The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.

The usefulness of D-dimer as a predictive marker for mortality in patients with COVID-19 hospitalized during the first wave in Italy.

BACKGROUND: The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating limited healthcare resources. AIMS: The primary aim was to study the value of D-dimer as a predictive marker for in-hospital mortality. METHODS: This was a cohort study. The study population consisted of hospitalized patients (age >18 years), who were diagnosed with COVID-19 based on real-time PCR at 9 hospitals during the first COVID-19 wave in Lombardy, Italy (Feb-May 2020). The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Model discrimination was assessed using Harrell's C-index and model calibration was assessed using a calibration plot. RESULTS: Out of 1049 patients, 507 patients (46%) had evaluable data. Of these 507 patients, 96 died within 30 days. The cumulative incidence of in-hospital mortality within 30 days was 19% (95CI: 16%-23%), and the majority of deaths occurred within the first 10 days. A prediction model containing D-dimer as the only predictor had a C-index of 0.66 (95%CI: 0.61-0.71). Overall calibration of the model was very poor. The addition of D-dimer to a model containing age, sex and co-morbidities as predictors did not lead to any meaningful improvement in either the C-index or the calibration plot. CONCLUSION: The predictive value of D-dimer alone was moderate, and the addition of D-dimer to a simple model containing basic clinical characteristics did not lead to any improvement in model performance.

Predictors of Helmet CPAP Failure in COVID-19 Pneumonia: A Prospective, Multicenter, and Observational Cohort Study.

Background: Continuous positive airway pressure (CPAP) can be beneficial in acute respiratory failure (ARF) due to coronavirus (COVID-19) pneumonia, but delaying endotracheal intubation (ETI) in nonresponders may increase mortality. We aimed at investigating the performance of composite respiratory indexes as possible predictors of CPAP failure in ARF due to COVID-19. Methods: This was a multicenter, prospective, observational, and cohort study conducted in the respiratory units of three University hospitals in Milan and in a secondary care hospital in Codogno (Italy), on consecutive adult patients with ARF due to COVID-19 pneumonia that underwent CPAP between March 2020 and March 2021. ETI transfer to the intensive care unit or death is defined CPAP failure. Predictors of CPAP failure were assessed before T0 and 1 hour after T1 CPAP initiation and included mROX index (ratio of PaO2/FiO2 to respiratory rate), alveolar-to-arterial (A-a) O2 gradient, and the HACOR (heart rate, acidosis, consciousness, oxygenation, and respiratory rate) score. Results: Three hundred and fifty four patients (mean age 64 years, 73% males) were included in the study; 136 (38.4%) satisfied criteria for CPAP failure. A-a O2 gradient, mROX, and HACOR scores were worse in patients who failed CPAP, both at T0 and T1 (p < 0.001 for all parameters). The HACOR score was associated with CPAP failure (odds ratio-OR-for every unit increase in HACOR = 1.361; 95%CI: 1.103-1.680; p=0.004; AUROC = 0.742; p < 0.001). CPAP failure was best predicted by a threshold of 4.50 (sensitivity = 53% and specificity = 87%). Conclusions: The HACOR score may be a reliable and early predictor of CPAP failure in patients treated for ARF in COVID-19 pneumonia.

Pro-coagulant imbalance in patients with community acquired pneumonia assessed on admission and one month after hospital discharge.

