Microvascular Alteration in COVID-19 Documented by Nailfold Capillaroscopy.

COVID-19 is a multisystemic disease that mainly affects and causes dysregulation of the endothelium, causing systemic manifestations. A nailfold video capillaroscopy is a safe, easy, and noninvasive method to evaluate microcirculation alteration. In this review, we analyzed the literature available to date regarding the object of nailfold video capillaroscopy (NVC) use in patients with a SARS-CoV-2 infection, both in the acute phase and after discharge. The scientific evidence pointed out the main alterations in capillary circulation shown by NVC, so reviewing the findings of each article allowed us to define and analyze the future prospects and needs for possibly including NVC within the management of patients with COVID-19, both during and after the acute phase.

COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters.

Clinical knowledge about SARS-CoV-2 infection mechanisms and COVID-19 pathophysiology have enormously increased during the pandemic. Nevertheless, because of the great heterogeneity of disease manifestations, a precise patient stratification at admission is still difficult, thus rendering a rational allocation of limited medical resources as well as a tailored therapeutic approach challenging. To date, many hematologic biomarkers have been validated to support the early triage of SARS-CoV-2-positive patients and to monitor their disease progression. Among them, some indices have proven to be not only predictive parameters, but also direct or indirect pharmacological targets, thus allowing for a more tailored approach to single-patient symptoms, especially in those with severe progressive disease. While many blood test-derived parameters quickly entered routine clinical practice, other circulating biomarkers have been proposed by several researchers who have investigated their reliability in specific patient cohorts. Despite their usefulness in specific contexts as well as their potential interest as therapeutic targets, such experimental markers have not been implemented in routine clinical practice, mainly due to their higher costs and low availability in general hospital settings. This narrative review will present an overview of the most commonly adopted biomarkers in clinical practice and of the most promising ones emerging from specific population studies. Considering that each of the validated markers reflects a specific aspect of COVID-19 evolution, embedding new highly informative markers into routine clinical testing could help not only in early patient stratification, but also in guiding a timely and tailored method of therapeutic intervention.

Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors.

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.

Idiopathic Pulmonary Fibrosis and Post-COVID-19 Lung Fibrosis: Links and Risks.

Idiopathic pulmonary fibrosis (IPF) is considered the paradigmatic example of chronic progressive fibrosing disease; IPF does not result from a primary immunopathogenic mechanism, but immune cells play a complex role in orchestrating the fibrosing response. These cells are activated by pathogen-associated or danger-associated molecular patterns generating pro-fibrotic pathways or downregulating anti-fibrotic agents. Post-COVID pulmonary fibrosis (PCPF) is an emerging clinical entity, following SARS-CoV-2 infection; it shares many clinical, pathological, and immune features with IPF. Similarities between IPF and PCPF can be found in intra- and extracellular physiopathological pro-fibrotic processes, genetic signatures, as well as in the response to antifibrotic treatments. Moreover, SARS-CoV-2 infection can be a cause of acute exacerbation of IPF (AE-IPF), which can negatively impact on IPF patients' prognosis. In this narrative review, we explore the pathophysiological aspects of IPF, with particular attention given to the intracellular signaling involved in the generation of fibrosis in IPF and during the SARS-CoV-2 infection, and the similarities between IPF and PCPF. Finally, we focus on COVID-19 and IPF in clinical practice.

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63–1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70–1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19.

Baseline Plasma Osteopontin Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients.

