Zonulin, a marker of gut permeability, is associated with mortality in a cohort of hospitalised peruvian COVID-19 patients.

Zonulin has previously been related to intestinal permeability in various inflammatory diseases, and more recently to the physiopathology of severe COVID-19 infections. We analysed serum samples from a previous study of a Peruvian cohort of hospitalised COVID-19 patients, for the quantification of zonulin by sandwich ELISA. Comparisons with clinical data, haematological and biochemical parameters and cytokine/chemokine levels were made. We found higher baseline zonulin levels in deceased patients, and zonulin was associated with fatal outcome in multivariable analyses, even after adjustment for age, gender, and obesity. There were also positive correlations between zonulin, creatinine, D-dimer values and prothrombin time, while inverse correlations were found for Sa/FiO2 ratio and CCL5 (RANTES). Further longitudinal studies are recommended to analyse the variation of zonulin levels over time as well as their relationship with long-COVID.

Systematic review with meta-analysis of mid-regional pro-adrenomedullin (MR-proadm) as a prognostic marker in Covid-19-hospitalized patients.

BACKGROUND: Mid-regional pro-adrenomedullin (MR-proADM) is useful for risk stratification in patients with sepsis and respiratory infections. The study's purpose was to assess the available data and determine the association between MR-proADM levels and mortality in COVID-19 participants. METHODS: A comprehensive literature search of medical electronic databases was performed including PubMed, Web of Science, Scopus, Cochrane, and grey literature for relevant data published from 1 January 2020, to 20 November 2022. Mean differences (MD) with 95% confidence intervals (CI) were calculated. RESULTS: Fourteen studies reported MR-proADM levels in survivors vs. non-survivors of COVID-19 patients. Pooled analysis showed that MR-proADM level in the survivor group was 0.841 ± 0.295 nmol/L for patients who survive COVID-19, compared to 1.692 ± 0.761 nmol/L for non-survivors (MD = -0.78; 95%CI: -0.92 to -0.64; p < 0.001). CONCLUSIONS: The main finding of this study is that mortality of COVID-19 is linked to MR-proADM levels, according to this meta-analysis. The use of MR-proADM might be extremely beneficial in triaging, assessing probable therapy escalation, predicting potential complications during therapy or significant clinical deterioration of patients, and avoiding admission which may not be necessary. Nevertheless, in order to confirm the obtained data, it is necessary to conduct large prospective studies that will address the potential diagnostic role of MR-proADM as a marker of COVID-19 severity.KEY MESSAGESSeverity of COVID-19 seems to be linked to MR-proADM levels and can be used as a potential marker for predicting a patient's clinical course.The use of MR-proADM might be beneficial in triaging, assessing probable therapy escalation, predicting potential complications during therapy or significant clinical deterioration of patients, and avoiding admission which may not be necessary.For patients with COVID-19, MR-proADM may be an excellent prognostic indicator because it is a marker of endothelial function that may predict the precise impact on the equilibrium between vascular relaxation and contraction and lowers platelet aggregation inhibitors, coagulation inhibitors, and fibrinolysis activators in favor of clotting factors.

Circulating MR-proADM levels, as an indicator of endothelial dysfunction, for early risk stratification of mid-term mortality in COVID-19 patients.

OBJECTIVES: Thromboinflammation, resulting from a complex interaction between thrombocytopathy, coagulopathy, and endotheliopathy, contributes to increased mortality in COVID-19 patients. MR-proADM, as a surrogate of adrenomedullin system disruption, leading to endothelial damage, has been reported as a promising biomarker for short-term prognosis. We evaluated the role of MR-proADM in the mid-term mortality in COVID-19 patients. METHODS: A prospective, observational study enrolling COVID-19 patients from August to October 2020. A blood sample for laboratory test analysis was drawn on arrival in the emergency department. The primary endpoint was 90-day mortality. The area under the curve (AUC) and Cox regression analyses were used to assess discriminatory ability and association with the endpoint. RESULTS: A total of 359 patients were enrolled, and the 90-day mortality rate was 8.9%. ROC AUC for MR-proADM predicting 90-day mortality was 0.832. An optimal cutoff of 0.80 nmol/L showed a sensitivity of 96.9% and a specificity of 58.4%, with a negative predictive value of 99.5%. Circulating MR-proADM levels (inverse transformed), after adjusting by a propensity score including eleven potential confounders, were an independent predictor of 90-day mortality (HR: 0.162 [95% CI: 0.043-0.480]) CONCLUSIONS: Our data confirm that MR-proADM has a role in the mid-term prognosis of COVID-19 patients and might assist physicians with risk stratification.

