Clinical outcomes in elderly patients with infections caused by NDM-producing Klebsiella pneumoniae: results from a real-life retrospective single center study in an endemic area.

Real-life outcomes data for elderly patients with infections caused by Klebsiella pneumoniae producing New Delhi metallo-beta-lactamase (NDM-Kp) are lacking. We conducted a retrospective cohort study enrolling 33 consecutive adult patients (mean age 77.4 years; 48.5% males; mean Charlson Comorbidity Index-CCI 5.9) hospitalized for NDM-Kp infections during a 24-month period in an Italian highly endemic area. 78.8% were admitted to Internal Medicine ward. 45.4% of patients had bloodstream infections (BSI), 39.4% urinary tract infections (UTI) without BSI, 9.1% respiratory tract infections and 6.1% intra-abdominal infections. 93.9% had rectal colonization.Adequate definitive antibiotic therapy (mainly represented by aztreonam plus ceftazidime/avibactam) was provided to 36.4% of cases. Mean age and CCI of patients adequately treated were significantly lower than those inadequately treated (71.2 vs 80.9 years, p = 0.041, and 4.6 vs 6.7, p = 0.040, respectively). Patients adequately treated had a mean hospitalization length significantly higher (28 vs 15 days, p = 0.016). The overall 30-day survival rate of patients adequately and inadequately treated was 83.3% and 57.1%, respectively: this difference was not statistically significant. Mean age and CCI of 22 patients who survived at 30 days were lower than those of 11 patients who died (73.7 vs 84.8 years, p = 0.003, and 5.3 vs 7.2, p = 0.049, respectively). Twelve survivors received an inadequate therapy: 8/12 had UTI. Six of nine patients inadequately treated who died within 30 days, died before microbiological diagnosis. Our study provides real-life data on outcomes of elderly and multimorbid patients hospitalized for infections caused by NDM-Kp. Further studies with larger sample size are warranted.

Transcranial ultrasonography imaging of a suprasellar meningioma: A case description and technical notes.

Background: Computed tomography (CT) and magnetic resonance (MR) represent the gold standard for evaluating intracranial tumours, such as meningiomas; most meningiomas can be managed by surveillance and clinical follow-up, therefore, the ideal technology should be cheap, non-invasive, safe and able to reduce radiation exposure. Transcranial colour-coded duplex sonography (TCCS) can detect space-occupying lesions, but its full potential for clinical practice is still unexpressed. Aims and Methods: We describe the ability of TCCS to directly and accurately image, in a 77-year-old woman hospitalised for septic shock and coma, a suprasellar meningioma with a spatial resolution very similar to CT. Results: The meningioma was clearly visualised as a roundish mass, with well-defined borders, heterogeneously hyperechogenic compared with the surrounding brain structures; multiple intralesional calcifications were detectable as highly echogenic spots. Latero-lateral and antero-posterior diameters were well measurable. Discussion: TCCS should not be considered as an alternative to CT and MR imaging, but it might have a complementary role, useful for use at the bedside in uncooperative or non-transportable patients and for follow-up, when an adequate acoustic window is guaranteed. Neurologists and neuroradiologists should further explore the full potential of this technology.

Ventilatory associated barotrauma in COVID-19 patients: A multicenter observational case control study (COVI-MIX-study).

BACKGROUND: The risk of barotrauma associated with different types of ventilatory support is unclear in COVID-19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence; we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. METHODS: This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. RESULTS: We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p<0.001). Receiving non-invasive ventilation (C-PAP/PSV) instead of conventional oxygen therapy (COT) increased the risk of barotrauma (OR 5.04, 95% CI 2.30 - 11.08, p<0.001), similarly for invasive mechanical ventilation (OR 6.24, 95% CI 2.86-13.60, p<0.001). High Flow Nasal Oxygen (HFNO), compared with COT, did not significantly increase the risk of barotrauma. Barotrauma frequency occurred in 1.00% [95% CI 0.88-1.16] of patients; these were older (p=0.022) and more frequently immunosuppressed (p=0.013). Barotrauma was shown to be an independent risk for death (OR 5.32, 95% CI 2.82-10.03, p<0.001). CONCLUSIONS: C-PAP/PSV compared with COT or HFNO increased the risk of barotrauma; otherwise HFNO did not. Barotrauma was recorded in 1.00% of patients, affecting mainly patients with more severe COVID-19 disease. Barotrauma was independently associated with mortality. TRIAL REGISTRATION: this case-control study was prospectively registered in clinicaltrial.gov as NCT04897152 (on 21 May 2021).