OBJECTIVES: Patients hospitalized because of community-acquired-pneumonia (CAP) are at risk of cardiovascular diseases. Although plasma procoagulant imbalance play a role, mechanisms are not completely understood. We aimed to investigate whether there is a measurable state of procoagulant imbalance following inflammation determined by CAP. METHODS: We analyzed blood from 51 CAP patients at admission and 51 healthy subjects (HS) for (i) pro and anticoagulants, (ii) thrombin generation (TG) with or without thrombomodulin (TM), which is the physiologic activator of the protein C anticoagulant pathway and(iii) by assessing the ratio between von Willebrand-factor (VWF) and its protease ADAMTS13. Thirty patients were re-analyzed one month after discharge when CAP was resolved. RESULTS: Median levels of TG parameters, including the endogenous thrombin potential (ETP), the ETP-TM-ratio (with/without TM), peak-thrombin and velocity index were higher in patients at baseline than HS. In particular, the median (IQR) ETP-TM-ratio in patients vs. HS was 0.88 (0.83-0.91) vs. 0.63 (0.48-0.71), p<0.001. Factor (F)VIII, a potent procoagulant involved in TG was higher in patients at baseline than HS [195 U/dL (100-388) vs. 127(108-145)], p<0.001]. The ratio of VWF/ADAMTS13 was higher at baseline than HS. Cumulatively, the findings indicate a state of pro-coagulant imbalance, which (although reduced), remained high [i.e., ETP-TM-ratio, 0.80 (0.74-0.84); FVIII, 152 U/dL (122-190)] one month after discharge when the infection was resolved. CONCLUSIONS: Patients with CAP possess a state of pro-coagulant imbalance, which remains substantially high, even when the infection is resolved. The findings suggest CAP patients as candidates for antithrombotic prophylaxis even after the resolution of infection. Clinical trials are warranted to assess the benefit/risk ratio of prophylaxis extension.

Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19.

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleeding.

Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: An observational cohort study.

BACKGROUND: Immunomodulants have been proposed to mitigate severe acute respiratory syndrome coronavirus 2-induced cytokine storm, which drives acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19). OBJECTIVE: We sought to determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation. METHODS: A secondary analysis of prospective observational cohort studies was carried out at an Italian tertiary health care facility. COVID-19 patients consecutively hospitalized (February 25, 2020, to March 30, 2020) with hyperinflammation (ferritin ≥1000 ng/mL and/or C-reactive protein >10 mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO2 Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO2:FiO2 ratio, Charlson index, baseline mechanical ventilation, hospitalization to inclusion lapse) risks were calculated (Cox proportional regression model). RESULTS: A total of 120 COVID-19 patients with hyperinflammation (median age, 62 years; 80.0% males; median PaO2:FiO2 ratio, 151; 32.5% on mechanical ventilation) were evaluated. Of these, 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 13.9% in treated patients and 35.6% in controls (Kaplan-Meier plots, P = .005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared with controls (hazard ratio, 0.33, 95% CI, 0.15-0.74, P = .007, and HR, 0.18, 95% CI, 0.07-0.50, P = .001, respectively). No significant differences in bloodstream infections or laboratory alterations were registered. CONCLUSIONS: Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized controlled trials including the use of either agent alone are needed to confirm these results.

Early detection of deep vein thrombosis in patients with coronavirus disease 2019: who to screen and who not to with Doppler ultrasound?

PURPOSE: Aim of the study is to evaluate the incidence of DVT in COVID-19 patients and its correlation with the severity of the disease and with clinical and laboratory findings. METHODS: 234 symptomatic patients with COVID-19, diagnosed according to the World Health Organization guidelines, were included in the study. The severity of the disease was classified as moderate, severe and critical. Doppler ultrasound (DUS) was performed in all patients. DUS findings, clinical, laboratory's and therapeutic variables were investigated by contingency tables, Pearson chi square test and by Student t test and Fisher's exact test. ROC curve analysis was applied to study significant continuous variables. RESULTS: Overall incidence of DVT was 10.7% (25/234): 1.6% (1/60) among moderate cases, 13.8% (24/174) in severely and critically ill patients. Prolonged bedrest and intensive care unit admission were significantly associated with the presence of DVT (19.7%). Fraction of inspired oxygen, P/F ratio, respiratory rate, heparin administration, D-dimer, IL-6, ferritin and CRP showed correlation with DVT. CONCLUSION: DUS may be considered a useful and valid tool for early identification of DVT. In less severely affected patients, DUS as screening of DVT might be unnecessary. High rate of DVT found in severe patients and its correlation with respiratory parameters and some significant laboratory findings suggests that these can be used as a screening tool for patients who should be getting DUS.

Predictors of Successful Oxygen Weaning in Older Patients Undergoing Pulmonary Rehabilitation.

