Outcome of COVID-19 patients with haematological malignancies after the introduction of vaccination and monoclonal antibodies: results from the HM-COV 2.0 study.

Patients with haematological malignancies (HM) and SARS-CoV-2 infection present a higher risk of severe COVID-19 and mortality. The aim of the study was to investigate whether vaccination and monoclonal antibodies (mAbs) have modified the outcomes of HM patients with COVID-19. This is a single-centre retrospective study in HM patients hospitalized due to SARS-CoV-2 infection from March 2020 to April 2022. Patients were divided into PRE-V-mAb group (patients hospitalized before the introduction of vaccination and mAbs) and POST-V-mAb group (patients hospitalized after the use of vaccine and mAbs). A total of 126 patients were included (65 PRE-V-mAb and 61 POST-V-mAb). POST-V-mAb patients showed a significantly lower risk of intensive care unit (ICU) admission (8.2% vs. 27.7%, p = 0.005), shorter viral shedding [17 (IQR 10-28) vs. 24 days (IQR 15-50), p = 0.011] and shorter hospitalization length [13 (IQR 7-23) vs. 20 (IQR 14-41) days, p = 0.0003] compared to the PRE-V-mAb group. Nevertheless, both in-hospital and 30-day mortality rates did not significantly differ between the two groups (29.5% POST-V-mAb vs. 36.9% PRE-V-mAb and 21.3% POST-V-mAb vs. 29.2% PRE-V-mAb, respectively). At the multivariable analysis, an active malignancy (p = 0.042), a critical COVID-19 at admission (p = 0.025) and the need for high-level of oxygen support at respiratory worsening [either HFNC/CPAP (p = 0.022) or mechanical ventilation (p = 0.011)] were independently associated with in-hospital mortality. In the subgroup of POST-V-mAb patients, receiving therapy with mAbs was a protective factor (p = 0.033). Despite the new therapeutic and preventive strategies available, HM patients with COVID-19 disease represent an extremely vulnerable group with still high mortality rates.

Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection.

BACKGROUND: SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear. METHODS: We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B2, and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation. RESULTS: Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B2 biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox (phagocyte oxidase) upregulation. CONCLUSIONS: The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.

Ceftazidime-Avibactam for the Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections in Patients With Liver Cirrhosis.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in patients with cirrhosis represent a significant therapeutic challenge as they are associated with poor outcomes due to high rates of treatment failure, and frequently induce liver decompensation. Aims: To evaluate treatment failure and in-hospital mortality in two cohorts of patients with cirrhosis and with CRKP infections treated with antibiotic regimens including or excluding Ceftazidime-avibactam. Methods: Data from hospitalized patients with liver cirrhosis and CRKP infections were extracted and retrospectively analyzed. Results: During the study period, 39 cirrhotic patients with confirmed invasive CRKP infections were enrolled. Overall, the median age was 60 years with a median MELD score of 16 points. Urinary tract infections were diagnosed in 46%, followed by pneumonia in 23%, and primary bacteremia in 18% of patients. Treatment failure was reported in 10 patients (26%), while in-hospital mortality in 15 patients (38%). A monotherapy was used in 8 patients (20.5%), while a combination therapy was required in 31 patients (79.5%). Ceftazidime-avibactam therapy was associated with lower rates of treatment failure (7% vs. 38%, P = 0.032) independent of severity of liver disease (Child Class) and mono or combination antibiotic therapy. Acute kidney injury, hepatorenal syndrome, and acute-on-chronic liver failure were the consequences more frequently observed in patients with treatment failure. In-hospital mortality was associated with treatment failure, and Ceftazidime-avibactam therapy improved in-hospital survival (log rank test: P = 0.035) adjusted for Child class and mono or combination therapy. Conclusion: Treatment including ceftazidime-avibactam was associated with a lower rate of treatment failure in cirrhotic patients with CRKP infections. Considering the favorable efficacy and outcomes of ceftazidime-avibactam, this drug should be considered for the treatment of these severe infections in patients with liver cirrhosis, though further investigation is required.

Convalescent plasma for haematological patients with SARS-CoV-2 pneumonia and severe depletion of B-cell lymphocytes following anti-CD20 therapy: a single-centre experience and review of the literature.

