneumonia., Conclusion: In pediatric HAdV pneumonia, TNFSF/TNFRSF members function as key molecules in local and systemic inflammatory network, and the plasma TNFSF13B and TNFSF14 may be the potential local and systemic inflammatory indicators of severe HAdV pneumonia in pediatric patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fan, Lu, Cao, Li, Yang, Huang, Ding, Wu and Lu.)

COVID-19, a novel coronavirus-related illness, has spread worldwide. Patients with apparently mild/moderate symptoms can suddenly develop severe pneumonia. Therefore, almost all COVID-19 patients require hospitalization, which can reduce limited medical resources in addition to overwhelming medical facilities. To identify predictive markers for the development of severe pneumonia, a comprehensive analysis of serum chemokines and cytokines was conducted using serial serum samples from COVID-19 patients. The expression profiles were analyzed along the time axis. Serum samples of common diseases were enrolled from a BioBank to confirm the usefulness of predictive markers. Five factors, IFN-λ3, IL-6, IP-10, CXCL9, and CCL17, were identified as predicting the onset of severe/critical symptoms. The factors were classified into two categories. Category A included IFN-λ3, IL-6, IP-10, and CXCL9, and their values surged and decreased rapidly before the onset of severe pneumonia. Category B included CCL17, which provided complete separation between the mild/moderate and the severe/critical groups at an early phase of SARS-CoV-2 infection. The five markers provided a high predictive value (area under the receiver operating characteristic curve (AUROC): 0.9-1.0, p < 0.001). Low expression of CCL17 was specifically observed in pre-severe COVID-19 patients compared with other common diseases, and the predictive ability of CCL17 was confirmed in validation samples of COVID-19. The factors identified could be promising prognostic markers to distinguish between mild/moderate and severe/critical patients, enabling triage at an early phase of infection, thus avoiding overwhelming medical facilities., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Six months since the outbreak of coronavirus disease (COVID-19), the pandemic continues to grow worldwide, although the outbreak in Wuhan, the worst-hit area, has been controlled. Thus, based on the clinical experience in Wuhan, we hypothesized that there is a relationship between the patient's CO 2 levels and prognosis. Methods: COVID-19 patients' information was retrospectively collected from medical records at the Leishenshan Hospital, Wuhan. Logistic and Cox regression analyses were conducted to determine the correlation between decreased CO 2 levels and disease severity or mortality risk. The Kaplan-Meier curve analysis was coupled with the log-rank test to understand COVID-19 progression in patients with decreased CO 2 levels. Curve fitting was used to confirm the correlation between computed tomography scores and CO 2 levels. Results: Cox regression analysis showed that the mortality risk of COVID-19 patients correlated with decreased CO 2 levels. The adjusted hazard ratios for decreased CO 2 levels in COVID-19 patients were 8.710 [95% confidence interval (CI): 2.773-27.365, P < 0.001], and 4.754 (95% CI: 1.380-16.370, P = 0.013). The adjusted odds ratio was 0.950 (95% CI: 0.431-2.094, P = 0.900). The Kaplan-Meier survival curves demonstrated that patients with decreased CO 2 levels had a higher risk of mortality. Conclusions: Decreased CO 2 levels increased the mortality risk of COVID-19 patients, which might be caused by hyperventilation during mechanical ventilation. This finding provides important insights for clinical treatment recommendations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hu, Li, Gao, Wang, Li, Chen, Huang, Huang, Li, Long, Liu, Guo and Wu.)

