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Fluoroquinolone prophylaxis’s (FQ-P) usefulness in patients with neutropenia is controversial. In recent decades, Italian epidemiological data has shown worrisome rates of FQ resistance. A single-center cohort study on 136 autologous stem cell transplantations (ASCTs) and 223 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) was performed from January 2018 to December 2020. Piperacillin/tazobactam was the first-line therapy for febrile neutropenia (FN). Since February 2019, FQ-P has been omitted. We evaluated the day +30 posttransplant cumulative incidence function (CIF) of gram-negative bacteria pre-engraftment bloodstream infections (PE-BSIs) and any changes in antimicrobial resistance, FN, and infection-related mortality (IRM). In ASCTs, ≥1 FN episode occurred in 74.3% of transplants, without differences among groups (P = .66). CIF of gram-negative bacteria PE-BSI was 10.1%, with a significant difference according to FQ-P (0% [LEVO-group] vs 14.1% [NO-LEVO-group], P = .016). CIF of IRM was 0% in both groups. In allo-HSCTs, ≥1 FN episode occurred in 96.4% of transplants, without differences among groups (P = .72). CIF of gram-negative bacteria PE-BSI was 28%, significantly higher without FQ-P (14.7% [LEVO-group] vs 34.4% [NO-LEVO-group], P = .003). CIF of IRM was 5%, superimposable in both groups (P = .62). Comparing antimicrobial resistance among gram-negative bacteria of allo-HSCT setting, in the group without FQ-P, a significantly higher proportion of pathogens was susceptible to piperacillin/tazobactam (71% vs 30%, P = .026), FQ (49% vs 10%, P = .03), and carbapenems (95% vs 50%, P = .001). FQ-P discontinuation increased gram-negative bacteria PE-BSI but did not impact IRM, both in the ASCT and allo-HSCT settings; importantly, it concurred to significantly decrease antimicrobial resistance in gram-negative bacteria.

Background: Infections of cardiovascular implantable electronic devices (CIED) are mainly due to Gram-positive bacteria (GPB). Data about Gram-negative bacteria CIED (GNB-CIED) infections are limited. This study aimed to investigate risk factors, clinical and diagnostic characteristics, and outcome of patients with GNB-CIED. Methods: A multicentre, international, retrospective, case-control-control study was performed on patients undergoing CIED implantation from 2015 to 2019 in 17 centres across Europe. For each patient diagnosed with GNB-CIED, one matching control with GPB-CIED infection and two matching controls without infection were selected. Results: A total of 236 patients were enrolled: 59 with GNB-CIED infection, 59 with GPB-CIED infection and 118 without infection. No between-group differences were found regarding clinical presentation, diagnostic and therapeutic management. A trend toward a higher rate of fluorodeoxyglucose positron emission computed tomography (FDG PET/CT) positivity was observed among patients with GNB than in those with GPB-CIED infection (85.7% vs. 66.7%; P = 0.208). Risk factors for GNB-CIED infection were Charlson Comorbidity Index Score (relative risk reduction, RRR = 1.211; P = 0.011), obesity (RRR = 5.122; P = 0.008), ventricular-pacing ventricular-sensing inhibited-response pacemaker implantation (RRR = 3.027; P = 0.006) and right subclavian vein site of implantation (RRR = 5.014; P = 0.004). At 180-day survival analysis, GNB-CIED infection was associated with increased mortality risk (HR = 1.842; P = 0.067). Conclusions: Obesity, high number of comorbidities and right subclavian vein implantation site were associated with increased risk of GNB-CIED infection. A prompt therapeutic intervention that may be guided using FDG PET/CT is suggested in patients with GNB-CIED infection, considering the poorer outcome observed in this group.

Background: Non-invasive mechanical ventilation (NIV) is effective for symptom relief and respiratory support in patients with respiratory insufficiency, severe comorbidities and no indication to intubation. Experience with NIV as the ceiling of treatment in severely compromised novel coronavirus disease (COVID-19) patients is lacking. Methods: We evaluated 159 patients with COVID-19-related acute respiratory syndrome (ARDS), 38 of whom with NIV as the ceiling of treatment, admitted to an ordinary ward and treated with continuous positive airway pressure (CPAP) and respiratory physiotherapy. Treatment failure and death were correlated with clinical and laboratory parameters in the whole cohort and in patients with NIV as the ceiling of treatment. Results: Patients who had NIV as the ceiling of treatment were elderly, with a low BMI and a high burden of comorbidities, showed clinical and laboratory signs of multi-organ insufficiency on admission and of rapidly deteriorating vital signs during the first week of treatment. NIV failure occurred overall in 77 (48%) patients, and 27/38 patients with NIV as the ceiling of treatment died. Congestive heart failure, chronic benign haematological diseases and inability/refusal to receive respiratory physiotherapy were independently associated to NIV failure and mortality. Need for increased positive end-expiratory pressures and low platelets were associated with NIV failure. Death was associated to cerebrovascular disease, need for CPAP cycles longer than 12h and, in the subgroup of patients with NIV as the ceiling of treatment, was heralded by vital sign deterioration within 48 h. Conclusions: NIV and physiotherapy are a viable treatment option for patients with severe COVID-19 and severe comorbidities.