More than three years have passed since the first case, and COVID-19 is still a health concern, with several open issues such as the lack of reliable predictors of a patient's outcome. Osteopontin (OPN) is involved in inflammatory response to infection and in thrombosis driven by chronic inflammation, thus being a potential biomarker for COVID-19. The aim of the study was to evaluate OPN for predicting negative (death or need of ICU admission) or positive (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. We enrolled 133 hospitalized, moderate-to-severe COVID-19 patients in a prospective observational study between January and May 2021. Circulating OPN levels were measured by ELISA at admission and at day 7. The results showed a significant correlation between higher plasma concentrations of OPN at hospital admission and a worsening clinical condition. At multivariate analysis, after correction for demographic (age and gender) and variables of disease severity (NEWS2 and PiO2/FiO2), OPN measured at baseline predicted an adverse prognosis with an odds ratio of 1.01 (C.I. 1.0-1.01). At ROC curve analysis, baseline OPN levels higher than 437 ng/mL predicted a severe disease evolution with 53% sensitivity and 83% specificity (area under the curve 0.649, p = 0.011, likelihood ratio of 1.76, (95% confidence interval (CI): 1.35-2.28)). Our data show that OPN levels determined at the admission to hospital wards might represent a promising biomarker for early stratification of patients' COVID-19 severity. Taken together, these results highlight the involvement of OPN in COVID-19 evolution, especially in dysregulated immune response conditions, and the possible use of OPN measurements as a prognostic tool in COVID-19.

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial.

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63-1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70-1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19.

Determinants of long COVID among adults hospitalized for SARS-CoV-2 infection: A prospective cohort study.

Rationale: Factors associated with long-term sequelae emerging after the acute phase of COVID-19 (so called "long COVID") are unclear. Here, we aimed to identify risk factors for the development of COVID-19 sequelae in a prospective cohort of subjects hospitalized for SARS-CoV-2 infection and followed up one year after discharge. Methods: A total of 324 subjects underwent a comprehensive and multidisciplinary evaluation one year after hospital discharge for COVID-19. A subgroup of 247/324 who consented to donate a blood sample were tested for a panel of circulating cytokines. Results: In 122 patients (37.8%) there was evidence of at least one persisting physical symptom. After correcting for comorbidities and COVID-19 severity, the risk of developing long COVID was lower in the 109 subjects admitted to the hospital in the third wave of the pandemic than in the 215 admitted during the first wave, (OR 0.69, 95%CI 0.51-0.93, p=0.01). Univariable analysis revealed female sex, diffusing capacity of the lungs for carbon monoxide (DLCO) value, body mass index, anxiety and depressive symptoms to be positively associated with COVID-19 sequelae at 1 year. Following logistic regression analysis, DLCO was the only independent predictor of residual symptoms (OR 0.98 CI 95% (0.96-0.99), p=0.01). In the subgroup of subjects with normal DLCO (> 80%), for whom residual lung damage was an unlikely explanation for long COVID, the presence of anxiety and depressive symptoms was significantly associated to persistent symptoms, together with increased levels of a set of pro-inflammatory cytokines: interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12, IL-1ß, IL-17. In logistic regression analysis, depressive symptoms (p=0.02, OR 4.57 [1.21-17.21]) and IL-12 levels (p=0.03, OR 1.06 [1.00-1.11]) 1-year after hospital discharge were independently associated with persistence of symptoms. Conclusions: Long COVID appears mainly related to respiratory sequelae, prevalently observed during the first pandemic wave. Among patients with little or no residual lung damage, a cytokine pattern consistent with systemic inflammation is in place.

CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients.

SARS-CoV-2 is the etiological agent of COVID-19, an extremely heterogenous disease that can cause severe respiratory failure and critical illness. To date, reliable biomarkers allowing for early patient stratification according to disease severity are still lacking. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in lung pathophysiology and immune modulation and is poorly investigated in the COVID-19 context. In this observational, prospective cohort study, we investigated the correlation between CGRP and clinical disease evolution in hospitalized moderate to severe COVID-19 patients. Between January and May 2021 (Italian third pandemic wave), 135 consecutive SARS-CoV-2 patients were diagnosed as being eligible for the study. Plasma CGRP level evaluation and routine laboratory tests were performed on blood samples collected at baseline and after 7 days of hospitalization. At baseline, the majority our patients had a moderate to severe clinical presentation, and higher plasma CGRP levels predicted a higher risk of in-hospital negative evolution (odds-ratio OR 2.84 [IQR 1.07-7.51]) and were correlated with pulmonary intravascular coagulopathy (OR 2.92 [IQR 1.19-7.17]). Finally, plasma CGRP levels were also correlated with plasma IP10 levels. Our data support a possible crosstalk between the lung and the neuroimmune axis, highlighting a crucial role for plasma CGRP in sustaining COVID-19-related hyperinflammation.