Skin Ulcers are Predictors of 30-Day Hospital Readmission, But are Under-represented in the DRG Coding: A Retrospective Case-Control Study From an Italian Internal Medicine Unit.

This study retrospectively analyzes all consecutive patients who underwent during a year hospital readmissions, defined as an admission to a hospital within 30 days of discharge, to an Italian Internal Medicine ward. All these data were compared with those from patients who underwent only 1 hospital admission in the same period. The aim of this study was to identify potential novel risk factors for hospital readmissions. In 2018, a total of 3012 patients were hospitalized. Among these, 14.1% (n = 426; mean age, 79.7 ± 11.9; range, 23-100) were defined as readmissions; data were compared with controls (n = 420; 13.9%; mean age, 75.9 ± 14.7; range, 22-99) who had only 1 hospitalization. Cases showed a significantly higher prevalence than controls regarding cerebrovascular disease (77.2% vs 48.1%), cognitive impairment (51.8% vs 26.9%), congestive heart failure (47.6% vs 20.2%), chronic kidney disease (31.7% vs 13.1%), and chronic obstructive pulmonary disease (23.0% vs 14.5%). Skin ulcers were significantly more prevalent among cases (45.1% vs 17.6%). Diagnosis-related group (DRG) analysis showed a higher proportion of "infectious disease" (24.4% vs 15.0%) among the cases than in controls. Despite skin ulcers were very frequent among cases and controls (45.1% vs 17.6%), they were codified as "skin wound" DRG only in 1.4% and 0.2%, respectively. At the DRGs analysis, sepsis (31.6% vs 19.1%), pneumonia (17.1% vs 7.6%), and kidney failure (9.6% vs 3.8%) represented the main significant cause of death in cases compared to controls. Our study confirms that readmissions to Internal Medicine departments are related to the severity of chronic diseases affecting patients. Skin ulcers are present in about half of patients who will be early readmitted within 30 days, but they are almost never reported in DRGs, so more accurate coding is needed. Key challenges for the future are sepsis prevention measures and investing resources in chronic disease assistance, including skin ulcer chronic management.

Primary septic arthritis of the knee caused by Neisseria meningitidis serogroup B in an elderly patient. Case report and review of the literature.

PURPOSE: Primary meningococcal arthritis (PMA) represents an uncommon clinical presentation of meningococcal infection, mainly reported among young people. Herein, a case of PMA of the knee in an elderly patient is described. CASE PRESENTATION: On January 2022, an 87-year-old patient arrived at hospital with continuous fever persisting for three days and a picture of pain, swelling, redness, and warmth of her left knee. An arthrocentesis was promptly performed and the inoculated synovial fluid turned positive with numerous Gram-negative diplococci at the microscopic examination. The identification of bacteria was done in 48 h using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) MS systems (VITEK®MS-bioMérieux) and standard microbiological procedures (VITEK®2 NH ID card-bioMérieux). Both methods identified the strain as N. meningitidis. The meningococcal isolate belonged to the serogroup B (MenB), Sequence type (ST)-162/clonal complex (cc)162. Two grams of ceftriaxone twice a day were administered for 21 days; than cefditoren pivoxil 400 mg twice a day for further 6 weeks after discharge. In Italy, from 2018 to January 2022, among 135 MenB, 31 MenB/cc162 were identified, of which only the case here reported was associated with an atypical clinical presentation. REVIEW OF THE LITERATURE: A total of 41 cases of PMA caused by N. meningitidis was reported in the literature, but only four occurred in elderly. To our knowledgements, no cases of PMA caused by MenB were previously reported among patients of more than 65 years of age.