Fluoroquinolone prophylaxis (FQ-P) usefulness in neutropenic patients is controversial. In recent decades, Italian epidemiological data has shown worrisome rates of FQ resistance. A single-center cohort study on 136 autologous stem cell transplantations (ASCTs) and 223 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) was performed from Jan-2018 to Dec-2020. Piperacillin/tazobactam was the first-line therapy for febrile neutropenia (FN). Since Feb-2019, FQ-P was omitted. We evaluated the day +30 post-transplant cumulative incidence function (CIF) of Gram-negative bacteria pre-engraftment blood-stream infections (PE-BSIs) and any changes in antimicrobial resistance, FN and infection-related mortality (IRM). In ASCTs, ≥1 FN episode occurred in 74.3% of transplants, without differences among groups [p=0.66]. CIF of Gram-negative bacteria PE-BSI was 10.1% with a significant difference according to FQ-P [0% (LEVO-group) versus 14.1% (NO-LEVO-group), p=0.016]. CIF of IRM was 0% in both groups. In allo-HSCTs, ≥1 FN episode occurred in 96.4% of transplants, without differences among groups [p=0.72]. CIF of Gram-negative bacteria PE-BSI was 28% and it was significantly higher without FQ-P [14.7% (LEVO-group) versus 34.4% (NO-LEVO-group), p=0.003]. CIF of IRM was 5%, superimposable in both groups [p=0.62]. Comparing antimicrobial resistance among Gram-negative bacteria in the setting of allo-HSCT, in the group without FQ-P a significantly higher proportion of pathogens was susceptible to piperacillin/tazobactam (71% versus 30%, p=0.026), FQ (49% versus 10%, p=0.03) and carbapenems (95% versus 50%, p=0.001). FQ-P discontinuation increased Gram-negative bacteria PE-BSI, but it did not impact IRM, both in ASCT and allo-HSCT setting; importantly, it concurred to decrease significantly antimicrobial resistance in Gram-negative bacteria.

The purpose of this study was to evaluate the impact of surgical timing on survival in patients with left-sided infective endocarditis (IE). This was a retrospective study including 313 patients with left-sided IE between 2009 and 2017. Surgery was defined as urgent (US) or early (ES) if performed within 7 or 28days, respectively. A multivariable Cox regression analysis including US and ES as time-dependent variables was performed to assess the impact on 1-year mortality. ES was associated with a better survival (aHR 0.349, 95% CI 0.135–0.902), as US (aHR 0.262, 95% CI 0.075–0.915). ES and US were associated with a better prognosis in patients with left-sided IE.

ObjectiveTo assess the prevalence, characteristics and prognostic value of pulmonary hypertension (PH) and right ventricular dysfunction (RVD) in hospitalised, non-intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19).MethodsThis single-centre, observational, cross-sectional study included 211 patients with COVID-19 admitted to non-ICU departments who underwent a single transthoracic echocardiography (TTE). Patients with poor acoustic window (n=11) were excluded. Clinical, imaging, laboratory and TTE findings were compared in patients with versus without PH (estimated systolic pulmonary artery pressure >35 mm Hg) and with versus without RVD (tricuspid annular plane systolic excursion ResultsA total of 200 patients were included in the final analysis (median age 62 (IQR 52–74) years, 65.5% men). The prevalence of PH and RVD was 12.0% (24/200) and 14.5% (29/200), respectively. Patients with PH were older and had a higher burden of pre-existing cardiac comorbidities and signs of more severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (radiological lung involvement, laboratory findings and oxygenation status) compared with those without PH. Conversely, patients with RVD had a higher burden of pre-existing cardiac comorbidities but no evidence of more severe SARS-CoV-2 infection compared with those without RVD. The presence of PH was associated with a higher rate of in-hospital death or ICU admission (41.7 vs 8.5%, pConclusionsAmong hospitalised non-ICU patients with COVID-19, PH (and not RVD) was associated with signs of more severe COVID-19 and with worse in-hospital clinical outcome.Trial registration numberNCT04318366

Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.

Background Biobanks are imperative infrastructures, particularly during outbreaks, when there is an obligation to acquire and share knowledge as quick as possible to allow for implementation of science-based preventive, diagnostic, prognostic and therapeutic strategies. Methods We established a COVID-19 biobank with the aim of collecting high-quality and well-annotated human biospecimens, in the effort to understand the pathogenic mechanisms underlying COVID-19 and identify therapeutic targets (COVID-BioB, NCT04318366). Here we describe our experience and briefly review the characteristics of the biobanks for COVID-19 that have been so far established. Results A total of 46,677 samples have been collected from 913 participants (63.3% males, median [IQR] age 62.2 [51.2 - 74.0] years) since the beginning of the program. Most patients (66.9%) had been admitted to hospital for COVID-19, with a median length of stay of 15.0 (9.0 - 27.0) days. A minority of patients (13.3% of the total) had been admitted for other reasons and subsequently tested positive for SARS-CoV-2. The remainder were managed at home after being seen at the Emergency Department. Conclusions Having a solid research infrastructure already in place, along with flexibility and adaptability to new requirements, allowed for the quick building of a COVID-19 biobank that will help expand and share the knowledge of SARS-CoV-2.

Objective: Exploring the association between frailty and mortality in a cohort of patients with COVID-19 respiratory insufficiency treated with continuous positive airway pressure. Methods: Frailty was measured using a Frailty Index (FI) created by using the baseline assessment data on comorbidities and body mass index and baseline blood test results (including pH, lactate dehydrogenase, renal and liver function, inflammatory indexes and anemia). FI > 0.25 identified frail individuals. Results: Among the 159 included individuals (81% men, median age of 68) frailty was detected in 69% of the patients (median FI score 0.3 ± 0.08). Frailty was associated to an increased mortality (adjusted HR 1.99, 95% CI 1.02–3.88, p = 0.04). Conclusions: Frailty is highly prevalent among patients with COVID-19, predicts poorer outcomes independently of age. A personalization of care balancing the risk and benefit of treatments (especially the invasive ones) in such complex patients is pivotal.