Mid-regional pro-adrenomedullin as a predictor of in-hospital mortality in adult patients with COVID-19: a single-centre prospective study.

BACKGROUND: To determine the predictive value of mid-regional pro-adrenomedullin (MR-proADM) compared to routine clinical and laboratory parameters in patients with COVID-19. METHODS: A total of 135 adult patients hospitalized with COVID-19 were included in a prospective single-centre study. In addition to routine parameters, the levels of MR-proADM in blood plasma were measured on the day of hospitalization. The patients were divided into 2 groups: those who survived and were discharged (n = 115, 85%) and those who did not survive (n = 20, 15%). Data are presented as median and interquartile range. RESULTS: The non-survivors had a statistically significantly greater age (73.4 [63.5-84.8] vs. 62.2 [50.3-71.4] years, P = 0.001), a lower level of haemoglobin oxygen saturation (91 [87-92] vs. 92 [92-93]%, P < 0.001), lower lymphocyte level (13 [7-30] vs. 21 [15-27]%, P = 0.03), higher lactate dehydrogenase (338 [273-480] vs. 280 [233-383] EU L-1, P = 0.04) and aspartate aminotransferase levels (49 [28-72] vs. 33 [23-47] EU L-1, P = 0.03), a higher National Early Warning (NEWS) score (7 [7- 8] vs. 6 [5-7] points, P < 0.001), and higher procalcitonin (0.16 [0.11-0.32] vs. 0.1 [0.07-0.18] ng mL-1, P = 0.006) and MR-proADM levels (1.288 [0.886-1.847] vs. 0.769 [0.6-0.955] nmol L-1, P < 0.001). MR-proADM had the highest predictive value for death during hospital stay (cut-off: 0.895 nmol L-1, AUC ROC 0.78 [95% CI: 0.66-0.90], sensitivity 75%, specificity 69%, OR 6.58 [95% CI: 2.22-19.51]). CONCLUSIONS: Compared with other indicators, MR-proADM has the highest predictive value for in-hospital mortality in patients with COVID-19.

Identification of COVID-19 patients at risk of hospital admission and mortality: a European multicentre retrospective analysis of mid-regional pro-adrenomedullin.

BACKGROUND: Mid-Regional pro-Adrenomedullin (MR-proADM) is an inflammatory biomarker that improves the prognostic assessment of patients with sepsis, septic shock and organ failure. Previous studies of MR-proADM have primarily focussed on bacterial infections. A limited number of small and monocentric studies have examined MR-proADM as a prognostic factor in patients infected with SARS-CoV-2, however there is need for multicenter validation. An evaluation of its utility in predicting need for hospitalisation in viral infections was also performed. METHODS: An observational retrospective analysis of 1861 patients, with SARS-CoV-2 confirmed by RT-qPCR, from 10 hospitals across Europe was performed. Biomarkers, taken upon presentation to Emergency Departments (ED), clinical scores, patient demographics and outcomes were collected. Multiclass random forest classifier models were generated as well as calculation of area under the curve analysis. The primary endpoint was hospital admission with and without death. RESULTS: Patients suitable for safe discharge from Emergency Departments could be identified through an MR-proADM value of ≤ 1.02 nmol/L in combination with a CRP (C-Reactive Protein) of ≤ 20.2 mg/L and age ≤ 64, or in combination with a SOFA (Sequential Organ Failure Assessment) score < 2 if MR-proADM was ≤ 0.83 nmol/L regardless of age. Those at an increased risk of mortality could be identified upon presentation to secondary care with an MR-proADM value of > 0.85 nmol/L, in combination with a SOFA score ≥ 2 and LDH > 720 U/L, or in combination with a CRP > 29.26 mg/L and age ≤ 64, when MR-proADM was > 1.02 nmol/L. CONCLUSIONS: This international study suggests that for patients presenting to the ED with confirmed SARS-CoV-2 infection, MR-proADM in combination with age and CRP or with the patient's SOFA score could identify patients at low risk where outpatient treatment may be safe.