A Severe Necrotizing Inflammatory Reaction of Leg Wounds Following Autologous Peripheral Blood Total Nucleated Cells Treatment in an Old Patient With Rheumatoid Arthritis and No-Option Chronic Limb-Threatening Ischemia: Is Cell Therapy Suitable for All Patients?

Chronic limb-threatening ischemia (CLTI) represents an unfavorable evolution of peripheral artery disease, characterized by pain at rest, ulceration, and gangrene and also by an increased risk of cardiovascular events, amputations, and death. According to scientific literature, in almost one third of cases affected by CLTI, defined as no-option CLTI patients, revascularization strategies are not feasible. In the past decade, several studies investigated the role of therapeutic angiogenesis through cell autologous therapy, administered through intramuscular injections or multiple local intralesional and perilesional injections. In this article, we report the case of a necrotizing inflammatory reaction in a patient affected by CLTI and chronic leg wounds that occurred on the multiple injection sites after autologous peripheral blood-derived mononuclear cells (PB-TNCs) transplantation. Since the patient was affected by corticosteroid-induced skin atrophy and rheumatoid arthritis, we hypothesize that an increased skin fragility and a mechanism of immune-mediated pathergy could have been main factors leading to worsening of wounds. This case report strongly suggests the urgent need to better define the indications and contraindications of cell therapy, and further studies of adequate methodology are required to definitively assess the efficacy and safety of autologous cell therapy by local injections of PB-TNCs in patients with chronic inflammatory disorder, such as rheumatoid arthritis, especially in case of concomitant marked skin atrophy. Pending definitive evidence from literature, a strong caution is needed in patients affected by chronic systemic inflammatory diseases, since multiple injections, acting as mechanical stimulus and pathergy trigger, might exacerbate a severe and uncontrolled inflammatory response.

Early 3-day course of remdesivir to prevent progression to severe Covid-19 in high-risk patients with hospital-acquired SARS-CoV-2 infection: preliminary results from two Italian outbreaks.

In multimorbid, unvaccinated and non-hospitalized patients, early administration of remdesivir, nirmatrelvir/ritonavir and molnupiravir was effective in reducing the risk of hospitalization or death from any cause. Similar data are lacking with regard to patients already hospitalized and who acquire in-hospital SARS-CoV-2 infection. We conducted a retrospective study during two outbreaks of SARS-CoV-2 infections involving 90 inpatients already hospitalized for medical or surgical conditions, in order to assess the effectiveness of early administration of remdesivir. Forty-seven cases were treated with a 3-day course of remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) within a median time of 1.4 day from testing positive, and were compared to a matched case-control cohort of 43 untreated patients; matching was based on age, sex, vaccination status, previous symptomatic infections by SARS-CoV-2, reasons for hospitalization (no significant differences). No case presented adverse events to remdesivir or death from COVID-19. No significant difference in overall in-hospital mortality was observed in cases compared to controls (17% vs 16.3%, p=0.925), but progression to severe pneumonia, although the difference was still not significant, showed an evident trend of a better outcome (8.5% vs 16.3%, p=0.261). Moreover, cases had a median discharge delay of 3 days (p=0.008).

Pulmonary Function and Psychological Burden Three Months after COVID-19: Proposal of a Comprehensive Multidimensional Assessment Protocol.

Persisting limitations in respiratory function and gas exchange, cognitive impairment, and mental health deterioration have been observed weeks and months after acute SARS-CoV-2 (COVID-19). The present study aims at assessing the impairment at three-months in patients who successfully recovered from acute COVID-19. We collected data from May to July 2020. Patients underwent a multidimensional extensive assessment including pulmonary function test, psychological tests, thoracic echo scan, and functional exercise capacity. A total of 21 patients (M:13; Age 57.05 ± 11.02) completed the global assessment. A considerable proportion of patients showed symptoms of post-traumatic stress disorder (28.6%), moderate depressive symptoms (9.5%), and clinical insomnia (9.5%); 14.3% of patients exhibited moderate anxiety. A total of eleven patients (52.4%) showed impaired respiratory gas exchange capacity (P-DLCO, DLCO ≤ 79% pred). Compared to patients with normal gas exchange, the P-DLCO subgroup perceived a significant worsening in quality of life (QoL) after COVID-19 (p = 0.024), higher fatigue (p = 0.005), and higher impact of lung disease (p = 0.013). In P-DLCO subgroup, higher echo score was positively associated with hospitalization length of stay (p = 0.047), depressive symptoms (p = 0.042), fatigue (p = 0.035), impairment in mental health (p = 0.035), and impact of lung disease in health status (p = 0.020). Pulmonary function and echo scan lung changes were associated to worsened QoL, fatigue, and psychological distress symptoms.