Aims Infection by SARS‐CoV‐2 may result in a systemic disease and a proportion of patients ranging 15%–44% experienced cardiac injury (CI) diagnosed by abnormal troponin levels. The aim of the present study was to analyse the clinical characteristics of a large series of hospitalized patients for COVID‐19 in order to identify predisposing and/or protective factors of CI and the outcome. Methods and results This is an observational, retrospective study on patients hospitalized in two Italian centres (San Raffaele Hospital and Cremona Hospital) for COVID‐19 and at least one high‐sensitivity cardiac troponin (hs‐cTnt) measurement during hospitalization. CI was defined if at least one hs‐cTnt value was above the 99th percentile. The primary end‐point was the occurrence of CI during hospitalization. We included 750 patients (median age 67, IQR 56–77 years; 69% males), of whom 46.9% had history of hypertension, 14.7% of chronic coronary disease and 22.3% of chronic kidney disease (CKD). Abnormal troponin levels (median troponin 74, IQR 34–147 ng/l) were detected in 390 patients (52%) during the hospitalization. At multivariable analysis age, CKD, cancer, C‐reactive protein (CRP) levels were independently associated with CI. Independent predictors of very high troponin levels were chronic kidney disease and CRP levels. Patients with CI showed higher rate of all‐cause mortality (40.0% vs. 9.1%, p = 0.001) compared to those without CI. Conclusion This large, multicentre Italian study confirmed the high prevalence of CI and its prognostic role in hospitalized patients with COVID‐19, highlighting the leading role of systemic inflammation for the occurrence of CI.

COVID-19 is frequently associated with the onset of secondary infections, especially in severe cases treated in the intensive care unit. While bacterial pathogens are the most frequently encountered causative agents, several factors put SARS-CoV-2 infected patients at a heightened risk of invasive fungal infections, which have been recognized as a substantial cause of morbidity and mortality in this population. Moreover, the frequent occurrence of these complications in severely ill subjects and the absence of pathognomonic features, together with the emergence of fungal species with reduced susceptibility to first-line treatments and the difficult to manage safety profile of several antifungal drugs, demand an additional focus on these rare but challenging complications. In this review, we will summarize the currently available literature on fungal superinfections in COVID-19 patients, exploring the pathogenesis, epidemiology, clinical features, treatment, and outcomes.

Background: The aim of this study was to quantify COVID-19 pneumonia features using CT performed at time of admission to emergency department in order to predict patients' hypoxia during the hospitalization and outcome. Methods: Consecutive chest CT performed in the emergency department between March 1st and April 7th 2020 for COVID-19 pneumonia were analyzed. The three features of pneumonia (GGO, semi-consolidation and consolidation) and the percentage of well-aerated lung were quantified using a HU threshold based software. ROC curves identified the optimal cut-off values of CT parameters to predict hypoxia worsening and hospital discharge. Multiple Cox proportional hazards regression was used to analyze the capability of CT quantitative features, demographic and clinical variables to predict the time to hospital discharge. Results: Seventy-seven patients (median age 56-years-old, 51 men) with COVID-19 pneumonia at CT were enrolled. The quantitative features of COVID-19 pneumonia were not associated to age, sex and time-from-symptoms onset, whereas higher number of comorbidities was correlated to lower well-aerated parenchyma ratio (rho = −0.234, p = 0.04) and increased semi-consolidation ratio (rho = −0.303, p = 0.008). Well-aerated lung (≤57%), semi-consolidation (≥17%) and consolidation (≥9%) predicted worst hypoxemia during hospitalization, with moderate areas under curves (AUC 0.76, 0.75, 0.77, respectively). Multiple Cox regression identified younger age (p < 0.01), female sex (p < 0.001), longer time-from-symptoms onset (p = 0.049), semi-consolidation ≤17% (p < 0.01) and consolidation ≤13% (p = 0.03) as independent predictors of shorter time to hospital discharge. Conclusion: Quantification of pneumonia features on admitting chest CT predicted hypoxia worsening during hospitalization and time to hospital discharge in COVID-19 patients.

Background: Myocardial injury (MI) can be detected during the acute phase of Coronavirus disease 19 (COVID-19) and is associated with a dismal prognosis. Recent imaging studies described the persistence of cardiac abnormalities after the recovery. The aim of the study was to investigate the spectrum of cardiac abnormalities at mid-term follow-up in patients recovered from COVID-19 using clinical assessment, laboratory tests, and imaging evaluation with comprehensive echocardiography. Methods: This is an observational, cross-sectional study assessing an unselected cohort of consecutive patients recovered from COVID-19. MI was defined by elevated plasma levels of high sensitive troponin T (hsTnT). At the follow-up, a complete examination including echocardiography was performed. Results: The 123 patients included were divided into two groups according to the presence of MI during hospitalization: group A (without MI) and group B (with MI). After a median of 85 days, group B patients were more frequently symptomatic for dyspnea and had significantly higher values of hsTnT and N-Terminal prohormone of Brain Natriuretic Peptide (NT-proBNP), compared to Group A. No differences between the two groups in left nor right ventricle dimension and ejection fraction were found. However, in group B a significant reduction of mean left ventricle global longitudinal strain was observed (-15.7±.7vs -18.1±.3 in group A, p&nbsp