Prognostic Value of Mid-Region Proadrenomedullin and In Vitro Interferon Gamma Production for In-Hospital Mortality in Patients with COVID-19 Pneumonia and Respiratory Failure: An Observational Prospective Study.

Coagulopathy and immune dysregulation have been identified as important causes of adverse outcomes in coronavirus disease (COVID-19). Mid-region proadrenomedullin (MR-proADM) is associated with endothelial damage and has recently been proposed as a prognostic factor in COVID-19. In non-COVID-19 immunocompromised patients, low in vitro interferon gamma (IFNγ) production correlates with infection risk and mortality. This prospective, monocentric, observational study included adult patients consecutively admitted with radiologic evidence of COVID-19 pneumonia and respiratory failure. MR-proADM and in vitro IFNγ production were measured at T0 (day 1 from admission) and T1 (day 7 from enrollment). One hundred patients were enrolled. Thirty-six percent were females, median age 65 (Q1-Q3 54.5-75) years, and 58% had ≥1 comorbidity. Only 16 patients had received COVID-19 vaccination before hospitalization. At admission, the median PaO2:FiO2 ratio was 241 (157-309) mmHg. In-hospital mortality was 13%. MR-proADM levels differed significantly between deceased and survivors both at T0 (1.41 (1.12-1.77) nmol/L vs. 0.79 (0.63-1.03) nmol/L, p < 0.001) and T1 (1.67 (1.08-1.96) nmol/L vs. 0.66 (0.53-0.95) nmol/L, p < 0.001). In vitro IFNγ production at T0 and T1 did not vary between groups. When only the subset of non-vaccinated patients was considered, both biomarkers at T1 resulted significantly associated with in-hospital mortality. AUROC for MR-proADM at T0 to predict in-hospital mortality was 0.87 (95%CI 0.79-0.94), with the best cut-off point at 1.04 nmol/L (92% sensitivity, 75% specificity and 98% negative predictive value). In patients with COVID-19 pneumonia and different degrees of respiratory failure, MR-proADM at admission and during hospitalization resulted strongly associated with in-hospital mortality. Low in vitro IFNγ production after the first week of hospitalization was associated with mortality in non-vaccinated patients possibly identifying the subgroup characterized by a higher degree of immune suppression.

Effects of Bevacizumab Combined with Chemotherapy on CT, CyFRA21-1, and ProGRP and Prognosis of Lung Cancer Patients under Nursing Intervention.

Objective: Molecular targeted drug therapy and chemotherapy are the main treatments for advanced non-small-cell lung cancer, and the combination of both has advantages in prolonging patients' progression-free survival and overall survival. This study investigated the effects of bevacizumab combined with chemotherapy under nursing intervention on CT, cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and gastrin-releasing peptide precursor (ProGRP) and prognosis of lung cancer patients. Methods: 102 patients with non-small-cell lung cancer admitted to our hospital from January 2018 to May 2019 were divided into observation group and control group, with 51 cases each. The control group was treated with basic chemotherapy, and the observation group was treated with bevacizumab in combination with the control group, and both groups used nursing interventions. The clinical effects, CYFRA21-1 and ProGRP levels, baseline data, CT parameters, 24-month cumulative survival, and the effects of CYFRA21-1 and ProGRP on long-term survival and lung function were compared. Results: The disease control rate of the observation group was 94.12%, which was significantly higher than that of the control group (76.47%); after 7 d, 30 d, 60 d, and 90 d of treatment, the levels of CYFRA21-1 and ProGRP were statistically downregulated. The difference in lymph node metastasis, lesion diameter, plain Eff-Z, venous stage, and arterial stage normalized iodine concentrations (NIC) was statistically significant; the survival rate at 24 months in the observation group was 74.51% (38/51); the cumulative survival rate at 24 months in the control group was 52.94% (27/51), and the difference was statistically significant (X 2 = 4.980, P = 0.026). The cumulative survival rate at 24 months was significantly lower in patients with high expression of CYFRA21-1 and ProGRP compared with those with low expression of CYFRA21-1 and ProGRP. After treatment, in the observation group, the forceful spirometry (FVC), forceful expiratory volume in one second (FEV1), and FEV1/FVC levels were significantly different from those before treatment and were significantly different from those in the control group. Conclusion: Bevacizumab in combination with standard chemotherapy regimens with nursing interventions could benefit patients with advanced non-small-cell lung cancer and had a good prospect of application.