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was classified as a pandemic by the World Health Organization and has caused over 550,000 deaths worldwide as of July 2020. Accurate and scalable point-of-care devices would increase screening, diagnosis, and monitoring of COVID-19 patients. Here, we demonstrate rapid label-free electrochemical detection of SARS-CoV-2 antibodies using a commercially available impedance sensing platform. A 16-well plate containing sensing electrodes was pre-coated with receptor binding domain (RBD) of SARS-CoV-2 spike protein, and subsequently tested with samples of anti-SARS-CoV-2 monoclonal antibody CR3022 (0.1 μg/ml, 1.0 μg/ml, 10 μg/ml). Subsequent blinded testing was performed on six serum specimens taken from COVID-19 and non-COVID-19 patients (1:100 dilution factor). The platform was able to differentiate spikes in impedance measurements from a negative control (1% milk solution) for all CR3022 samples. Further, successful differentiation and detection of all positive clinical samples from negative control was achieved. Measured impedance values were consistent when compared to standard ELISA test results showing a strong correlation between them (R 2 =0.9). Detection occurs in less than five minutes and the well-based platform provides a simplified and familiar testing interface that can be readily adaptable for use in clinical settings., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The 2019 SARS CoV-2 (COVID-19) pandemic has illustrated the need for rapid and accurate diagnostic tests. In this work, a multiplexed grating-coupled fluorescent plasmonics (GC-FP) biosensor platform was used to rapidly and accurately measure antibodies against COVID-19 in human blood serum and dried blood spot samples. The GC-FP platform measures antibody-antigen binding interactions for multiple targets in a single sample, and has 100% selectivity and sensitivity (n = 23) when measuring serum IgG levels against three COVID-19 antigens (spike S1, spike S1S2, and the nucleocapsid protein). The GC-FP platform yielded a quantitative, linear response for serum samples diluted to as low as 1:1600 dilution. Test results were highly correlated with two commercial COVID-19 antibody tests, including an enzyme linked immunosorbent assay (ELISA) and a Luminex-based microsphere immunoassay. To demonstrate test efficacy with other sample matrices, dried blood spot samples (n = 63) were obtained and evaluated with GC-FP, yielding 100% selectivity and 86.7% sensitivity for diagnosing prior COVID-19 infection. The test was also evaluated for detection of multiple immunoglobulin isotypes, with successful detection of IgM, IgG and IgA antibody-antigen interactions. Last, a machine learning approach was developed to accurately score patient samples for prior COVID-19 infection, using antibody binding data for all three COVID-19 antigens used in the test., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Veras et al.)

This study compared the laboratory indexes in 40 non-severe COVID-19 patients with those in 57 healthy controls. In the peripheral blood system of non-severe symptom COVID-19 patients, lymphocytes, eosinophils, basophils, total procollagen type 1 amino-terminal propeptide, osteocalcin N-terminal, thyroid-stimulating hormone, growth hormone, and insulin-like growth factor-binding protein 3 significantly decreased, and total protein, albumin, alanine transaminase, alkaline phosphatase, γ-glutamyl transferase, activated partial thromboplastin time, prothrombin time, fibrinogen, D-dimer, fibrinogen degradation products, human epididymal protein 4, serum ferritin, and C-reactive protein were elevated. SARS-CoV-2 infection can affect hematopoiesis, hemostasis, coagulation, fibrinolysis, bone metabolism, thyroid, parathyroid glands, the liver, and the reproductive system.

Infection from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), though mainly a respiratory disease, can impair many systems, including causing hematological complications. Lymphopenia and hypercoagulability have been reported in adults with coronavirus disease 2019 (COVID-19) and are considered markers of poor prognosis. This review summarizes the hematological findings in children with SARS-CoV-2 infection. The majority of infected children had a normal leukocyte count, while the most common white blood cell abnormality was leukopenia. Lymphopenia, which may be a marker of severe disease, was rarer in children than in adults, possibly due to their immature immune system or due to the less severe manifestation of COVID-19 in this age group. Age may have an impact, and in neonates and infants the most common abnormality was lymphocytosis. Abnormalities of red blood cells and platelets were uncommon. Anemia and hypercoagulability were reported mainly in children presenting the novel multisystem inflammatory syndrome (MIS) associated with SARS-CoV-2., (© 2020 Wiley Periodicals LLC.)