Objectives During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, dramatic endothelial cell damage with pulmonary microvascular thrombosis have been was hypothesized to occur. The aim was to assess whether pulmonary vascular thrombosis (PVT) is due to recurrent thromboembolism from peripheral deep vein thrombosis or to local inflammatory endothelial damage, with a superimposed thrombotic late complication. Design Observational study. Setting Medical and intensive care unit wards of a teaching hospital. Participants The authors report a subset of patients included in a prospective institutional study (CovidBiob study) with clinical suspicion of pulmonary vascular thromboembolism. Interventions Computed tomography pulmonary angiography and evaluation of laboratory markers and coagulation profile. Measurements and Main Results Twenty-eight of 55 (50.9%) patients showed PVT, with a median time interval from symptom onset of 17.5 days. Simultaneous multiple PVTs were identified in 22 patients, with bilateral involvement in 16, mostly affecting segmental/subsegmental pulmonary artery branches (67.8% and 96.4%). Patients with PVT had significantly higher ground glass opacity areas (31.7% [22.9-41] v 17.8% [10.8-22.1], p < 0.001) compared with those without PVT. Remarkably, in all 28 patients, ground glass opacities areas and PVT had an almost perfect spatial overlap. D-dimer level at hospital admission was predictive of PVT. Conclusions The findings identified a specific radiologic pattern of coronavirus disease 2019 (COVID-19) pneumonia with a unique spatial distribution of PVT overlapping areas of ground-glass opacities. These findings supported the hypothesis of a pathogenetic relationship between COVID-19 lung inflammation and PVT and challenged the previous definition of pulmonary embolism associated with COVID-19 pneumonia., Graphical abstract Computed Tomography Pulmonary Angiography (CTPA) imaging demonstrating, in three different clinical scenarios, eventual filling defects in branches of the pulmonary arteries (white arrows) and their spatial distribution according to the corresponding ventilation maps (white asterisks indicate normal lung parenchyma). In (a) [non COVID-19 pneumonia] and (c) [non COVID-19 ARDS] filling defects are electively found in the branches of the pulmonary arteries accountable for the vascularization of healthy lung segments. On the contrary, in (b) [COVID-19 pneumonia] there is an almost perfect topographical overlap between filling defects distribution and pneumonia extent.Image, graphical abstract

The purpose of this study was to evaluate the impact of surgical timing on survival in patients with left-sided infective endocarditis (IE). This was a retrospective study including 313 patients with left-sided IE between 2009 and 2017. Surgery was defined as urgent (US) or early (ES) if performed within 7 or 28 days, respectively. A multivariable Cox regression analysis including US and ES as time-dependent variables was performed to assess the impact on 1-year mortality. ES was associated with a better survival (aHR 0.349, 95% CI 0.135-0.902), as US (aHR 0.262, 95% CI 0.075-0.915). ES and US were associated with a better prognosis in patients with left-sided IE.

Objectives The aim of our study was to describe the incidence and predictive factors of secondary infections in patients with coronavirus disease 2019 (COVID-19). Methods This was a cohort study of patients hospitalized with COVID-19 at IRCCS San Raffaele Hospital between 25th February and 6th April 2020 (NCT04318366). We considered secondary bloodstream infections (BSIs) or possible lower respiratory tract infections (pLRTIs) occurring 48 hours after hospital admission until death or discharge. We calculated multivariable Fine–Gray models to assess factors associated with risk of secondary infections. Results Among 731 patients, a secondary infection was diagnosed in 68 patients (9.3%); 58/731 patients (7.9%) had at least one BSI and 22/731 patients (3.0%) at least one pLRTI. The overall 28-day cumulative incidence was 16.4% (95%CI 12.4–21.0%). Most of the BSIs were due to Gram-positive pathogens (76/106 isolates, 71.7%), specifically coagulase-negative staphylococci (53/76, 69.7%), while among Gram-negatives (23/106, 21.7%) Acinetobacter baumanii (7/23, 30.4%) and Escherichia coli (5/23, 21.7%) predominated. pLRTIs were caused mainly by Gram-negative pathogens (14/26, 53.8%). Eleven patients were diagnosed with putative invasive aspergillosis. At multivariable analysis, factors associated with secondary infections were low baseline lymphocyte count (≤0.7 versus >0.7 per 109/L, subdistribution hazard ratios (sdHRs) 1.93, 95%CI 1.11–3.35), baseline PaO2/FiO2 (per 100 points lower: sdHRs 1.56, 95%CI 1.21–2.04), and intensive-care unit (ICU) admission in the first 48 hours (sdHR 2.51, 95%CI 1.04–6.05). Conclusions Patients hospitalized with COVID-19 had a high incidence of secondary infections. At multivariable analysis, early need for ICU, respiratory failure, and severe lymphopenia were identified as risk factors for secondary infections.