Acute Kidney Injury (AKI) is Associated With Increased in-Hospital Mortality and With Impairment of Renal, Lung, Motor and Immune Function 1 Year After Discharge For COVID-19

BACKGROUND AND AIMS AKI is the most frequent complication after respiratory failure in COVID-19. AKI increases mortality risk, length of hospital stay and healthcare costs, with possible progression towards CKD. Study aims: (1) evaluation of AKI incidence in 1020 COVID-19 hospitalized patients;(2) comparison of AKI incidence in COVID-19 versus pre-pandemic period;(3) establishment of out-patient follow-up for monitoring kidney, lung, motor and immune function;(4) creation of a biobank for biomarker discovery studies. METHOD AKI incidence was calculated matching laboratory and administrative data of 26 214 hospitalized patients in 2018–2019 and in 1020 COVID-19 patients in 2020–2021: KDIGO algorithms were applied for AKI grading. After 12 months from discharge, 232 COVID AKI patients and relative controls matched for age and gender were evaluated for kidney (eGFR, biomarkers of tubular damage NGAL, CCl-14, DKK-3), lung (DLCO, CT scan) and neuro-motor (SPPB, 2-min walking test, post-traumatic stress test-IES) function. RESULTS Before the pandemic, in-hospital AKI incidence was 18% (10% KDIGO 1, 5% KDIGO 2, 3% KDIGO 3): median age of AKI patients was 69. In-hospital mortality was 3.5% in non-AKI group versus 15% in AKI group in accordance with KDIGO stages. In COVID patients, AKI incidence increased to 37% (20% KDIGO 1.11% KDIGO 2, 6% KDIGO 3): median age of patients was 54. In-hospital mortality was 31% in the AKI group;AKI is an independent risk factor for death. After 12 months from hospital discharge, COVID AKI patients showed a persistent reduction of respiratory function (severe DLCO impairment < 60%) related to the extent of CT scan abnormalities. AKI patients also presented the motor function impairment and a worse post-traumatic stress response. GFR reduction was 1.8 mL/min in non-AKI patients versus 9.7 mL/min in AKI COVID patients not related to age. Urinary DKK-3 and CCL-14 were also higher in the AKI group. Last, IgG response after SARS-CoV-2 vaccination was significantly lower in the AKI group. CONCLUSION AKI incidence was significantly increased during COVID-19 in respect to the pre-pandemic period, with an association with higher mortality in class 2–3 KDIGO. In the post-COVID follow-up, AKI was associated with lung and neuro-motor function impairment, a defective antibody response and a sudden GFR decline concomitant to the persistence of tubular injury biomarkers. These results suggest the importance of nephrological and multidisciplinary follow-up of frail patients who developed AKI during hospitalization for COVID-19.Figure 1: Kaplan–Maier curves of survival for hospitalized COVID-19 patients on the basis of AKI-specific cut off of RPA.Table 1. Univariate and multivariate logistic regression analyses for AKI in hospitalized patients with COVID-19UNIVARIATE MODELMULTIVARIATE MODELOdds ratio95% CIPOdds ratio95% CIPAge, years1.000.97–1.03.9600.960.91–1.01.146Male gender0.870.32–2.33.7770.260.05–1.23.090Charlson index1.110.90–1.38.3251.160.89–1.53.266Hypertension2.791.13–6.88.0251.250.30–5.30.759Diabetes0.560.14–2.29.422Heart failure1.190.25–5.70.828Creatinine, mg/dL4.841.23–29.13.02650.74.62–556.01.001RPA < 24 HU2.220.86–5.74.1004.561.27–16.44.020

Ongoing Mycophenolate Treatment Impairs Anti-SARS-CoV-2 Vaccination Response in Patients Affected by Chronic Inflammatory Autoimmune Diseases or Liver Transplantation Recipients: Results of the RIVALSA Prospective Cohort.