Detection of a pituitary macroadenoma with transcranial ultrasonography: Principles and potential clinical applications.

Transcranial color-coded duplex sonography (TCCS) allows to study intracranial vessels through the intact skull, but the visualization of normal and pathologic brain structures in adults is often suboptimal due to inadequate acoustic window. The full potential of TCCS for clinical practice remains unfulfilled. Here, we describe the ability of TCCS to detect a non-functioning pituitary macroadenoma in a 58-year-old man affected by headache. The macroadenoma was visualized as a roundish, well-defined mass, mildly hyperechogenic compared to the hypoechogenic mesencephalic brainstem but mainly hypoechogenic compared to the surrounding intracranial structures. Intracranial vessels represented useful landmarks. Using tissue harmonic imaging mode, the borders of the macroadenoma were visualized more clearly. Macroadenoma characteristics were confirmed by magnetic resonance imaging. Neurosonologists should be aware of the possibility to incidentally find, during routinary TCCS, pituitary macroadenomas or other brain tumors (as incidentalomas), worthy to be recognized and referred for further investigations.

Recognition in Emergency Department of Septic Patients at Higher Risk of Death: Beware of Patients without Fever.

Background and Objectives: Chances of surviving sepsis increase markedly upon prompt diagnosis and treatment. As most sepsis cases initially show-up in the Emergency Department (ED), early recognition of a septic patient has a pivotal role in sepsis management, despite the lack of precise guidelines. The aim of this study was to identify the most accurate predictors of in-hospital mortality outcome in septic patients admitted to the ED. Materials and Methods: We compared 651 patients admitted to ED for sepsis (cases) with 363 controls (non-septic patients). A Bayesian mean multivariate logistic regression model was performed in order to identify the most accurate predictors of in-hospital mortality outcomes in septic patients. Results: Septic shock and positive qSOFA were identified as risk factors for in-hospital mortality among septic patients admitted to the ED. Hyperthermia was a protective factor for in-hospital mortality. Conclusions: Physicians should bear in mind that fever is not a criterium for defining sepsis; according to our results, absence of fever upon presentation might be indicative of greater severity and diagnosis of sepsis should not be delayed.

D-Dimer as Biomarker for Early Prediction of Clinical Outcomes in Patients With Severe Invasive Infections Due to Streptococcus Pneumoniae and Neisseria Meningitidis.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection; no current clinical measure adequately reflects the concept of dysregulated response. Coagulation plays a pivotal role in the normal response to pathogens (immunothrombosis), thus the evolution toward sepsis-induced coagulopathy could be individuate through coagulation/fibrinolysis-related biomarkers. We focused on the role of D-dimer assessed within 24 h after admission in predicting clinical outcomes in a cohort of 270 patients hospitalized in a 79 months period for meningitis and/or bloodstream infections due to Streptococcus pneumoniae (n = 162) or Neisseria meningitidis (n = 108). Comparisons were performed with unpaired t-test, Mann-Whitney-test or chi-squared-test with continuity correction, as appropriate, and multivariable logistic regression analysis was performed with Bayesian model averaging. In-hospital mortality was 14.8% for the overall population, significantly higher in S. pneumoniae than in N. meningitidis patients: 19.1 vs. 8.3%, respectively (p = 0.014). At univariable logistic regression analysis the following variables were significantly associated with in-hospital mortality: pneumococcal etiology, female sex, age, ICU admission, SOFA score, septic shock, MODS, and D-dimer levels. At multivariable analysis D-dimer showed an effect only in N. meningitidis subgroup: as 500 ng/mL of D-dimer increased, the probability of unfavorable outcome increased on average by 4%. Median D-dimer was significantly higher in N. meningitidis than in S. pneumoniae patients (1,314 vs. 1,055 ng/mL, p = 0.009). For N. meningitidis in-hospital mortality was 0% for D-dimer <500 ng/mL, very low (3.5%) for D-dimer <7,000 ng/mL, and increased to 26.1% for D-dimer >7,000 ng/mL. Kaplan-Meier analysis of in-hospital mortality showed for N. meningitidis infections a statistically significant difference for D-dimer >7,000 ng/mL compared to values <500 ng/mL (p = 0.021) and 500-3,000 ng/mL (p = 0.002). For S. pneumoniae the mortality risk resulted always high, over 10%, irrespective by D-dimer values. In conclusion, D-dimer is rapid to be obtained, at low cost and available everywhere, and can help stratify the risk of in-hospital mortality and complications in patients with invasive infections due to N. meningitidis: D-dimer <500 ng/mL excludes any further complications, and a cut-off of 7,000 ng/mL seems able to predict a significantly increased mortality risk from much <10% to over 25%.