OBJECTIVES: To identify clinical and/or functional variables predictive of successful oxygen-weaning among older patients affected by respiratory insufficiency undergoing pulmonary rehabilitation. DESIGN: Retrospective study. SETTING AND PARTICIPANTS: Data are from 154 patients aged 65 years and older (mean age = 78.1 years; female 50.6%) admitted to a pulmonary rehabilitation unit to follow an in-patient program. Patients must require oxygen therapy at admission. METHODS: All patients performed the 6-Minute Walking Test at admission and before discharge as well as a spirometry at a steady state. Multivariate logistic regressions were performed to identify positive and negative predictors of successful oxygen weaning. RESULTS: Successful oxygen weaning was obtained in 47 participants (30.5%). The restrictive pattern was associated with a 4-fold likelihood of successful oxygen weaning at the end of the rehabilitation program compared with the obstructive one. A positive association was also found for arterial oxygenation index (PaO2/FiO2 ratio) at baseline. A decreased likelihood of successful oxygen weaning was reported for the subjective dyspnea perception score at exertion evaluated with a modified Borg scale. CONCLUSIONS AND IMPLICATIONS: The restrictive pattern, PaO2/FiO2 ratio, and modified Borg dyspnea scale score under exertion were significantly associated with successful oxygen-weaning. The identified predictors may support clinicians at precociously identifying patients who may not require oxygen therapy after discharge. Therefore, these findings would make it possible for clinicians to better tailor the rehabilitation program.

Prevalence, risk factors and outcomes of patients coming from the community with sepsis due to multidrug resistant bacteria.

BACKGROUND: Although previous studies showed an increasing prevalence of infections due to multi-drug resistant (MDR) bacteria in the community, specific data on sepsis are lacking. We aimed to assess prevalence, risk factors and outcomes of patients with sepsis due to MDR bacteria. METHODS: An observational, retrospective study was conducted on consecutive adult patients coming from the community and admitted to the Policlinico Hospital, Milan, Italy, with a diagnosis of sepsis between January 2011 and December 2015. Primary study outcome was in-hospital mortality. RESULTS: Among 518 patients, at least one MDR bacteria was isolated in 88 (17%). ESBL+ Enterobacteriaceae were the most prevalent MDR bacteria (9.7%) followed by MRSA (3.9%). Independent risk factors for sepsis due to MDR bacteria were septic shock (OR: 2.2; p = 0.002) and hospitalization in the previous 90 days (OR: 2.3; p = 0.003). Independent risk factors for sepsis due to ESBL+ bacteria were hospitalization in the previous 90 days (OR: 2.1; p = 0.02) and stroke (OR: 2.1; p = 0.04). A significantly higher mortality was detected among patients with vs. without MDR bacteria (40.2% vs. 23.1% respectively, p = 0.001). Independent risk factors for mortality among patients with sepsis were coagulation dysfunction (OR: 3.2; p = 0.03), septic shock (OR: 3.2; p = 0.003), and isolation of a MDR bacteria (OR: 4.6; p < 0.001). CONCLUSION: In light of the prevalence and impact of MDR bacteria causing sepsis in patients coming from the community, physicians should consider ESBL coverage when starting an empiric antibiotic therapy in patients with specific risk factors, especially in the presence of septic shock.

Appropriateness of prescription of oral anticoagulant therapy in acutely hospitalized older people with atrial fibrillation. Secondary analysis of the SIM-AF cluster randomized clinical trial.

AIMS: To assess the appropriateness of oral anticoagulant (OAC) prescription and its associated factors in acutely hospitalized elderly patients. METHODS: Data were obtained from the prospective phase of SIM-AF (SIMulation-based technologies to improve the appropriate use of oral anticoagulants in hospitalized elderly patients with Atrial Fibrillation) randomized controlled trial, aimed to test whether an educational intervention improved OAC prescription, compared to current clinical practice, in internal medicine wards. In this secondary analysis, appropriateness of OAC prescription was assessed at hospital admission and discharge. RESULTS: For 246 patients, no significant differences were found between arms (odds ratio 1.38, 95% confidence interval [CI] 0.84-2.28) in terms of appropriateness of OAC prescription. Globally, 92 patients (37.4%, 95% CI = 31.6-43.6%) were inappropriately prescribed or not prescribed at hospital discharge. Among 51 patients inappropriately prescribed, 82% showed errors on dosage, being mainly under-dosed (n = 29, 56.9%), and among 41 inappropriately not prescribed, 98% were taking an antiplatelet drug. Factors independently associated with a lower probability of appropriateness at discharge were those related to a higher risk of bleeding (older age, higher levels of aspartate aminotransferase, history of falls, alcohol consumption) and antiplatelet prescription at admission. The prescription of OACs at admission was the strongest predictor of appropriateness at discharge (odds ratio = 7.43, 95% CI = 4.04-13.73). CONCLUSIONS: A high proportion of hospitalized older patients with AF remains inappropriately prescribed or nonprescribed with OACs. The management of these patients at hospital admission is the strongest predictor of prescription appropriateness at discharge.