Vaccines are the most effective means to prevent the potentially deadly effects of SARS-CoV-2 infection, but not all vaccinated individuals gain the same degree of protection. Patients undergoing chronic immunosuppressive therapy due to autoimmune diseases or liver transplants, for example, may show impaired anti-SARS-CoV-2 antibody response after vaccination. We performed a prospective observational study with parallel arms, aiming to (a) evaluate seroconversion after anti-SARS-CoV-2 mRNA vaccine administration in different subgroups of patients receiving immunosuppressive treatment for rheumatological or autoimmune diseases or to prevent organ rejection after liver transplantation and (b) identify negative predictors of IgG anti-SARS-CoV-2 development. Out of 437 eligible patients, 183 individuals were enrolled at the Rheumatology and Hepatology Tertiary Units of "Maggiore della Carità" University Hospital in Novara: of those, 52 were healthy subjects, while among the remaining 131 patients, 30 had a diagnosis of spondyloarthritis, 25 had autoimmune hepatitis, 10 were liver transplantation recipients, 23 suffered from connective tissue diseases (including 10 cases that overlapped with other diseases), 40 were treated for rheumatoid arthritis, and 5 had vasculitis. Moreover, all patients were receiving chronic immunosuppressive therapy. The immunogenicity of mRNA COVID-19 vaccines was evaluated by measuring IgG anti-SARS-CoV-2 antibody titers before vaccination and after 10, 30, and 90 days since the first dose administration. Of the selected cohort of patients, 24.0% did not develop any detectable anti-SARS-CoV-2 IgG after a complete mRNA-based two doses primary vaccination cycle. At univariate analysis, independent predictors of an absent antibody response to vaccine were a history of liver transplantation (OR 11.5, 95% CI 2.5-53.7, p = 0.0018), the presence of a comorbid active neoplasia (OR 26.4, 95% CI 2.8-252.4, p = 0.0045), and an ongoing immunosuppressive treatment with mycophenolate (MMF) (OR 14.0, 95% CI 3.6-54.9, p = 0.0002) or with calcineurin inhibitors (OR 17.5, 95% CI 3.1-99.0, p = 0.0012). At multivariate analysis, only treatment with MMF (OR 24.8, 95% CI 5.9-103.2, p < 0.0001) and active neoplasia (OR 33.2, 95% CI 5.4-204.1, p = 0.0002) were independent predictors of seroconversion failure. These findings suggest that MMF dose reduction or suspension may be required to optimize vaccine response in these patients.

Anxiety, Stress and Depression in COVID-19 Survivors From an Italian Cohort of Hospitalized Patients: Results From a 1-Year Follow-Up