Convalescent plasma (CP) therapy might be effective in patients with haematological malignanciesand B-cell depletion. We report a single-centre experience of COVID-19 patients with non-Hodgkinlymphoma and absence of B-cells as a consequence of anti-CD20 therapy successfully treated withCP from October 2020 to May 2021. CP was given in the presence of pneumonia with respiratoryfailure despite standard treatment and consisted of three infusions on an alternate-day basis. A reviewof the current literature on this topic was also performed. Six patients were identified (medianage 59.5 years (range 50-73)). The last anti-CD20 drug administration occurred 60 days before infection(range 0-360). CP was administered after a median of 51 days (range 9-120) from SARS-CoV-2diagnosis, with an early improvement in all but one subject. We suggest a possible clinical benefitof convalescent CP treatment in COVID-19 patients with haematological malignancies and B-celldepletion having persistent/recurrent pneumonia.

First report of spondylodiscitis caused by Bacillus circulans in an immunocompetent patient: Clinical case and review of the literature.

Bacillus circulans is mainly considered an opportunistic pathogen in immunocompromised patients. However, many different infections have been described in the literature: bacteremia, abscesses, meningitis, endophthalmitis, and wound infections. We observed a spondylodiscitis caused by Bacillus circulans in an immunocompetent patient. To date, this is the first case reported in literature. Vertebral osteomyelitis represents for clinicians a challenging infection to manage and treat, because of its insidious and indolent course. The diagnosis is frequently difficult and can often be delayed for several months and initially be misdiagnosed and mismanaged. For this reason, the clinical case was described and all published cases of infection caused by Bacillus circulans were reviewed.

Coronavirus 2019 Infectious Disease Epidemic: Where We Are, What Can Be Done and Hope For.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads mainly by means of aerosols (microdroplets) in enclosed environments, especially those in which temperature and humidity are regulated by means of air-conditioning. About 30% of individuals infected with SARS-CoV-2 develop coronavirus disease 2019 (COVID-19) disease. Among them, approximately 25% require hospitalization. In medicine, cases are identified as those who become ill. During this pandemic, cases have been identified as those with a positive SARS-CoV-2 polymerase chain reaction test, including approximately 70% who were asymptomatic-this has caused unnecessary anxiety. Individuals more than 65 years old, those affected by obesity, diabetes, asthma, or are immune-depressed owing to cancer and other conditions, are at a higher risk of hospitalization and of dying of COVID-19. Healthy individuals younger than 40 years very rarely die of COVID-19. Estimates of the COVID-19 mortality rate vary because the definition of COVID-19-related deaths varies. Belgium has the highest death rate at 154.9 per 100,000 persons, because it includes anyone who died with symptoms compatible with COVID-19, even those never tested for SARS-CoV-2. The United States includes all patients who died with a positive test, whether they died because of, or with, SARS-CoV-2. Countries that include only patients in which COVID-19 was the main cause of death, rather than a cofactor, have lower death rates. Numerous therapies are being developed, and rapid improvements are anticipated. Because of disinformation, only approximately 50% of the U.S. population plans to receive a COVID-19 vaccine. By sharing accurate information, physicians, health professionals, and scientists play a key role in addressing myths and anxiety, help public health officials enact measures to decrease infections, and provide the best care for those who become sick. In this article, we discuss these issues.

Procalcitonin in the Assessment of Ventilator Associated Pneumonia: A Systematic Review.

BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common nosocomial infection, associated with considerable mortality and morbidity in critically ill patients; however, its diagnosis and management remain challenging since clinical assessment is often poorly reliable. The aim of this systematic review was to evaluate the role of PCT in the diagnosis and management of critical ill patients affected by VAP. METHODS: We performed a systematic review of the evidence published over the last 10 years and currently available in medical literature search databases (Pubmed, Embase, Web of Knowledge, Cochrane Libraries) and searching clinical trial registries. We regarded as predefined outcomes the role of PCT in diagnosis, therapeutic monitoring, antibiotic discontinuation and prognosis. The Open Science Framework Registration number was doi.org/10.17605/OSF. IO/ZGFKQ RESULTS: 761 articles were retrieved and a total of 18 studies (n° of patients = 1774) were selected and analyzed according to inclusion criteria. In this 2020 update, the systematic review showed that currently, conflicting and inconclusive data are available about the role of PCT in the diagnosis of VAP and in the prediction (i) of the efficacy of antibiotic therapy, and (ii) of the clinical outcome. These studies, instead, seem to agree on the utility of PCT in the management of antibiotic therapy discontinuation. CONCLUSIONS: Currently there is insufficient evidence to support the role of PCT in the routine assessment of patients with VAP. The value of the results published appears to be limited by the deep methodological differences that characterize the various studies available at the present being.