Introduction: Characteristics of blood coagulation and its relation to clinical outcomes in COVID-19 patients are still rarely reported. We aimed to investigate the blood coagulation function and its influences on clinical outcomes of patients with syndrome coronavirus 2 (SARS-CoV-2) infection., Methods: A total of 71 severe patients with confirmed SARS-CoV-2 infection who were treated in Wuhan First Hospital from February 12 to March 20, 2020, were enrolled. The blood coagulation data in these patients and in 61 healthy controls were collected. The patients with COVID-19 were divided into two groups: the aggravated group and the nonaggravated group, respectively, basing on whether the patients' conditions turned to critically ill or not after admission., Results: Compared with healthy controls, patients with COVID-19 had significant performances with coagulation dysfunction, including dramatically elevated values of FIB, PT, APTT, INR, FDP, and D-Dimers but markedly reduced AT value (P < .05). Importantly, more noteworthy coagulation disorders similar to the differences between patients and controls were found in the aggravated patients with conditions deterioration after admission than those in the nonaggravated patients without conditions deterioration (P < .05). Moreover, the aggravated patients possessed a longer hospital stay and a higher mortality compared with the nonaggravated patients (P < .001). The coagulation parameters of COVID-19 patients were widely and closely related to the indexes of liver function and inflammation (P < .05), indicating the coagulation dysfunction of these patients may be caused by liver injury and inflammatory storm., Conclusion: Severe patients with SARS-CoV-2 infection often possess coagulation dysfunction on admission. A certain correlation exists in coagulation disorder and adverse clinical outcome among severe COVID-19 patients., (© 2020 John Wiley & Sons Ltd.)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic has been emerged as a cardinal public health problem. Children have their own specific clinical features; notably, they seem to be escaping the severe respiratory adverse effects. The international scientific community is rapidly carrying out studies, driving to the need to reassess knowledge of the disease and therapeutic strategies., Aim: To assess the characteristics of COVID-19 infected children worldwide of all ages, from neonates to children and adolescents, and how they differ from their adult counterparts., Search Strategy: An electronic search in PubMed was conducted, using combinations of the following keywords: coronavirus, SARS-CoV-2, COVID-19, children. The search included all types of articles written in English between January 1, 2019 until August 15, 2020., Results: The search identified 266 relevant articles. Children were mainly within family clusters of cases and have relatively milder clinical presentation compared with adults; children were reported to have better outcomes with a significantly lower mortality rate. Cough and fever were the most common symptoms while pneumonia was the cardinal respiratory manifestation of infected children. Laboratory results and thoracic imaging give varying results., Conclusions: Children were mainly family cluster cases and usually presented with a mild infection, although cases presented with the multisystem inflammatory syndrome are becoming more apparent. Studies determining why the manifestations of SARS-CoV-2 infection are so variable may help to gain a better understanding of the disease and accelerate the development of vaccines and therapies., (© 2020 Wiley Periodicals LLC.)

Purpose: To assess the reliability of CXR and to describe CXR findings and clinical and laboratory characteristics associated with positive and negative CXR., Methods: Retrospective two-center study on consecutive patients admitted to the emergency department of two north-western Italian hospitals in March 2020 with clinical suspicion of COVID-19 confirmed by RT-PCR and who underwent CXR within 24 h of the swab execution. 260 patients (61% male, 62.8 ± 15.8 year) were enrolled. CXRs were rated as positive (CXR+) or negative (CXR-), and features reported included presence and distribution of airspace opacities, pleural effusion and reduction in lung volumes. Clinical and laboratory data were collected. Statistical analysis was performed with nonparametric tests, binary logistic regression (BLR) and ROC curve analysis., Results: Sensitivity of CXR was 61.1% (95%CI 55-67%) with a typical presence of bilateral (62.3%) airspace opacification, more often with a lower zone (88.7%) and peripheral (43.4%) distribution. At univariate analysis, several factors were found to differ significantly between CXR+ and CXR-. The BLR confirmed as significant predictors only lactate dehydrogenase (LDH), C-reactive protein (CRP) and interval between the onset of symptoms and the execution of CXR. The ROC curve procedure determined that CRX+ was associated with LDH > 500 UI/L (AUC = 0.878), CRP > 30 mg/L (AUC = 0.830) and interval between the onset of symptoms and the execution of CXR > 4 days (AUC = 0.75). The presence of two out of three of the above-mentioned predictors resulted in CXR+ in 92.5% of cases, whereas their absence in 7.4%., Conclusion: CXR has a low sensitivity. LDH, CRP and interval between the onset of symptoms and the execution of CXR are major predictors for a positive CXR.