Objectives To evaluate ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) use in haematological patients with febrile neutropenia receiving high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT). Methods A retrospective study was conducted to assess C/A and C/T efficacy through infection-related mortality (IRM) and bacteraemia clearance for carbapenem-resistant Gram-negative bacteria (CR-GNB) pre-engraftment blood-stream infections (PE-BSIs) between January–December 2018. Results Seventy patients underwent allogeneic HSCT: C/A and C/T were dispensed in 13% and 3%, respectively. C/A was administered as definite therapy for carbapenem-resistant Klebsiella pneumoniae (CR-Kp) PE-BSI in four carriers (bacteraemia clearance in 5 days), empirical therapy for a clinically documented infection in two patients (one carrier with pneumonia and one non-carrier with shock) and empirical therapy for fever of unknown origin in three CR-Kp carriers. C/T was administered as definite therapy for carbapenem-resistant Pseudomonas aeruginosa (CR-Pa) intra-abdominal infection in one carrier and empirical therapy for a clinically documented infection (pneumonia) in one non-carrier. Among patients without PE-BSIs and with Gram-positive bacteria PE-BSIs, IRM was 0% at +30 days; conversely, it was 30% in GNB PE-BSIs (two CR-Kp and one CR-Pa C/T-resistant). Thirty-nine patients underwent autologous HSCT: C/A and C/T were administered, respectively, as definite therapy for CR-Kp PE-BSI in one carrier (bacteraemia clearance in 3 days) and for Pa PE-BSI (three strains, one CR-Pa) in one non-carrier (bacteraemia clearance in 2 days). Overall, IRM at +30 days was 0%. Conclusions Monitoring multidrug-resistant GNB colonisation enabled selection of carriers who benefit from prompt administration of new antibiotics, improving HSCT outcomes in a high-risk population. C/A and C/T were effective in bacteraemia clearance; unfortunately, multidrug-resistant GNB PE-BSIs were still a burden to IRM.

The widespread use of T lymphocyte-associated antigen-4 (CTLA-4) and programmed death (PD)-1 and PD ligand-1 (PDL1)-targeted agents in cancer patients as immunotherapy has raised some issues on their safety profile. Regarding infectious complications, it has emerged that these compounds do not intrinsically increase susceptibility to opportunistic infections, which mainly correlate with the co-administration of systemic immunosuppressive therapy (high-dose corticosteroids and anti-tumor necrosis factors inhibitors) to cure immune-related adverse events (colitis, hepatitis, pneumonitis and pancreatitis), well-known complications of these targeted drugs. These observations lead experts' opinion to suggest primary anti-Pneumocystis prophylaxis in patients undergoing CTLA-4 and PD-1/PDL1 agents who will receive prednisone 20 mg daily for ≥ 4 weeks. Few data on invasive fungal infections in this context are available. We report here a case of probable invasive pulmonary aspergillosis (p-IPA) complicating first-line immunotherapy with pembrolizumab for metastatic lung cancer that was further aggravated by multidrug-resistant Pseudomonas aeruginosa superinfection of fungal cavities; the patient received concurrent systemic corticosteroid therapy as anti-edema treatment for cerebral metastases. Reviewing literature about Aspergillus diseases in subjects receiving CTLA-4 and PD-1 and PDL1-targeted agents, we found three cases of invasive aspergillosis and one case of exacerbation of chronic progressive pulmonary aspergillosis after nivolumab treatment; to the best of our knowledge, this is the first report of p-IPA complicating pembrolizumab immunotherapy. Briefly, in this new setting of biological/targeted drugs, waiting for growing clinical experience, we recommend a high level of alertness in diagnosing any infectious complications.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has attracted interest because of its global rapid spread, clinical severity, high mortality rate, and capacity to overwhelm healthcare systems [1, 2]. SARS-CoV-2 transmission occurs mainly through droplets, although surface contamination contributes and debate continues on aerosol transmission [3–5].

The rapid evolution of the health emergency linked to the spread of severe acute respiratory syndrome coronavirus 2 requires specifications for the rehabilitative management of patients with coronavirus disease 2019 (COVID-19). The symptomatic evolution of patients with COVID-19 is characterized by 2 phases: an acute phase in which respiratory symptoms prevail and a postacute phase in which patients can show symptoms related to prolonged immobilization, to previous and current respiratory dysfunctions, and to cognitive and emotional disorders. Thus, there is the need for specialized rehabilitative care for these patients. This communication reports the experience of the San Raffaele Hospital of Milan and recommends the setup of specialized clinical pathways for the rehabilitation of patients with COVID-19. In this hospital, between February 1 and March 2, 2020, about 50 patients were admitted every day with COVID-19 symptoms. In those days, about 400 acute care beds were created (intensive care/infectious diseases). In the following 30 days, from March 2 to mid-April, despite the presence of 60 daily arrivals to the emergency department, the organization of patient flow between different wards was modified, and several different units were created based on a more accurate integration of patients' needs. According to this new organization, patients were admitted first to acute care COVID-19 units and then to COVID-19 rehabilitation units, post-COVID-19 rehabilitation units, and/or quarantine/observation units. After hospital discharge, telemedicine was used to follow-up with patients at home. Such clinical pathways should each involve dedicated multidisciplinary teams composed of pulmonologists, physiatrists, neurologists, cardiologists, physiotherapists, neuropsychologists, occupational therapists, speech therapists, and nutritionists.

This study measured respiratory parameters of 15 non-ICU patients before, during, and after receiving noninvasive ventilation in the prone position.

Objectives Ceftobiprole is a relatively new cephalosporin with broad-spectrum activity and good tolerability. Despite its promising characteristics, to our knowledge, only two case reports, previously published also by some of us, is available concerning its administration for the treatment of infective endocarditis. Hereby we report our experience in this field. Methods All the patients with infective endocarditis treated with ceftobiprole were enrolled. Results 12 cases of endocarditis were treated with ceftobiprole, 11/12 in combination with daptomycin and 1/12 as monotherapy. Gram-positive bacteria were isolated in 12/12 patients; 3 cases were polymicrobial. Cure rate was 83% (10/12 patients). In 9/12 (75%) cases, patients were switched to ceftobiprole following failure of previous antimicrobial regimen. In 3/3 patients in which ceftobiprole was administered because of persistently positive blood culture, bacteraemia clearance was rapidly achieved. Conclusions Ceftobiprole, especially in combination, could be a promising alternative treatment for infective endocarditis.