Simulation-Based Education for Physicians to Increase Oral Anticoagulants in Hospitalized Elderly Patients with Atrial Fibrillation.

PURPOSE: This study was intended to determine whether a simulation-based education addressed to physicians was able to increase the proportion of hospitalized elderly with atrial fibrillation prescribed with oral anticoagulants (OACs) compared with the usual practice. METHODS: We conducted a cluster randomized trial (from April 2015 to September 2018) on 32 Italian internal medicine and geriatric wards randomized 1:1 to intervention or control arms. The physicians of wards randomized to intervention received a computer-based e-learning tool with clinical scenarios (Dr Sim), and those of wards randomized to control received no formal educational intervention. The primary outcome was the OAC prescription rate at hospital discharge in the intervention and control arms. RESULTS: Of 452 patients scrutinized, 247 were included in the analysis. Of them, 186 (75.3%) were prescribed with OACs at hospital discharge. No difference was found between the intervention and control arms in the post-intervention phase (odds ratio, 1.46; 95% confidence interval [CI], 0.81-2.64). The differences from the pre- to post-intervention phases in the proportions of patients prescribed with OACs (15.1%; 95% CI, 0%-31.5%) and with direct oral anticoagulants (DOACs) (20%; 95% CI, 0%-39.8%) increased more in the intervention than in the control arm. CONCLUSIONS: This simulation-based course did not succeed in increasing the rate of elderly patients prescribed with OACs at hospital discharge compared with the usual practice. Notwithstanding, over time there was a greater increase in the intervention than in the control arm in the proportion of patients prescribed with OACs and DOACs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03188211.

Emergency department visits in older people: pattern of use, contributing factors, geographical differences and outcomes.

AIMS: To assess the pattern of use of Emergency Departments (EDs), factors contributing to the visits, geographical distribution and outcomes in people aged 65 years or more living in the Italian Lombardy Region in 2012. METHODS: Based on an administrative database the study population was divided into groups according to the number of ED visits. A multinomial logistic regression model was performed to compare the characteristics of each group. The Getis-Ord's G statistic was used to evaluate the clusters of high and low visit prevalence odd ratios (OR) at district level. To estimate the severity of the disease leading to ED attendance, visits were stratified based on the level of emergency and outcome. RESULTS: About 2 million older people were included in the analyses: 78 % had no ED visit, 15 % only 1, 7 % 2 or more. Male sex, age 85 years or more, high number of drugs, ED visits and hospital admissions in the previous year and the location of an ED within 10 km from the patient's place were all factors associated with a higher risk to have more ED visits. Clusters of high and low prevalence of visits were found for occasional users. Overall, 83 % of ED visit with a low emergency triage code at admission had as visit outcome discharge at home. CONCLUSIONS: In older people several variables were associated with an increased risk to have a high number of ED visits. Most of the visits were done for non-urgent problems and significant geographic differences were observed for occasional users.

Cardiovascular autonomic alterations in hospitalized patients with community-acquired pneumonia.

BACKGROUND: Alterations of cardiac autonomic control (CAC) are associated with poor outcomes in patients with infectious and non-infectious diseases. No evaluation of CAC in patients with community-acquired pneumonia (CAP) has been performed so far. The aim of the study was to assess CAC in patients with CAP and evaluate the impact of its alterations on disease severity and clinical outcomes in a multicenter, prospective, observational study. METHODS: Consecutive patients hospitalized for CAP were enrolled between 2011 and 2013 two university hospitals in Italy. CAC was assessed by linear spectral and non-linear symbolic analysis of heart rate variability. The presence of severe CAP was evaluated on hospital admission. The primary study outcome was time to clinical stability (TCS) during hospitalization. RESULTS: Among the 75 patients enrolled (median age: 75 years; 57 % males), a significantly lower total variability and reduction of sympathetic rhythmical component with predominant respiratory modulation was detected in comparison to controls. Among CAP patients affected by a severe CAP on admission, CAC showed a lower sympathetic modulation and predominant parasympathetic oscillatory rhythm. At the multivariate analysis, variables independently correlated with a TCS >7 days were total power, as marker of total variability, [OR (95 % CI): 0.997 (0.994-1.000), p = 0.0454] and sympathetic modulation [OR (95 % CI): 0.964 (0.932-0.998), p = 0.0367]. CONCLUSIONS: Loss of sympathetic rhythmical oscillation is associated with a more severe disease and worse early clinical outcome in hospitalized patients with CAP.