Reinfection of SARS-CoV-2 - analysis of 23 cases from the literature.

INTRODUCTION: The duration of immunity after infection from SARS-CoV-2 conferring protection from subsequent COVID-19 episodes is not yet fully understood. We reviewed the literature for cases of documented reinfection. MATERIALS AND METHODS: A comprehensive computerized search in PubMed, through 15 December 2020, using the following terms in combination: COVID-19, SARS-CoV-2, reinfection, reactivation, recurrence. To exclude cases due to prolonged viral shedding or protracted infection, only cases occurring at least 12 weeks apart or confirmed as being sustained by genetically different viruses by viral genome analysis were included. RESULTS: We identified 23 cases globally, for which viral genome analysis was performed in 10 cases and serology in 19 cases. The mean interval between the two episodes was 15 weeks. Mean age of cases was 44.5 years, and 10 (43.5%) were women. In 17/23 cases, no comorbidity was observed. In 10 cases, the first episode was more severe than the ensuing episode, whereas in seven cases the ensuing episode was more severe. In four cases, there was no difference in severity and in two cases both episodes were asymptomatic. CONCLUSIONS: From this sample of 23 cases, a clear pattern of the second episode being less or more severe did not emerge. A better understanding of immunity to SARS-CoV-2, necessary to assess the probability of a second infection and the durability of protection conferred by vaccination, is warranted.

Mono vs. combo regimens with novel beta-lactam/beta-lactamase inhibitor combinations for the treatment of infections due to carbapenemase-producing Enterobacterales: insights from the literature.

Ceftazidime-avibactam (CZA), meropenem-vaborbactam (MVB) and imipenem-relebactam (I-R) are combinations of old ß-lactams with novel non-ß-lactam ß-lactamase inhibitors (BLBLIs) able to inhibit some carbapenemases, such as the KPC-type, thus are becoming the standard for difficult-to-treat carbapenemase-producing Enterobacterales (CPE); a practical question is whether these novel BLBLIs should be used as monotherapy or as part of a combination regimen with other antibiotics, and if so, with which ones, to reduce the emergence of resistant strains and to optimize their efficacy. In this short review, we assessed clinical outcomes in patients with CPE-infections treated with the novel BLBLIs as mono- or combo-regimens, and laboratory studies on the synergistic effects with other antimicrobials. Available evidence on combination therapy is scarce and mainly limited to retrospective studies involving 630 patients treated with CZA: aminoglycosides were used in 39.6% of 336 patients treated with combo-regimens, followed by polymyxin B/colistin (24.4%), tigecycline (24.1%), carbapenems (13.4%) and fosfomycin (5.4%). Aminoglycosides could be useful in case of bloodstream and severe urinary infections. Pneumonia is a risk factor for CZA-resistance emergence: fosfomycin, due to favorable lung pharmacokinetics/pharmacodynamics, could represent an interesting partner; fosfomycin could be added also for osteomyelitis. Tigecycline could be preferred for intrabdominal and skin-soft tissue infections. Due to nephrotoxicity and lack of in vitro synergy, the association CZA/colistin seems not optimal. MVB and I-R were mostly used as monotherapies. Currently, there is no definitive evidence whether combinations are more effective than monotherapies; further studies are warranted, and to date only personal opinions can be provided.