Nox2 activation in Covid-19.

Nox2 is responsible for artery dysfunction via production of reactive oxidant species. RNA viruses may activate Nox2, but it is unknown if this occurs in coronavirus 2019(Covid-19). Nox2 activation by soluble Nox2-derived peptide(sNox2-dp) was measured in patients hospitalized for Covid-19 (n = 182) and controls (n = 91). sNox2-dp values were higher in Covid-19 patients versus controls and in severe versus non severe Covid-19. Patients with thrombotic events(n = 35,19%) had higher sNox2-dp than thrombotic event-free ones. A logistic regression analysis showed that sNox2 and coronary heart disease predicted thrombotic events. Oxidative stress by Nox2 activation is associated severe disease and thrombotic events in Covid-19 patients.

Bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii: Clinical features, therapy and outcome from a multicenter study.

OBJECTIVES: bloodstream infections (BSI) due to multidrug-resistant (MDR) Acinetobacter baumannii (AB) have been increasingly observed among hospitalized patients. METHODS: prospective, observational study conducted among 12 large tertiary-care hospitals, across 7 Italian regions. From June 2017 to June 2018 all consecutive hospitalized patients with bacteremia due to MDR-AB were included and analyzed in the study. RESULTS: During the study period 281 episodes of BSI due to MDR-AB were observed: 98 (34.8%) episodes were classified as primary bacteremias, and 183 (65.2%) as secondary bacteremias; 177 (62.9%) of them were associated with septic shock. Overall, 14-day mortality was observed in 172 (61.2%) patients, while 30-day mortality in 207 (73.6%) patients. On multivariate analysis, previous surgery, continuous renal replacement therapy, inadequate source control of infection, and pneumonia were independently associated with higher risk of septic shock. Instead, septic shock and Charlson Comorbidity Index >3 were associated with 14-day mortality, while adequate source control of infection and combination therapy with survival. Finally, septic shock, previous surgery, and aminoglycoside-containing regimen were associated with 30-day mortality, while colistin-containing regimen with survival. CONCLUSIONS: BSI caused by MDR-AB represents a difficult challenge for physicians, considering the high rates of septic shock and mortality associated with this infection.

De-escalation and discontinuation strategies in high-risk neutropenic patients: an interrupted time series analyses of antimicrobial consumption and impact on outcome.

Febrile neutropenia (FN) is the main reason for antibiotic prescription in hematology wards where, on the other hand, antibiotic stewardship (AS) is poorly explored. The objectives of the present study were to evaluate (1) the impact of an AS intervention on antibiotic consumption and (2) the applicability and acceptance rate of the intervention and its clinical impact. A persuasive AS intervention based on European Conference on Infection in Leukaemia (ECIL) guidelines for FN was implemented in a high-risk hematology ward in a tertiary referral public university hospital. This included the creation and diffusion of flow charts on de-escalation and discontinuation of antibiotics for FN, and the introduction in the team of a doctor dedicated to the implementation of flow charts and to antibiotic prescription revision. All consecutive patients receiving antibiotics during hospitalization were included. A segmented linear regression model was performed for the evaluation of antibiotic consumption, taking into account 1-year pre-intervention period and 6-month intervention period. Overall, 137 consecutive antibiotic prescriptions were re-evaluated, 100 prescriptions were for FN. A significant reduction of the level of carbapenem consumption was observed during the intervention period (level change (estimate coefficient ± standard error) = - 135.28 ± 59.49; p = 0.04). Applicability and acceptability of flow charts were high. No differences in terms of intensive care unit transfers, bacteremia incidence, and mortality were found. A persuasive AS intervention in hematology significantly reduced carbapenem consumption without affecting outcome and was well accepted. This should encourage further applications of ECIL guidelines for FN.