Mid-regional proadrenomedullin, C-terminal proendothelin-1 values, and disease course are not different in critically ill SARS-CoV-2 pneumonia patients with obesity.

BACKGROUND/OBJECTIVES: Patients affected by obesity and Coronavirus disease 2019, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appear to have a higher risk for intensive care (ICU) admission. A state of low-grade chronic inflammation in obesity has been suggested as one of the underlying mechanisms. We investigated whether obesity is associated with differences in new inflammatory biomarkers mid-regional proadrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), and clinical outcomes in critically ill patients with SARS-CoV-2 pneumonia. SUBJECTS/METHODS: A total of 105 critically ill patients with SARS-CoV-2 pneumonia were divided in patients with obesity (body mass index (BMI) ≥ 30 kg/m2, n = 42) and patients without obesity (BMI < 30 kg/m2, n = 63) and studied in a retrospective observational cohort study. MR-proADM, CT-proET-1 concentrations, and conventional markers of white blood count (WBC), C-reactive protein (CRP), and procalcitonin (PCT) were collected during the first 7 days. RESULTS: BMI was 33.5 (32-36.1) and 26.2 (24.7-27.8) kg/m2 in the group with and without obesity. There were no significant differences in concentrations MR-proADM, CT-proET-1, WBC, CRP, and PCT at baseline and the next 6 days between patients with and without obesity. Only MR-proADM changed significantly over time (p = 0.039). Also, BMI did not correlate with inflammatory biomarkers (MR-proADM rho = 0.150, p = 0.125, CT-proET-1 rho = 0.179, p = 0.067, WBC rho = -0.044, p = 0.654, CRP rho = 0.057, p = 0.564, PCT rho = 0.022, p = 0.842). Finally, no significant differences in time on a ventilator, ICU length of stay, and 28-day mortality between patients with or without obesity were observed. CONCLUSIONS: In critically ill patients with confirmed SARS-CoV-2 pneumonia, obesity was not associated with differences in MR-proADM, and CT-proET-1, or impaired outcome. TRIAL REGISTRATION: Netherlands Trial Register, NL8460.

Zonulin and claudin-5 levels in multisystem inflammatory syndrome and SARS-CoV-2 infection in children.

AIM: SARS-CoV-2 infection in children is generally asymptomatic or mild; however, it can lead to a life-threatening clinical condition, multisystem inflammatory syndrome in children (MIS-C), days or weeks after the infection. Increased intestinal permeability isa possible triggering factor at the onset of the hyperinflammation associated with MIS-C. Zonulin and claudin-5 are involved in intestinal permeability. In this study, we aimed to investigate serum zonulin and claudin-5 levels in SARS-CoV-2 infection and MIS-C disease. METHODS: The study group consisted of children diagnosed with MIS-C or SARS-CoV-2 infection who presented to a university hospital paediatric emergency or infectious diseases departments. The control group included well patients seen at the General Pediatrics units for routine follow-up. Serum zonulin and claudin-5 levels were measured at the time of diagnosis. RESULTS: Fifteen patients were included in the MIS-C group, 19 in the SARS-CoV-2 infection group and 21 in the control group. The mean zonulin level in the MIS-C group was significantly higher than in the control group (P < 0.001). Mean Claudin-5 levels were Psignificantly lower in the SARS-CoV-2 infection group than in the control group (P < 0.001). CONCLUSION: These results indicate that increased intestinal permeability may be involved in the pathogenesis of SARS-CoV-2 infection and MIS-C disease. Larger clinical trials are needed to clarify the role of serum zonulin and claudin-5 on intestinal permeability in MIS-C and SARS-CoV-2 infection in children.