Background Mental health-related symptoms can persist over time beyond the most common respiratory clinical features of COVID-19. A recent meta-analysis underlined that mental health sequalae may be relevant for COVID-19 survivors and reported the following prevalence rates: 20% for post-traumatic stress disorder, 22% for anxiety, 36% for psychological distress, and 21% for depression. In the context of a multi-disciplinary follow-up project, we already investigated the mid-term (4 months) psychiatric outcomes in a sample of COVID-19 survivors. Patients were re-assessed after 1-year since hospital discharge. Methods Follow-up conducted after 1 year involved 196 individuals recovered from COVID-19. Patients were assessed with a multi-disciplinary approach;including both a clinical interview performed by an experienced psychiatrist, trained in the use of the Mini-International Neuropsychiatric Interview (MINI) to assess the presence of anxiety, stress, and depressive symptoms and the following self-administered questionnaires: Beck Anxiety Inventory, Beck Depression Inventory-II, Resilience Scale for Adults, Impact of Event Scale, and COVID-19 Peritraumatic Distress Index (CPDI). Results Anxiety (p < 0.0001) and depressive (p < 0.0003) symptoms registered at the clinical interview showed a significant improvement from the 4 to 12-months follow-up. Logistic regression model showed that female gender (p = 0.006), arterial hypertension (p = 0.01), obesity (0.04), anxiety (p < 0.0001), and depressive (p = 0.02) symptoms at 4-months follow-up were associated with persistence of anxiety symptoms at 12 months. At logistic regression analysis female gender (p = 0.02) and depressive symptoms at 4-months follow-up (p = 0.01) were associated with depressive symptoms after 12 months. Conclusion Severity of the disease in the acute phase, in this study, was not a determining factor in identifying subjects at risk of developing clinically relevant anxiety and depression as a consequence of COVID-19 disease. Findings from the logistic regressions suggest that the factors most affecting depression and anxiety in COVID survivors after 12 months were female gender, the presence of anxiety and depression after 4 months and some physical symptoms, not necessarily COVID-related. Impact of infection and consequent hospitalization for COVID-19 did no longer represent a relevant issue for depressive symptoms, compared to other general factors.

Baseline plasma SARS-CoV-2 RNA detection predicts an adverse COVID-19 evolution in moderate to severe hospitalized patients.

BACKGROUND: SARS-CoV-2 is a single-stranded RNA virus, known to be the causative agent of COVID-19. As the resulting disease shows a very heterogeneous range of clinical manifestations, the identification of early biomarkers allowing patients stratification according to the expected disease severity is still an unmet clinical need. METHODS: In this observational prospective cohort study, 137 consecutive patients, testing positive for SARS-CoV-2 infection by nasopharyngeal swab RT-PCR or antigenic test, were enrolled to evaluate their plasma viral load at the time of hospitalization. RESULTS: Even if all of them had a molecular diagnosis of COVID-19, only 29 patients showed a detectable plasma SARSCoV-2 RNAemia. Such viremic patients also showed other clinical and laboratory finding alterations (increased troponin I, IL-6, RDW-CV and creatinine levels along with decreased platelet count and glomerular filtration rate). A plasma detectable RNA viral load predicted in hospital death or ICU admission with an odds ratio of 3.53 (C.I. 1.44-8.64, p=0.0058), while the lack of a detectable viral load was associated with a faster recovery, with an odds ratio of 4.06 (C.I. 1.72-9.59, p=0.0014). These findings were confirmed in multivariate models including age, sex and baseline National Early Warning Score 2 and arterial oxygen tension over inspired oxygen fraction ratio. CONCLUSIONS: Our data thus suggest that plasma viral RNA load at the time of hospital admission could represent a useful independent biomarker allowing early patients' stratification according to the expected disease evolution, and driving clinical decisions tailored on the specific needs of the individual patient.

Baseline Plasma Gas6 Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients.

Reliable biomarkers allowing early patients' stratification for the risk of adverse outcomes in COVID-19 are lacking. Gas6, together with its tyrosine kinase receptors named TAM, is involved in the regulation of immune homeostasis, fibrosis, and thrombosis. Our aim was to evaluate whether Gas6, sAxl, and sMerTK could represent early predictors of disease evolution either towards a negative (death or need of ICU admission) or a positive (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. To this purpose, between January and May 2021 (corresponding to third pandemic wave in Italy), 139 consecutive SARS-CoV-2 positive patients were enrolled in a prospective observational study. Plasma levels of these molecules were measured by ELISA at the time of hospitalization and after 7 and 14 days. We observed that higher plasma Gas6 concentrations at hospital admission were associated with a worsening in clinical conditions while lower sMerTK concentrations at baseline and after 7 days of hospitalization were associated with a more favorable outcome. At multivariate analysis, after correction for demographic and COVID-19 severity variables (NEWS2 and PiO2/FiO2), only Gas6 measured at baseline predicted an adverse prognosis with an odds ratio of 1.03 (C.I. 1.01-10.5). At ROC curve analysis, baseline Gas6 levels higher than 58.0 ng/ml predicted a severe disease evolution with 53.3% sensitivity and 77.6% specificity (area under the curve 0.653, p = 0.01, likelihood ratio of 2.38, IQR: 1.46-3.87). Taken together, these results support the hypothesis that a dysregulation in the Gas6/TAM axis could play a relevant role in modulating the course of COVID-19 and suggest that plasma Gas6 may represent a promising prognostic laboratory parameter for this condition.