A challenging case of carbapenemase-producing Klebsiella pneumoniae septic thrombophlebitis and right mural endocarditis successfully treated with ceftazidime/avibactam.

INTRODUCTION: The emergence of carbapenemase-producing Klebsiella pneumonia (KPC-Kp) has become a significant problem in terms of public health and clinical outcome in many hospitals in Southern Europe. Treatment options are usually limited and effective treatment of infections caused by these pathogens is a considerable challenge for clinicians. Ceftazidime-avibactam has been recently approved for the treatment of difficult-to-treat infections due to aerobic Gram-negative organisms in patients with limited treatment options. CASE REPORT: We reported the first case of KPC-Kp septic thrombophlebitis and right atrial endocarditis associated with metastatic lung abscesses successfully treated with a prolonged ceftazidime/avibactam plus ertapenem treatment course, suggesting that this combination therapy could be safe and effective for serious Gram-negative infections. Interestingly, we also observed an apparent discrepancy between clinical and microbiological courses: the patient became rapidly afebrile; hemodynamically stable and his procalcitonin levels showed a prompt decreasing trend. Nevertheless, blood cultures remained persistently positive for a prolonged period. CONCLUSION: In conclusion, ceftazidime-avibactam plus ertapenem was a safe and effective therapy of serious endovascular infection due to KPC-Kp. Moreover, in this setting, follow-up blood cultures might represent an irreplaceable tool to guide the therapy.

Role of oral nystatin prophylaxis in cardiac surgery with prolongedextracorporeal circulation.

Duration >120 minutes of extracorporeal circulation (ECC) during cardiopulmonary bypass procedure was associated to an increased risk of candidemia in the intensive care unit (ICU). To evaluate oral nystatin prophylaxis in cardiac surgery considering its exclusive effect on Candida, in the absence of systemic effects and selection of resistant strains to polyene. We conducted an observational study in the postcardiac surgery ICU of Policlinico "Umberto I" of Rome. From January 2014, all patients with a prolonged ECC >120 minutes were systematically treated with oral nystatin (Prophylaxis group). This group was compared with all patients hospitalised in the same ICU, who have not received oral nystatin after ECC >120 minutes (No prophylaxis group). Overall, 672 consecutive patients were analyzed: 318 (47.3%) patients belonged to the no prophylaxis group, and 354 (52.7%) patients to the prophylaxis group. Diagnosis of candidemia was confirmed in 7 (2.2%) patients, all belonged to the no prophylaxis group. At multivariate analysis, oral nystatin prophylaxis showed a protective effect for development of candidemia after cardiac surgery. Oral nystatin prophylaxis, in patients who underwent a ECC >120 minutes, seems to reduce development of candidemia; however, the real efficacy of such prophylaxis approach requires further investigation.

Candida endocarditis: systematic literature review from 1997 to 2014 and analysis of 29 cases from the Italian Study of Endocarditis.

INTRODUCTION: Candida Endocarditis (CE) is a deadly disease. It is of paramount importance to assess risk factors for acquisition of both Candida native (NVE) and prosthetic (PVE) valve endocarditis and relate clinical features and treatment strategies with the outcome of the disease. Areas covered: We searched the literature using the Pubmed database. Cases of CE from the Italian Study on Endocarditis (SEI) were also included. Overall, 140 cases of CE were analyzed. Patients with a history of abdominal surgery and antibiotic exposure had higher probability of developing NVE than PVE. In the PVE group, time to onset of CE was significantly lower for biological prosthesis compared to mechanical prosthesis. In the whole population, greater age and longer time to diagnosis were associated with increased likelihood of death. Patients with effective anti-biofilm treatment, patients who underwent cardiac surgery and patients who were administered chronic suppressive antifungal treatment showed increased survival. For PVE, moderate active anti-biofilm and highly active anti-biofilm treatment were associated with lower mortality. Expert commentary: Both NVE and PVE could be considered biofilm-related diseases, pathogenetically characterized by Candida intestinal translocation and initial transient candidemia. Cardiac surgery, EAB treatment and chronic suppressive therapy might be crucial in increasing patient survival.

Clinical features and outcome of patients with descending necrotizing mediastinitis: prospective analysis of 34 cases.