Proadrenomedullin Predicts Severe Disease in Children With Suspected Community-acquired Pneumonia.

BACKGROUND: Proadrenomedullin (proADM), a vasodilatory peptide with antimicrobial and anti-inflammatory properties, predicts severe outcomes in adults with community-acquired pneumonia (CAP) to a greater degree than C-reactive protein and procalcitonin. We evaluated the ability of proADM to predict disease severity across a range of clinical outcomes in children with suspected CAP. METHODS: We performed a prospective cohort study of children 3 months to 18 years with CAP in the emergency department. Disease severity was defined as mild (discharged home), mild-moderate (hospitalized but not moderate-severe or severe), moderate-severe (eg, hospitalized with supplemental oxygen, broadening of antibiotics, complicated pneumonia), and severe (eg, vasoactive infusions, chest drainage, severe sepsis). Outcomes were examined using proportional odds logistic regression within the cohort with suspected CAP and in a subset with radiographic CAP. RESULTS: Among 369 children, median proADM increased with disease severity (mild: median [IQR], 0.53 [0.43-0.73]; mild-moderate: 0.56 [0.45-0.71]; moderate-severe: 0.61 [0.47-0.77]; severe: 0.70 [0.55-1.04] nmol/L) (P = .002). ProADM was significantly associated with increased odds of developing severe outcomes (suspected CAP: OR, 1.68; 95% CI, 1.2-2.36; radiographic CAP: OR, 2.11; 95% CI, 1.36-3.38) adjusted for age, fever duration, antibiotic use, and pathogen. ProADM had an AUC of 0.64 (95% CI, .56-.72) in those with suspected CAP and an AUC of 0.77 (95% CI, .68-.87) in radiographic CAP. CONCLUSIONS: ProADM was associated with severe disease and discriminated moderately well children who developed severe disease from those who did not, particularly in radiographic CAP.

Characteristics of procalcitonin in hospitalized COVID-19 patients and clinical outcomes of antibiotic use stratified by procalcitonin levels.

We examined the characteristics of pro-calcitonin (PCT) in hospitalized COVID-19 patients (cohort 1) and clinical outcomes of antibiotic use stratified by PCT in non-critically ill patients without bacterial co-infection (cohort 2). Retrospective reviews were performed in adult, hospitalized COVID-19 patients during March-May 2020. For cohort 1, we excluded hospital transfers, renal disease and extra-pulmonary infection without isolated pathogen(s). For cohort 2, we further excluded microbiologically confirmed infection, 'do not resuscitate ± do not intubate' status, and intensive care unit (ICU). For cohort 1, PCT was compared between absent/low-suspicion and proven bacterial co-infections. Factors associated with elevated PCT and sensitivity/specificity/PPV/NPV of PCT cutoffs for identifying bacterial co-infections were explored. For cohort 2, clinical outcomes including mechanical ventilation within 5 days (MV5) were compared between the antibiotic and non-antibiotic groups stratified by PCT ≥ 0.25 µg/L. Nine hundred and twenty four non-ICU and 103 ICU patients were included (cohort 1). The median PCT was higher in proven vs. absent/low-suspicion of bacterial co-infection. Elevated PCT was significantly associated with proven bacterial co-infection, ICU status and oxygen requirement. For PCT ≥ 0.25 µg/L, sensitivity/specificity/PPV/NPV were 69/65/6.5/98% (non-ICU) and 75/33/8.6/94% (ICU). For cohort 2, 756/1305 (58%) patients were included. Baseline characteristics were balanced between the antibiotic and non-antibiotic groups except PCT ≥ 0.25 µg/L (antibiotic:non-antibiotic = 59%:24%) and tocilizumab use (antibiotic:non-antibiotic = 5%:2%). 23% (PCT < 0.25 µg/L) and 58% (PCT ≥ 0.25 µg/L) received antibiotics. Antibiotic group had significantly higher rates of MV5. COVID-19 severity inferred from ICU status and oxygen requirement as well as the presence of bacterial co-infections were associated with elevated PCT. PCT showed poor PPV and high NPV for proven bacterial co-infections. The use of antibiotics did not show improved clinical outcomes in COVID-19 patients with PCT ≥ 0.25 µg/L outside of ICU when bacterial co-infections are of low suspicion.