18 months computed tomography follow-up after Covid-19 interstitial pneumonia.

BACKGROUND: Our aim is to evaluate the possible persistence of lung parenchyma alterations, in patients who have recovered from Covid-19. DESIGN AND METHODS: We enrolled a cohort of 115 patients affected by Covid-19, who performed a chest CT scan in the Emergency Department and a chest CT 18 months after hospital discharge. We performed a comparison between chest CT scan 18 months after discharge and spirometric data of patients enrolled. We obtained quantitative scores related to well-aerated parenchyma, interstitial lung disease and parenchymal consolidation. A radiologist recorded the characteristics indicated by the Fleischner Society and "fibrotic like" changes, expressed through a CT severity score ranging from 0 (no involvement) to 25 (maximum involvement). RESULTS: 115 patients (78 men, 37 women; mean age 60.15 years old ±12.52). On quantitative analysis, after 18 months, the volume of normal ventilated parenchyma was significantly increased (16.34 points on average ±14.54, p<0.0001). Ground-glass opacities and consolidation values tend to decrease (-9.80 and -6.67 points, p<0.0001). On semiquantitative analysis, pneumonia extension, reactive lymph nodes and crazy paving reached statistical significance (p<0.0001). The severity score decreased by 2.77 points on average (SD 4.96; p<0.0001). There were not statistically significant changes on "fibrotic-like" changes correlated with level of treatment and there was not a statistically significant correlation between CT lung score and spirometric results obtained 18 months after discharge. CONCLUSIONS: Patients recovered from Covid-19 seem to have an improvement of ventilated parenchyma and "fibrotic-like" alterations. The level of treatment does not appear to influence fibrotic changes.

Prognostic Markers in Hospitalized COVID-19 Patients: The Role of IP-10 and C-Reactive Protein.

BACKGROUND: SARS-CoV-2 is responsible for COVID-19, a clinically heterogeneous disease, ranging from being completely asymptomatic to life-threating manifestations. An unmet clinical need is the identification at disease onset or during its course of reliable biomarkers allowing patients' stratification according to disease severity. In this observational prospective cohort study, patients' immunologic and laboratory signatures were analyzed to identify independent predictors of unfavorable (either death or intensive care unit admission need) or favorable (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. METHODS: Between January and May 2021 (third wave of the pandemic), we enrolled 139 consecutive SARS-CoV-2 positive patients hospitalized in Northern Italy to study their immunological and laboratory signatures. Multiplex cytokine, chemokine, and growth factor analysis, along with routine laboratory tests, were performed at baseline and after 7 days of hospital stay. RESULTS: According to their baseline characteristics, the majority of our patients experienced a moderate to severe illness. At multivariate analysis, the only independent predictors of disease evolution were the serum concentrations of IP-10 (at baseline) and of C-reactive protein (CRP) after 7 days of hospitalization. Receiver-operating characteristic (ROC) curve analysis confirmed that baseline IP - 10 > 4271 pg/mL and CRP > 2.3 mg/dL at 7 days predict a worsening in clinical conditions (87% sensitivity, 66% specificity, area under the curve (AUC) 0.772, p < 0.001 and 83% sensitivity, 73% specificity, AUC 0.826, p < 0.001, respectively). CONCLUSIONS: According to our results, baseline IP-10 and CRP after 7 days of hospitalization could be useful in driving clinical decisions tailored to the expected disease trajectory in hospitalized COVID-19 patients.

Predictors of Mortality and Cardiovascular Outcome at 6 Months after Hospitalization for COVID-19.

