Editorial of Special Issues "Gut Microbiota-Host Interactions: From Symbiosis to Dysbiosis 2.0".

The gastrointestinal (GI) tract is where external agents meet the internal environment [...].

Performance of existing clinical scores and laboratory tests for the diagnosis of invasive candidiasis in critically ill, nonneutropenic, adult patients: A systematic review with qualitative evidence synthesis.

BACKGROUND: The Fungal Infections Definitions in Intensive Care Unit (ICU) patients (FUNDICU) project aims to provide standard sets of definitions for invasive fungal diseases in critically ill, adult patients. OBJECTIVES: To summarise the available evidence on the diagnostic performance of clinical scores and laboratory tests for invasive candidiasis (IC) in nonneutropenic, adult critically ill patients. METHODS: A systematic review was performed to evaluate studies assessing the diagnostic performance for IC of clinical scores and/or laboratory tests vs. a reference standard or a reference definition in critically ill, nonneutropenic, adult patients in ICU. RESULTS: Clinical scores, despite the heterogeneity of study populations and IC prevalences, constantly showed a high negative predictive value (NPV) and a low positive predictive value (PPV) for the diagnosis of IC in the target population. Fungal antigen-based biomarkers (with most studies assessing serum beta-D-glucan) retained a high NPV similar to that of clinical scores, with a higher PPV, although the latter showed important heterogeneity across studies, possibly reflecting the targeted or untargeted use of these tests in patients with a consistent clinical picture and risk factors for IC. CONCLUSIONS: Both clinical scores and laboratory tests showed high NPV for the diagnosis of IC in nonneutropenic critically ill patients. The PPV of laboratory tests varies significantly according to the baseline patients' risk of IC. This qualitative synthesis will provide the FUNDICU panel with baseline evidence to be considered during the development of definitions of IC in critically ill, nonneutropenic adult patients in ICU.

Clinical, virological and immunological evolution of the olfactory and gustatory dysfunction in COVID-19.

PURPOSE: New-onset olfactory and gustatory dysfunction (OGD) represents a well-acknowledged COVID-19 red flag. Nevertheless, its clinical, virological and serological features are still a matter of debate. MATERIALS AND METHODS: For this cohort study, 170 consecutive subjects with new-onset OGD were consecutively recruited. Otolaryngological examination, OGD subjective grading, nasopharyngeal swabs (NS) for SARS-CoV-2 RNA detection and serum samples (SS) collection for SARS-CoV-2 IgG quantification were conducted at baseline and after one (T1), two (T2) and four weeks (T3). RESULTS: SARS-CoV-2 infection was confirmed in 79% of patients. Specifically, 43% of positive patients were detected only by SS analysis. The OGD was the only clinical complaint in 10% of cases. Concurrent sinonasal symptoms were reported by 45% of patients. Subjective improvement at T3 was reported by 97% of patients, with 40% recovering completely. Hormonal disorders and RNA detectability in NS were the only variables associated with OGD severity. Recovery rate was higher in case of seasonal influenza vaccination, lower in patients with systemic involvement and severe OGD. Not RNA levels nor IgG titers were correlated with recovery. CONCLUSION: Clinical, virological and serological features of COVID-19 related OGD were monitored longitudinally, offering valuable hints for future research on the relationship between host characteristics and chemosensory dysfunctions.

The experience of the health care workers of a severely hit SARS-CoV-2 referral Hospital in Italy: incidence, clinical course and modifiable risk factors for COVID-19 infection.

BACKGROUND: During the COVID-19 pandemic, the health care workers (HCWs) at the frontline have been largely exposed to infected patients, running a high risk of being infected by the SARS-CoV-2 virus.Since limiting transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in health care setting is crucial to avoid the community spread of SARS-CoV-2, we want to share our experience as an early hit hospital where standard infection control practices have been conscientiously applied and effective. We believe that our example, as first and hardest hit country, might be a warning and aid not only for those who have been hit later, but also for a second fearful wave of contagion. In addition, we want to offer an insight on modifiable risk factors for HWs-related infection. METHODS: Demographic, lifestyle, work-related and comorbidities data of 1447 HCWs, which underwent a nasopharyngeal swab for SARS-CoV-2, were retrospectively collected. For the 164 HCWs positive for SARS-CoV-2, data about safety in the workplace, symptoms and clinical course of COVID-19 were also collected. Cumulative incidence of SARS-CoV-2 infection was estimated. Risk factors for SARS-CoV-2 infection were assessed using a multivariable Poisson regression. RESULTS: The cumulative incidence of SARS-CoV-2 infection among the screened HCWs was 11.33% (9.72-13.21). Working in a COVID-19 ward, being a former smoker (versus being a person who never smoked) and BMI was positively associated with SARS-CoV-2 infection, whereas being a current smoker was negatively associated with this variable. CONCLUSIONS: Assuming an equal accessibility and proper use of personal protective equipment of all the HCWs of our Hospital, the great and more prolonged contact with COVID-19 patients remains the crucial risk factor for SARS-CoV-2. Therefore, increased and particular care needs to be focused specifically on the most exposed HCWs groups, which should be safeguarded. Furthermore, in order to limit the risk of asymptomatic spread of SARS-CoV-2 infection, the HCWs mild symptoms of COVID-19 should be considered when evaluating the potential benefits of universal staff testing.