Prognostic value of copeptin and mid-regional proadrenomedullin in COVID-19-hospitalized patients.

BACKGROUND: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality. METHODS: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC). RESULTS: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001). CONCLUSIONS: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.

Clinical Utility of Midregional Proadrenomedullin in Patients with COVID-19.

OBJECTIVE: The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19. METHODS: We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated. RESULTS: Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3-2.95 vs median, 0.82 nmol/L; interquartile range, 0.57-1.03; P <.0001). Receiver operating characteristic curve analysis showed good accuracy of MR-proADM for predicting mortality. A MR-proADM value of 1.73 nmol/L was established as the best cutoff value, with 90% sensitivity and 95% specificity (P <.0001). CONCLUSION: We found that MR-proADM could represent a prognostic biomarker of COVID-19.

The Effect of Bacterial Infections, Probiotics and Zonulin on Intestinal Barrier Integrity.

The intestinal barrier plays an extremely important role in maintaining the immune homeostasis of the gut and the entire body. It is made up of an intricate system of cells, mucus and intestinal microbiota. A complex system of proteins allows the selective permeability of elements that are safe and necessary for the proper nutrition of the body. Disturbances in the tightness of this barrier result in the penetration of toxins and other harmful antigens into the system. Such events lead to various digestive tract dysfunctions, systemic infections, food intolerances and autoimmune diseases. Pathogenic and probiotic bacteria, and the compounds they secrete, undoubtedly affect the properties of the intestinal barrier. The discovery of zonulin, a protein with tight junction regulatory activity in the epithelia, sheds new light on the understanding of the role of the gut barrier in promoting health, as well as the formation of diseases. Coincidentally, there is an increasing number of reports on treatment methods that target gut microbiota, which suggests that the prevention of gut-barrier defects may be a viable approach for improving the condition of COVID-19 patients. Various bacteria-intestinal barrier interactions are the subject of this review, aiming to show the current state of knowledge on this topic and its potential therapeutic applications.

Endothelial dysfunction and Mid-Regional proAdrenomedullin: What role in SARS-CoV-2 infected Patients?

BACKGROUND: Endothelial dysfunction, a major complication of SARS-CoV-2 infectionplaying a key-role in multi-organ damage, carries high risk of mortality. AIM: To investigate the potential role of Mid-Regional pro-Adrenomedullin (MR-proADM) in detecting endothelial damage with a view to stratifying the risk of adverse events (length of stay, death, admission in Intensive Care Unit) and/or disease resolution. MATERIALS AND METHODS: In 135 consecutive patients with SARS-CoV-2 infection, MR-proADM was measured in EDTA-K2 plasma samples using B.R.A.H.M.S. KRYPTOR® COMPACT Plus method (Thermo Fisher Scientific, Hennigsdorf, Germany) RESULTS: Patients were subdivided into three groups based on their MR-proADM value (nmol/L): 1 (n = 20, MR-proADM ≤ 0.55); 2 (n = 82, 0.55 < MR-proADM ≤ 1.50); 3 (n = 33, MR-proADM > 1.50). The higher the MR-proADM value, the greater the patients' age, the more frequent the occurrence of pneumonia, the requiring of more aggressive treatment, the longer the hospitalization and the more frequent a fatal event. Significant differences were found between the three groups for MR-proADM, White-blood cell count, Neutrophil count, D-dimer, C-reactive Protein, Procalcitonin and hs-Troponin I. At logistic regression,it was found that MR-proADM and Log10D-dimer were the most significant predictors of adverse events. CONCLUSION: The findings made in the present study highlight the relevance of MR-proADM values in providing clinically useful information, particularly for stratifying COVID-19 patients according to the risk of a more severe form of disease and to the development of adverse events.