Validity of "Sepsis-3" criteria in identifying patients with community-onset sepsis in Internal Medicine wards; a prospective, multicenter study.

BACKGROUND: Few data are available on the validity of "Sepsis-3" criteria in identifying patients with sepsis in internal medicine wards (IMWs). Real-life data about this topic and on the prevalence of sepsis in IMWs could be useful for improving hospital organization. OBJECTIVES: To assess the validity of "Sepsis-3" criteria in identifying patients with community-onset sepsis in IMWs. Secondary objectives: to evaluate the prevalence of these patients in IMWs and to compare "Sepsis-3" and "Sepsis-1" criteria. METHODS: Multicenter, prospective, observational, cohort study, carried out in 22 IMWs of Tuscany (Italy). All patients admitted to each of the study centers over a period of 21-31 days were evaluated within 48 hours; those with clinical signs of infection were enrolled. The main outcome was in-hospital mortality. RESULTS: 2,839 patients were evaluated and 938 (33%) met the inclusion criteria. Patients with sepsis diagnosed according to "Sepsis-3" were 522, representing 55.6% of patients with infection and 18.4% of all patients hospitalized; they were older than those without sepsis (79.4±12.5 vs 74.6±15.2 years, p<0.001). In-hospital mortality was significantly higher in patients with sepsis compared to others (13.8% vs 4.6%; p<0.001). "Sepsis-3" criteria showed greater predictive validity for in-hospital mortality than "Sepsis-1" criteria (AUROC=0.71; 95%CI, 0.66-0.77 vs 0.60; 95%CI 0.54-0.66; p=0.0038). CONCLUSIONS: "Sepsis-3" criteria are able to identify patients with community-onset sepsis in IMWs, whose prevalence and in-hospital mortality are remarkably high. Medical departments should adapt their organization to the needs for care of these complex patients.

The Paradox of the Low Prevalence of Current Smokers Among COVID-19 Patients Hospitalized in Nonintensive Care Wards: Results From an Italian Multicenter Case-Control Study.

INTRODUCTION: COVID-19, a respiratory illness due to SARS-CoV-2 coronavirus, was first described in December 2019 in Wuhan, rapidly evolving into a pandemic. Smoking increases the risk of respiratory infections; thus, cessation represents a huge opportunity for public health. However, there is scarce evidence about if and how smoking affects the risk of SARS-CoV-2 infection. METHODS: We performed an observational case-control study, assessing the single-day point prevalence of smoking among 218 COVID-19 adult patients hospitalized in seven Italian nonintensive care wards and in a control group of 243 patients admitted for other conditions to seven COVID-19-free general wards. We compared proportions for categorical variables by using the χ 2 test and performed univariate and multivariate logistic regression analyses to identify the variables associated with the risk of hospitalization for COVID-19. RESULTS: The percentages of current smokers (4.1% vs 16%, p = .00003) and never smokers (71.6% vs 56.8%, p = .0014) were significantly different between COVID-19 and non-COVID 19 patients. COVID-19 patients had lower mean age (69.5 vs 74.2 years, p = .00085) and were more frequently males (59.2% vs 44%, p = .0011). In the logistic regression analysis, current smokers were significantly less likely to be hospitalized for COVID-19 compared with nonsmokers (odds ratio = 0.23; 95% confidence interval, 0.11-0.48, p < .001), even after adjusting for age and gender (odds ratio = 0.14; 95% confidence interval, 0.06-0.31, p < .001). CONCLUSIONS: We reported an unexpectedly low prevalence of current smokers among COVID-19 patients hospitalized in nonintensive care wards. The meaning of these preliminary findings, which are in line with those currently emerging in literature, is unclear; they need to be confirmed by larger studies. IMPLICATIONS: An unexpectedly low prevalence of current smokers among patients hospitalized for COVID-19 in some Italian nonintensive care wards is reported. This finding could be a stimulus for the generation of novel hypotheses on individual predisposition and possible strategies for reducing the risk of infection from SARS-CoV-2 and needs to be confirmed by further larger studies designed with adequate methodology.