The obesity paradox: Analysis from the SMAtteo COvid-19 REgistry (SMACORE) cohort.

BACKGROUND AND AIMS: Obesity has been suggested as a possible risk factor for a more severe course of COVID-19; however, conclusive evidence is lacking and few studies have investigated the role of BMI as a risk factor for admission to intensive care unit (ICU) and mortality. We retrospectively analyzed a COVID-19 cohort recruited during the first 40 days of the epidemic in Italy. We examined the association between obesity and 30-day mortality, admission to ICU, mortality and length of hospital stay in patients with COVID-19. METHODS AND RESULTS: Demographic, clinical and outcome data were retrospectively analyzed in 331 patients with COVID-19 admitted to hospital between 21 February and 31 March 2020. The predictive effect of obesity on mortality was assessed using a Cox proportional-hazard regression model, its effect on ICU admission and mortality in the ICU using logistic regressions, and its effect on length of hospital stay using a linear regression. Seventy-four of 331 patients had a BMI ≥30 kg/m2. Among obese patients, 21 (28.4%) required admission in ICU and 25 died (33.8%). After controlling for sex, age, comorbidities and clinical data, obesity was not significantly associated with mortality, mortality in ICU and length of hospital stay. The effect of obesity on ICU admission remained significant after controlling for sex, age, interstitial lung disease, heart disease and serum C-reactive protein. CONCLUSIONS: Obese patients with COVID-19 were more likely to be admitted to ICU than non-obese patients. However, there were no significant differences in mortality between the two groups.

Clinical characteristics of coronavirus disease (COVID-19) early findings from a teaching hospital in Pavia, North Italy, 21 to 28 February 2020.

We describe clinical characteristics, treatments and outcomes of 44 Caucasian patients with coronavirus disease (COVID-19) at a single hospital in Pavia, Italy, from 21-28 February 2020, at the beginning of the outbreak in Europe. Seventeen patients developed severe disease, two died. After a median of 6 days, 14 patients were discharged from hospital. Predictors of lower odds of discharge were age > 65 years, antiviral treatment and for severe disease, lactate dehydrogenase > 300 mg/dL.

Direct-Acting Antivirals in Hepatitis C Virus-Associated Diffuse Large B-cell Lymphomas.

BACKGROUND: International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported. SUBJECTS, MATERIALS, AND METHODS: We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like). RESULTS: Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%). CONCLUSION: Excellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity. IMPLICATIONS FOR PRACTICE: Hepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.

The impact of HIV infection and men who have sex with men status on hepatitis A infection: The experience of two tertiary centres in Northern Italy during the 2017 outbreak and in the 2009-2016 period.

Hepatitis A is a self-limiting infection representing the most common cause of viral hepatitis worldwide. Despite being a low incidence region, in the European Union, an increasing number of cases have been reported since summer 2016, resulting in a large outbreak in 2017, involving mainly men who have sex with men (MSM). Some reports described a different clinical course of hepatitis A virus in patients infected by human immunodeficiency virus (HIV) or MSM. We consecutively collected all the hospitalized cases of hepatitis A referred to two tertiary centres in Northern Italy in 2017 and retrospectively analysed the electronic records of the 2009-2016 period (pre-2017). We evaluated demographics data, risk factors, comorbidities and laboratory results to see whether MSM status or HIV infection influenced the disease. Overall, 117 cases were identified in 2017:107 (91%) were male, 78 reported themselves as MSM (66%) and 17 (14.5%) were infected by HIV. For the pre-2017 period, 48 cases were reported: 29 (60%) were male and 3 (6.2%) were infected by HIV. After stratification for HIV infection, MSM status and occurrence period, no differences were found in aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase; bilirubin, alkaline phosphatase and bilirubin values, hospitalization length, HIV viral load and CD4 + cells count. HIV-positive patients presented a higher number of patients with INR > 1.5 at admission. MSM status and HIV infection did not affect neither the clinical course nor the severity of hepatitis A.

Developing definitions for invasive fungal diseases in critically ill adult patients in intensive care units. Protocol of the FUNgal infections Definitions in ICU patients (FUNDICU) project.