PURPOSE: We aimed to investigate clinical features of patients with descending necrotizing mediastinitis (DNM) in order to improve management and outcome. METHODS: We prospectively examined all patients with DNM admitted to the Intensive Care Unit (ICU) during the period from April 2007 to December 2013. Demographics, clinical features, microbiology, medical and surgical treatment data were recorded. Survivor and nonsurvivor groups were analyzed to identify factors associated with mortality. RESULTS: Overall, 34 patients with DNM have been included. The mean age was 46.8 ± 11.2 years (range 24-70). The male/female ratio was 3.25. DNM arose from odontogenic infection in 22 (65%) patients; from peritonsillar abscess in 9 (26%) patients and from paranasal sinus in 3 (9%) patients. Microbiological cultures revealed a high percentage of aerobic/anaerobic coinfection. Nonsurvivors were statistically more likely to have higher SAPS II score (mean difference 19.1, 95% CI 12.3-25.9 P < 0.01) and more severe disease (P < 0.01) than survivors. Positive correlation was found between time to ICU admission after head or neck infection diagnosis and SAPS II score (ρ = 0.5, P = 0.03). The same was true for ICU length of stay and time to ICU admission (ρ = 0.6, P < 0.01) and time to surgery (ρ = 0.5, P = 0.03). Surgical treatments consisted in: transcervical drainage in 14 cases, (42%); irrigation through subxiphoid and cervical incisions of the anterior mediastinum with additional percutaneous thoracic drainage when necessary in ten cases, (29 %); thoracotomy with radical mediastinal surgical debridement, excision of necrotic tissue and decortication in ten cases, (29%). We have found a mortality rate of 12%. Patients with DNM type IIB were admitted to the ICU later than patients with DNM type I and type IIA (mean difference 3.2 days, 95% CI 1.2-5.1, P 0.02). CONCLUSIONS: Prompt ICU admission in order to manage severe sepsis and/or septic shock, along with early and aggressive surgery and adequate antimicrobial therapy, could be key factors in reducing DNM mortality.

Diagnostic and therapeutic appropriateness in bone and joint infections: results of a national survey.

The impact of infectious diseases (ID) specialist consultation in the management of many types of bacterial infections has been fully demonstrated but not for bone and joint infections (BJIs). Nineteen ID Italian centres collected of data from June 2009 to May 2012. Italian guidelines (2009) were used to determine the appropriateness of the diagnostic and therapeutic process of BJIs before and after consulting an ID specialist. Data on 311 patients were collected: 111 cases of prosthetic joint infection, 99 osteomyelitis, 64 spondylodiscitis and 37 fixation device infection. A significant increase of microbiological investigations, imaging techniques and blood inflammation markers were noted after consulting the ID specialist. Moreover, inappropriateness of treatment duration, dosage, and number of administrations significantly decreased after consultation. Infectious disease specialist intervention in the management of BJIs significantly increases the appropriateness both in performing instrumental and laboratory analysis, but especially in determining the correct therapy.

New Insight on Epidemiology and Management of Bacterial Bloodstream Infection in Patients with Hematological Malignancies.

Bloodstream infections (BSI) are a significant cause of morbidity and mortality in onco-hematologic patients. The Gram-negative bacteria were the main responsible for the febrile neutropenia in the sixties; their impact declined due to the use of fluoroquinolone prophylaxis. This situation was followed by the gradual emergence of Gram-positive bacteria also following the increased use of intravascular devices and the introduction of new chemotherapeutic strategies. In the last decade, the Gram-negative etiology is raising again because of the emergence of resistant strains that make questionable the usefulness of current strategies for prophylaxis and empirical treatment. Gram-negative BSI attributable mortality is relevant, and the appropriate empirical treatment significantly improves the prognosis; on the other hand the adequate delayed treatment of Gram-positive BSI does not seem to have a high impact on survival. The clinician has to be aware of the epidemiology of his institution and colonizations of his patients to choose the most appropriate empiric therapy. In a setting of high endemicity of multidrug-resistant infections also the choice of targeted therapy can be a challenge, often requiring strategies based on off-label prescriptions and low grade evidence. In this review, we summarize the current evidence for the best targeted therapies for difficult to treat bacteria BSIs and future perspectives in this topic. We also provide a flow chart for a rational approach to the empirical treatment of febrile neutropenia in a multidrug resistant, high prevalence setting.