Clinical outcome data of patients discharged after Coronavirus disease 2019 (COVID-19) are limited and no study has evaluated predictors of cardiovascular prognosis in this setting. Our aim was to assess short-term mortality and cardiovascular outcome after hospitalization for COVID-19. A prospective cohort of 296 consecutive patients discharged after COVID-19 from two Italian institutions during the first wave of the pandemic and followed up to 6 months was included. The primary endpoint was all-cause mortality. The co-primary endpoint was the incidence of the composite outcome of major adverse cardiac and cerebrovascular events (MACCE: cardiovascular death, myocardial infarction, stroke, pulmonary embolism, acute heart failure, or hospitalization for cardiovascular causes). The mean follow-up duration was 6 ± 2 months. The incidence of all-cause death was 4.7%. At multivariate analysis, age was the only independent predictor of mortality (aHR 1.08, 95% CI 1.01-1.16). MACCE occurred in 7.2% of patients. After adjustment, female sex (aHR 2.6, 95% CI 1.05-6.52), in-hospital acute heart failure during index hospitalization (aHR 3.45, 95% CI 1.19-10), and prevalent atrial fibrillation (aHR 3.05, 95% CI 1.13-8.24) significantly predicted the incident risk of MACCE. These findings may help to identify patients for whom a closer and more accurate surveillance after discharge for COVID-19 should be considered.

Pattern of Emergency Department referral during the COVID-19 outbreak in Italy.

BACKGROUND: The Coronavirus disease (COVID-19) outbreak is putting the European National Health Systems under pressure. Interestingly, Emergency Department (ED) referrals for other reasons than COVID-19 seem to have declined steeply. In the present paper, we aimed to verify how the COVID-19 outbreak changed ED referral pattern. METHODS: We retrospectively reviewed the clinical records of patients referred to the ED of a University Hospital in Northern Italy from 1 March to 13 April 2020. We compared the following data with those belonging to the same period in 2019: number of EDs accesses, rate of hospital admission, frequencies of the most common causes of ED referral, priority codes of access. RESULTS: The number of ED referrals during the COVID-19 outbreak was markedly reduced when compared to the same period in 2019 (3059 vs. 5691; -46.3%). Conversely, the rate of hospital admission raised from 16.9% to 35.4% (P<0.0001), with a shift toward higher priority codes of ED admission. In 2020, we observed both a reduction of the number of patients referred for both traumatic (513, 16.8% vs. 1544, 27.1%; χ2=118.7, P<0.0001) and non-traumatic (4147 vs. 2546) conditions. Among the latter, suspected COVID-19 accounted for 1101 (43.2%) accesses. CONCLUSIONS: The COVID-19 pandemic completely changed the pattern of ED referral in Italy, with a marked reduction of the accesses to the hospitals. This could be related to a limited exposure to traumas and to a common fear of being infected during EDs in-stay. This may limit the misuse of EDs for non-urgent conditions but may also delay proper referrals for urgent conditions.

Metabolomics Diagnosis of COVID-19 from Exhaled Breath Condensate.

Infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe respiratory tract damage and acute lung injury. Therefore, it is crucial to study breath-associated biofluids not only to investigate the breath's biochemical changes caused by SARS-CoV-2 infection, but also to discover potential biomarkers for the development of new diagnostic tools. In the present study, we performed an untargeted metabolomics approach using a bidimensional gas chromatography mass spectrometer (GCxGC-TOFMS) on exhaled breath condensate (EBC) from COVID-19 patients and negative healthy subjects to identify new potential biomarkers for the noninvasive diagnosis and monitoring of the COVID-19 disease. The EBC analysis was further performed in patients with acute or acute-on-chronic cardiopulmonary edema (CPE) to assess the reliability of the identified biomarkers. Our findings demonstrated that an abundance of EBC fatty acids can be used to discriminate COVID-19 patients and that they may have a protective effect, thus suggesting their potential use as a preventive strategy against the infection.