Thirty and ninety days mortality predictive value of admission and in-hospital procalcitonin and mid-regional pro-adrenomedullin testing in patients with dyspnea. Results from the VERyfing DYspnea trial.

INTRODUCTION: Mid-regional pro-atrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and mid-regional pro-adrenomedullin (MR-proADM) demonstrated usefulness for management of emergency department patients with dyspnea. METHODS: To evaluate in patients with dyspnea, the prognostic value for 30 and 90 days mortality and readmission of PCT, MR-proADM, and MR-proANP, a multicenter prospective study was performed evaluating biomarkers at admission, 24 and 72 hours after admission. Based on final diagnosis, patients were divided into acute heart failure (AHF), primary lung diseases, or both (AHF + NO AHF). RESULTS: Five hundred one patients were enrolled. Procalcitonin and MR-proADM values at admission and at 72 hours were significantly (P < .001) predictive for 30-day mortality: baseline PCT with an area under the curve (AUC) of 0.70 and PCT at 72 hours with an AUC of 0.61; baseline MR-proADM with an AUC of 0.62 and MR-proADM at 72 hours with an AUC of 0.68. As for 90-day mortality, both PCT and MR-proADM baseline and 72 hours values showed a significant (P < .0001) predictive ability: baseline PCT with an AUC of 0.73 and 72 hours PCT with an AUC of 0.64; baseline MR-proADM with an AUC of 0.66 and 72 hours MR-proADM with an AUC of 0.71. In AHF, group biomarkers predicted rehospitalization and mortality at 90 days, whereas in AHF + NO AHF group, they predict mortality at 30 and 90 days. CONCLUSIONS: In patients admitted for dyspnea, assessment of PCT plus MR-proADM improves risk stratification and management. Combined use of biomarkers is able to predict in the total cohort both rehospitalization and death at 30 and 90 days.

Diagnostic role of copeptin in patients presenting with chest pain in the emergency room.

BACKGROUND: Chest pain is a frequent symptom leading patients to the Emergency Room. Copeptin, the C-terminal fragment of arginin-vasopressin, is a marker of stressful situations. Recent studies showed that normal levels of copeptin combined with normal troponin accurately rule out the diagnosis of acute coronary syndrome (ACS). In this observational, prospective, multicenter study we evaluated if negative levels of copeptin combined with negative troponin (Tn-T) can correctly rule out the diagnosis of ACS and also of other life-threatening causes of chest pain. RESULTS: Of 472 enrolled patients (64.6% males, mean age 60.1yrs), 28 (5.9%) were diagnosed with ST-elevation myocardial infarction (STEMI), 28 (5.9%) with non ST-elevation myocardial infarction (NSTEMI), 43 (9.1%) with unstable angina (UA), 13 (2.8%) with potentially life-threatening non-ACS pathologies (aortic dissection, pulmonary embolism, pulmonary edema, sepsis), 360 (76.2%) with benign causes of chest pain. Copeptin levels were significantly higher in ACS patients with STEMI and NSTEMI than in those with other diagnoses, but not in those with UA. The combination of copeptin and troponin-T attained a negative predictive value of 86.6% for ACS, of 97.9% for other potentially life-threatening non-ACS diseases and of 85% for all potentially lethal diseases (ACS plus others). CONCLUSIONS: The combined use of troponin and copeptin significantly improved the diagnostic accuracy of troponin alone both in ACS (STEMI and NSTEMI) and in other life-threatening diseases. Measurement of this marker might be therefore considered not only for a rule-out strategy but also as a warning sign of a life-threatening disease.