Zonulin as a biomarker and potential therapeutic target in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) occurs during or recently following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is characterized by persistent fever, inflammation, and severe illness requiring hospitalization. The majority of patients with MIS-C also present with gastrointestinal (GI) symptoms, including abdominal pain, vomiting, and diarrhea. In this issue of the JCI, Yonker, Gilboa, and colleagues identified zonulin as a biomarker of GI permeability in children with MIS-C and present the results of an intriguing proof-of-concept study indicating that zonulin may represent a potential therapeutic target for MIS-C treatment and prevention. Their findings suggest that intestinal mucosal dysfunction and epithelial barrier breakdown may represent a biological mechanism underlying the development of MIS-C in SARS-CoV-2-infected children.

Endothelium-associated biomarkers mid-regional proadrenomedullin and C-terminal proendothelin-1 have good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia: A prospective cohort study.

PURPOSE: We assessed the ability of mid-regional proadrenomedullin (MR-proADM) and C-terminal proendothelin-1 (CT-proET-1) to predict 28-day mortality in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. METHODS: Biomarkers were collected during the first seven days in this prospective observational cohort study. We investigated the relationship between biomarkers and mortality in a multivariable Cox regression model adjusted for age and SOFA score. RESULTS: In 105 critically ill patients with confirmed SARS-CoV-2 pneumonia 28-day mortality was 28.6%. MR-proADM and CT-proET-1 were significantly higher in 28-day non-survivors at baseline and over time. ROC curves revealed high accuracy to identify non-survivors for baseline MR-proADM and CT-proET-1, AUC 0.84, (95% CI 0.76-0.92), p < 0.001 and 0.79, (95% CI 0.69-0.89), p < 0.001, respectively. The AUC for prediction of 28-day mortality for MR-proADM and CT-proET-1 remained high over time. MR-proADM ≥1.57 nmol/L and CT-proET-1 ≥ 111 pmol/L at baseline were significant predictors for 28-day mortality (HR 6.80, 95% CI 3.12-14.84, p < 0.001 and HR 3.72, 95% CI 1.71-8.08, p 0.01). CONCLUSION: Baseline and serial MR-proADM and CT-proET-1 had good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia. TRIAL REGISTRATION: NEDERLANDS TRIAL REGISTER, NL8460.

Immunohistochemical findings in the lungs of COVID-19 subjects: evidence of surfactant dysregulation.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is characterized by quantitative and qualitative changes in surfactant composition, leading to surfactant dysregulation with alveolar collapse and acute respiratory hypoxic failure. Recently, surfactant has been hypothesized to play a relevant role in COVID-19, representing a strong defender against SARS-CoV-2 infection. The aim of our work was the study of immunohistochemical surfactant expression in the lungs of patients died following SARS-CoV-2 ARDS, in order to shed light on a possible therapeutic surfactant administration. PATIENTS AND METHODS: We investigated four patients who died due to ARDS following SARS-COV-2 infection and four patients submitted to lung biopsy, in the absence of SARS-CoV-2 infection. In all 8 cases, lung specimens were immunostained with anti-surfactant protein A (SP-A) and B (SP-B). RESULTS: In control subjects, reactivity for SP-B was restricted to type II alveolar cells. Immunostaining for SP-A was observed on the surface of alveolar spaces. In the COVID-19 positive lungs, immunoreactivity for SP-B was similar to that observed in control lungs; SP-A was strongly expressed along the alveolar wall. Moreover, dense aggregates of SP-A positive material were observed in the alveolar spaces. CONCLUSIONS: Our immunohistochemical data show the dysregulation of surfactant production in COVID-19 patients, particularly regarding SP-A expression. The increased presence of SP-A in condensed masses inside alveolar spaces could invalidate the therapeutic efficacy of the treatment with exogenous surfactant.

Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.

BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.

Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.