Febrile neutropenia and sepsis are common and life-threatening complications in hematological diseases. This study was performed retrospectively in 514 patients treated for febrile neutropenia at our institute, to investigate the clinical usefulness of a molecular tool, LightCycler® SeptiFast test (SF), to promptly recognize pathogens causing sepsis in hematological patients. We collected 1837 blood samples of 514 consecutive hematological patients. The time of processing is short. Overall, 757 microorganisms in 663 episodes were detected by molecular test and standard blood cultures (BC): 73.6% Gram-positive bacteria, 23.9% Gram-negative bacteria, and 2.5% fungal species. This large analysis demonstrated a significant episode-to episode agreement (71.9%) between the two methods, higher in negative samples (89.14%), and a specificity of 75.89%. Clinical variables that gave a statistically significant contribution to their concordance were absolute neutrophil count, ongoing antimicrobial therapy, timing of test execution, and organ localization of infection. The large analysis highlights the potential of molecular-based assays directly performed on blood samples, especially if implementing the detection of antibiotic resistance genes, which was lacking in the used study.

Objective To assess the prevalence, characteristics and prognostic value of pulmonary hypertension (PH) and right ventricular dysfunction (RVD) in hospitalised, non-intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). Methods This single-centre, observational, cross-sectional study included 211 patients with COVID-19 admitted to non-ICU departments who underwent a single transthoracic echocardiography (TTE). Patients with poor acoustic window (n=11) were excluded. Clinical, imaging, laboratory and TTE findings were compared in patients with versus without PH (estimated systolic pulmonary artery pressure >35 mm Hg) and with versus without RVD (tricuspid annular plane systolic excursion

Background National health-system hospitals of Lombardy faced a heavy burden of admissions for acute respiratory distress syndromes associated with coronavirus disease (COVID-19). Data on patients of European origin affected by COVID-19 are limited. Methods All consecutive patients aged ≥18 years, coming from North-East of Milan's province and admitted at San Raffaele Hospital with COVID-19, between February 25th and March 24th, were reported, all patients were followed for at least one month. Clinical and radiological features at admission and predictors of clinical outcomes were evaluated. Results Of the 500 patients admitted to the Emergency Unit, 410 patients were hospitalized and analyzed: median age was 65 (IQR 56–75) years, and the majority of patients were males (72.9%). Median (IQR) days from COVID-19 symptoms onset was 8 (5–11) days. At hospital admission, fever (≥ 37.5 °C) was present in 67.5% of patients. Median oxygen saturation (SpO2) was 93% (range 60–99), with median PaO2/FiO2 ratio, 267 (IQR 184–314). Median Radiographic Assessment of Lung Edema (RALE) score was 9 (IQR 4–16). More than half of the patients (56.3%) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. The probability of overall survival at day 28 was 66%. Multivariable analysis showed older age, coronary artery disease, cancer, low lymphocyte count and high RALE score as factors independently associated with an increased risk of mortality. Conclusion In a large cohort of COVID-19 patients of European origin, main risk factors for mortality were older age, comorbidities, low lymphocyte count and high RALE.

Background The incidence of health care–associated infections in patients with head and neck cancer receiving chemotherapy and/or radiotherapy (RT) is unknown. This retrospective study investigated the most common pathogens and their antibiotic sensitivity/resistance patterns in patients with head and neck cancer. Methods Infection rates in patients with head and neck cancer were analyzed over 2 periods (January 2005 to December 2009 and January 2010 to November 2012). Results In the first period, 140 health care-associated infections were observed among 2288 admissions, mostly because of gram-negative pathogens affecting the respiratory tract. In the second period, 212 health care-associated infections were observed. An increase in antibiotic resistance was reported. Health care-associated infections were more frequent with: male sex, age

BACKGROUND: ST22-IV is a successful hospital-associated MRSA clone. Due to its known ability to replace other MRSA clones in hospitals, it became a dominant clone in Europe and beyond. So far, there are no studies investigating the relationship between the epidemiological success of MRSA clones and their capacity to withstand commonly encountered stresses. METHODS: We investigated the fitness of ST22-IV in comparison with the replaced clone ST228-I, evaluating its resistance to oxidative stress, autolytic activity, growth at high osmolarity and in acid and alkaline environments and survival under desiccation and heat shock. We also compared their phenotypic characteristics and examined the impact of antibiotic consumption on epidemiological success. RESULTS: Here we demonstrate that the dominance of ST22-IV is linked neither to changes in antibiotic consumption nor to acquisition of additional resistances over time. Strong α-haemolysin activity, the production of β-haemolysin and the presence of an active agr could partly explain the virulence of ST22-IV previously observed in a murine model of pneumonia. Most importantly, we show that ST22-IV compared with ST228-I, besides retaining susceptibility to most antibiotics over time, has a superior capacity to survive under all stress conditions tested, which bacteria commonly face during their life cycle. CONCLUSIONS: Our results support our hypothesis that ST22-IV has a fitness advantage over ST228-I. This fitness advantage could have allowed ST22-IV to displace ST228-I without acquiring additional resistances and could help explain its epidemic success in hospital settings and its spread in Europe and beyond.