Intussusceptive angiogenesis in Covid-19: hypothesis on the significance and focus on the possible role of FGF2.

The interest on the role of angiogenesis in the pathogenesis and progression of human interstitial lung diseases is growing, with conventional sprouting (SA) and non-sprouting intussusceptive angiogenesis (IA) being differently represented in specific pulmonary injury patterns. The role of viruses as key regulators of angiogenesis is known for several years. A significantly enhanced amount of new vessel growth, through a mechanism of IA, has been reported in lungs of patients who died from Covid-19; among the angiogenesis-related genes, fibroblast growth factor 2 (FGF2) was found to be upregulated. These findings are intriguing. FGF2 plays a role in some viral infections: the upregulation is involved in the MERS-CoV-induced strong apoptotic response crucial for its highly lytic replication cycle in lung cells, whereas FGF2 is protective against the acute lung injury induced by H1N1 influenza virus, improving the lung wet-to-dry weight ratio. FGF2 plays a role also in regulating IA, acting on pericytes (crucial for the formation of intraluminal pillars), and endothelium, and FGF2-induced angiogenesis may be promoted by inflammation and hypoxia. IA is a faster and probably more efficient process than SA, able to modulate vascular remodeling through pruning of redundant or inefficient blood vessels. We can speculate that IA might have the function of restoring a functional vascular plexus consequently to extensive endothelialitis and alveolar capillary micro-thrombosis observed in Covid-19. Anti-Vascular endothelial growth factor (anti-VEGF) strategies are currently investigated for treatment of severe and critically ill Covid-19 patients, but also FGF2, and its expression and/or signaling, might represent a promising target.

Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key?

To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein-Kinin (KKS), the Coagulation/Fibrinolysis and the Renin-Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg9]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19.

Personalized machine learning approach to predict candidemia in medical wards.

PURPOSE: Candidemia is a highly lethal infection; several scores have been developed to assist the diagnosis process and recently different models have been proposed. Aim of this work was to assess predictive performance of a Random Forest (RF) algorithm for early detection of candidemia in the internal medical wards (IMWs). METHODS: A set of 42 potential predictors was acquired in a sample of 295 patients (male: 142, age: 72 ± 15 years; candidemia: 157/295; bacteremia: 138/295). Using tenfold cross-validation, a RF algorithm was compared with a classic stepwise multivariable logistic regression model; discriminative performance was assessed by C-statistics, sensitivity and specificity, while calibration was evaluated by Hosmer-Lemeshow test. RESULTS: The best tuned RF algorithm demonstrated excellent discrimination (C-statistics = 0.874 ± 0.003, sensitivity = 84.24% ± 0.67%, specificity = 91% ± 2.63%) and calibration (Hosmer-Lemeshow statistics = 12.779 ± 1.369, p = 0.120), markedly greater than the ones guaranteed by the classic stepwise logistic regression (C-statistics = 0.829 ± 0.011, sensitivity = 80.21% ± 1.67%, specificity = 84.81% ± 2.68%; Hosmer-Lemeshow statistics = 38.182 ± 15.983, p < 0.001). In addition, RF suggests a major role of in-hospital antibiotic treatment with microbioma highly impacting antimicrobials (MHIA) that are found as a fundamental risk of candidemia, further enhanced by TPN. When in-hospital MHIA therapy is not performed, PICC is the dominant risk factor for candidemia, again enhanced by TPN. When PICC is not used and MHIA therapy is not performed, the risk of candidemia is minimum, slightly increased by in-hospital antibiotic therapy. CONCLUSION: RF accurately estimates the risk of candidemia in patients admitted to IMWs. Machine learning technique might help to identify patients at high risk of candidemia, reduce the delay in empirical treatment and improve appropriateness in antifungal prescription.