BACKGROUND: The reliability of diagnostic criteria for invasive fungal diseases (IFD) developed for severely immunocompromised patients is questionable in critically ill adult patients in intensive care units (ICU). OBJECTIVES: To develop a standard set of definitions for IFD in critically ill adult patients in ICU. METHODS: Based on a systematic literature review, a list of potential definitions to be applied to ICU patients will be developed by the ESCMID Study Group for Infections in Critically Ill Patients (ESGCIP) and the ESCMID Fungal Infection Study Group (EFISG) chairpersons. The proposed definitions will be evaluated by a panel of 30 experts using the RAND/UCLA appropriateness methods. The panel will rank each of the proposed definitions on a 1-9 scale trough a dedicated questionnaire, in two rounds: one remote and one face-to-face. Based on their median rank and the level of agreement across panel members, selected definitions will be organised in a main consensus document and in an executive summary. The executive summary will be made available online for public comments. CONCLUSIONS: The present consensus project will seek to provide standard definitions for IFD in critically ill adult patients in ICU, with the ultimate aims of improving their clinical outcome and facilitating the comparison and generalizability of research findings.

The Possible Role of Gut Microbiota and Microbial Translocation Profiling During Chemo-Free Treatment of Lymphoid Malignancies.

The crosstalk between gut microbiota (GM) and the immune system is intense and complex. When dysbiosis occurs, the resulting pro-inflammatory environment can lead to bacterial translocation, systemic immune activation, tissue damage, and cancerogenesis. GM composition seems to impact both the therapeutic activity and the side effects of anticancer treatment; in particular, robust evidence has shown that the GM modulates the response to immunotherapy in patients affected by metastatic melanoma. Despite accumulating knowledge supporting the role of GM composition in lymphomagenesis, unexplored areas still remain. No studies have been designed to investigate GM alteration in patients diagnosed with lymphoproliferative disorders and treated with chemo-free therapies, and the potential association between GM, therapy outcome, and immune-related adverse events has never been analyzed. Additional studies should be considered to create opportunities for a more tailored approach in this set of patients. In this review, we describe the possible role of the GM during chemo-free treatment of lymphoid malignancies.

Beyond the gut bacterial microbiota: The gut virome.

The gastrointestinal tract is colonized with a highly different population of bacterial, viral, ad fungal species; viruses are reported to be dominant. The composition of gut virome is closely related to dietary habits and surrounding environment. Host and their intestinal microbes live in a dynamic equilibrium and viruses stimulate a low degree of immune responses without causing symptoms (host tolerance). However, intestinal phages could lead to a rupture of eubiosis and may contribute to the shift from health to disease in humans and animals. Viral nucleic acids and other products of lysis of bacteria serve as pathogen-associated molecular patterns (PAMPs) and could trigger specific inflammatory modulations. At the same time, phages could elicit innate antiviral immune responses. Toll-like receptors (TLRs) operated as innate antiviral immune sensors and their activation triggers signaling cascades that lead to inflammatory response. J. Med. Virol. 88:1467-1472, 2016. © 2016 Wiley Periodicals, Inc.

Emerging biological agents for hepatitis C.

INTRODUCTION: New direct-acting antiviral agents have changed the landscape of treatment of chronic HCV infection. Despite current treatments are well tolerated with a high rate of sustained virological response (SVR), some medical needs remain. Nowadays there are a large number of approved medications for the treatment of HCV infection; nevertheless, new studies are conducted to find new agents and new combinations. AREAS COVERED: A literature research of new antiviral compounds indicated for the treatment of HCV infection was achieved by an online search of medication undergoing development on Pubmed and clinicalTrials.gov clinical trials registry. We considered phase I/II studies and some randomized Phase III trials. EXPERT OPINION: More knowledge about impact of HCV eradication on disease progression and more confidence regarding drug-drug interaction are needed. Furthermore, each treatment should be individualized targeting the patients needs with the aim not only to obtain viral suppression but also to stop progression of liver disease and HCV related conditions, and to improve patient health status.

An update on integrase inhibitors: new opportunities for a personalized therapy? The NEXTaim Project.

Thanks to the development of antiretroviral agents to control HIV replication, HIV infection has turned from a fatal disease into a treatable chronic infection. The present work collects the opinions of several experts on the efficacy and safety of recently approved second generation of integrase inhibitors and, in particular, on the role of this new class of drugs in antiretroviral therapy. The availability of new therapeutic options represents an opportunity to ameliorate the efficacy of cART in controlling HIV replication also within viral reservoirs. The personalization of the treatment driven mainly by the management of comorbidities, HIV-HCV co-infections and aging, will be easier with antiretroviral drugs without drug-drug interactions and with a better toxicity and tolerability profile. Future assessment of economic impact for the introduction of new innovative drugs in the field of antiretroviral therapy will likely need some degree of adjustment of the evaluation criteria of costs and benefit which are currently based almost exclusively on morbidity and mortality.