Human herpesvirus 6 (HHV-6) is increasingly recognized as a potentially life-threatening pathogen in allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively evaluated 54 adult patients who developed positivity to HHV-6 after alloSCT. The median time from alloSCT to HHV-6 reactivation was 34 days. HHV-6 was present in plasma samples from 31 patients, in bone marrow (BM) of 9 patients, in bronchoalveolar lavage fluid and liver or gut biopsy specimens from 33 patients, and in cerebrospinal fluid of 7 patients. Twenty-nine patients developed acute graft-versus-host disease (GVHD), mainly grade III-IV, and 15 had concomitant cytomegalovirus reactivation. The median absolute CD3+ lymphocyte count was 207 cells/µL. We reported the following clinical manifestations: fever in 43 patients, skin rash in 22, hepatitis in 19, diarrhea in 24, encephalitis in 10, BM suppression in 18, and delayed engraftment in 11. Antiviral pharmacologic treatment was administered to 37 patients; nonetheless, the mortality rate was relatively high in this population (overall survival [OS] at 1 year, 38% ± 7%). A better OS was significantly associated with a CD3+ cell count ≥200/µL at the time of HHV-6 reactivation (P = .0002). OS was also positively affected by the absence of acute GVHD grade III-IV (P = .03) and by complete disease remission (P = .03), but was not significantly influenced by steroid administration, time after alloSCT, type of antiviral prophylaxis, plasma viral load, or organ involvement. Although HHV-6 detection typically occurred early after alloSCT, better T cell immune reconstitution seems to have the potential to improve clinical outcomes. Our findings provide new insight into the interplay between HHV-6 and the transplanted immune system.

Background. The impact of human immunodeficiency virus (HIV)‐associated tuberculosis on CD4 T-cell count response to combined antiretroviral therapy (cART) is poorly investigated. Methods. A collaborative analysis including HIV-infected patients prospectively enrolled in 4 Italian clinical cohorts was conducted. Patients were grouped according to Centers for Disease Control and Prevention stage at the start of cART as having tuberculosis, having AIDS but not tuberculosis (nontuberculosis AIDS), and not having AIDS (AIDS free). Time to CD4 T-cell count of at least 100, 200, and 300 cells/lL above pre-cART levels and to CD4 T-cell count of .500 cells/lL were major end points. Survival analysis with time-fixed and time-dependent covariates was used. Results. A total of 6528 patients were eligible; 125 patients (2%) had tuberculosis, 1062 (16%) had nontuberculosis AIDS, and 5341 (82%) were AIDS free. Patients with tuberculosis had a significantly reduced chance of CD4 T-cell count increase compared with AIDS-free patients as well as those with nontuberculosis AIDS, regardless of the primary outcome considered for a given value of confounders measured at baseline (eg, for .200 cells/lL above baseline; relative hazard, 0.71; P 5 .02), although it was no longer significant after further adjustment for current level of viral load suppression (relative hazard, 0.80; P 5 .11). There was a trend for reduced virological response in patients treated concomitantly for tuberculosis and HIV infection compared with those who were treated separately in time (P 5 .09). Conclusions. HIV-infected patients starting cART with a tuberculosis diagnosis showed an impaired immune recovery to cART compared with AIDS-free patients and those with nontuberculosis AIDS. It seems to be driven mainly by a delay in achieving viral suppression. Whether this may be due to interactions between antituberculosis drugs and antiretrovirals needs to be investigated.

Background The aim of the study was to estimate the cumulative incidence of pre-engraftment blood stream infections (PE-BSI), its predictive factors and the infection-related mortality (IRM) after hematopoietic cell transplantation (HCT) from any donor type, with post-transplant cyclophosphamide (PT-Cy). Methods Retrospective cohort study on 235 adults who underwent peripheral blood HCT from every donor type with PT-Cy platform, from 2013 to 2017 at San Raffaele Scientific Institute. The Poisson regression was used to estimate the crude incidence rate (IR) of PE-BSI. The Fine-Gray competing risk model was applied to estimate the cumulative incidence function (CIF) of the first PE-BSI and its predictive factors and of IRM. Results Patients’ characteristics are reported in Table 1. During 5,316 person-days of follow-up (PDFU), 77 PE-BSI episodes occurred in 72 patients: IR = 1.45 per 100-PDFU [95% confidence interval (95% CI) 1.13–1.77]. The median time to PE-BSI was 13 days (IQR: 7–17) and the estimated CIF at 28 days was 32% (95% CI: 26–39%); no differences in CIF according to donor type [30% vs. 34% vs. 32% in match-related, match-unrelated and haploidentical donor, respectively; Gray’s test: P = 0.968]. Among the 87 isolated pathogens, 60% were Gram-positive bacteria (GPB), 39% Gram-negative bacteria (GNB) and 1% nontuberculous mycobacteria. CIFs of GNB and GPB PE-BSI by type of donor are shown in Figure 1. By multivariate analysis (Table 2), after adjustment for age, sex, year of HCT, donor type and disease phase at HCT, the CIF of any PE-BSI was higher in subjects with absolute neutrophils count ≤500 for ≥7 days before HCT [adjusted hazard ratio (AHR) = 2.90] and in multi-drug resistant (MDR) GNB rectal carriers before HCT [AHR = 2.68]. These covariates were confirmed as independent factors also for GNB PE-BSI. Overall, IRM at 30 days was 5% (95% CI: 2–8%) with no differences by donor type (Gray’s test: P = 0.106). Conclusion HCT with PT-Cy platform showed a 32% of cumulative incidence of PE-BSI at 28 days and donor type did not affect its occurrence, which was conversely increased by prolonged and severe neutropenia and MDR GNB rectal carriage before HCT. Haploidentical setting did not retain a higher IRM at 30 days than match-related and match-unrelated donors. Disclosures All authors: No reported disclosures.

Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections are an emerging cause of death after hematopoietic stem cell transplantation (HSCT). In allogeneic transplants, mortality rate may rise up to 60%. We retrospectively evaluated 540 patients receiving a transplant from an auto- or an allogeneic source between January 2011 and October 2015. After an Institutional increase in the prevalence of KPC-Kp bloodstream infections (BSI) in June 2012, from July 2012, 366 consecutive patients received the following preventive measures: (i) weekly rectal swabs for surveillance; (ii) contact precautions in carriers (iii) early-targeted therapy in neutropenic febrile carriers. Molecular typing identified KPC-Kp clone ST512 as the main clone responsible for colonization, BSI and outbreaks. After the introduction of these preventive measures, the cumulative incidence of KPC-Kp BSI (P=0.01) and septic shocks (P=0.01) at 1 year after HSCT was significantly reduced. KPC-Kp infection-mortality dropped from 62.5% (pre-intervention) to 16.6% (post-intervention). Day 100 transplant-related mortality and KPC-Kp infection-related mortality after allogeneic HSCT were reduced from 22% to 10% (P=0.001) and from 4% to 1% (P=0.04), respectively. None of the pre-HSCT carriers was excluded from transplant. These results suggest that active surveillance, contact precautions and early-targeted therapies, may efficiently control KPC-Kp spread and related mortality even after allogeneic HSCT.

Coadministration of posaconazole and sirolimus in allogeneic hematopoietic stem cell transplant recipients

The incidence of health care-associated infections in patients with head and neck cancer receiving chemotherapy and/or radiotherapy (RT) is unknown. This retrospective study investigated the most common pathogens and their antibiotic sensitivity/resistance patterns in patients with head and neck cancer.Infection rates in patients with head and neck cancer were analyzed over 2 periods (January 2005 to December 2009 and January 2010 to November 2012).In the first period, 140 health care-associated infections were observed among 2288 admissions, mostly because of gram-negative pathogens affecting the respiratory tract. In the second period, 212 health care-associated infections were observed. An increase in antibiotic resistance was reported. Health care-associated infections were more frequent with: male sex, age65 years, important comorbidities, smoking, proton pump inhibitors (PPIs), prophylaxis, and/or central venous catheter (CVC), locally advanced disease, and chemotherapy/RT, especially after the third week of treatment.Health care-associated infections increased over time, with corresponding increases in gram-negative pathogens and resistant strains. Prevention and treatment protocols should be implemented in institutions treating patients with head and neck cancer. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1009-E1013, 2016.

Clostridium difficile infection (CDI) became a public health problem for the global spreading of the so-called hypervirulent PCR ribotypes (RTs) 027 and 078, associated with increases in the transmission and severity of the disease. However, especially in Europe, several RTs are prevalent, and the concept of hypervirulence is currently debated. We investigated the toxin and resistance profiles and the genetic relatedness of 312 C. difficile strains isolated in a large Italian teaching hospital during a 5-year period. We evaluated the role of CDI-related antibiotic consumption and infection control practices on the RT predominance in association with their molecular features and transmission capacity. Excluding secondary cases due to nosocomial transmission, RT018 was the predominant genotype (42.4%) followed by RT078 (13.6%), while RT027 accounted for 0.8% of the strains. RT078 was most frequently isolated from patients in intensive care units. Its prevalence significantly increased over time, but its transmission capacity was very low. In contrast, RT018 was highly transmissible and accounted for 95.7% of the secondary cases. Patients with the RT018 genotype were significantly older than those with RT078 and other RTs, indicating an association between epidemic RT and age. We provide here the first epidemiological evidence to consider RT018 as a successful epidemic genotype that deserves more attention in clinical practice.

Identification of individuals infected withMycobacterium tuberculosisis essential for the control of tuberculosis (TB). The specificity of the currently used tuberculin skin test (TST) is poor because of the broad antigenic cross-reactivity of purified protein derivative (PPD) with BCG vaccine strains and environmental mycobacteria. Both ESAT-6 and CFP-10, two secretory proteins that are highly specific forM. tuberculosiscomplex, elicit strong T-cell responses in subjects with TB. Using an enzyme-linked immunospot (ELISPOT)-IFN-γ assay and a restricted pool of peptides derived from ESAT-6 and CFP-10, we have previously demonstrated a high degree of specificity and sensitivity of the test for the diagnosis of TB. Here, 119 contacts of individuals with contagious TB who underwent TST and the ELISPOT-IFN-γ assay were consecutively recruited. We compared the efficacy of the two tests in detecting latent TB infection and defined a more appropriate TST cutoff point. There was little agreement between the tests (k = 0.33,P< 0.0001): 53% of the contacts with a positive TST were ELISPOT negative, and 7% with a negative TST were ELISPOT positive. Furthermore, respectively 76 and 59% of the ELISPOT-negative contacts responded in vitro to BCG and PPD, suggesting that most of them were BCG vaccinated or infected with nontuberculous mycobacteria. The number of spot-forming cells significantly correlated with TST induration (P< 0.0001). Our in-house ELISPOT assay based on a restricted pool of highly selected peptides is more accurate than TST for identifying individuals with latent TB infection and could improve chemoprophylaxis for the control of TB.