A local outbreak as mirror-like scenario for COVID-19 worldwide progression. Clinical presentation to the Emergency Department during one of the first sub-regional outbreak in Italy A lesson to learn

BACKGROUND: One of the most precocious Italian COVID-19 outbreaks began in February 2020 in Medicina, a small town in the province of Bologna. We compared the characteristics of different cohorts, to identify potential predictive factors for outcome: patients of Medicina outbreak versus those of the surrounding district (Imola), and before or after the local medical intervention. METHOD(S): Between March the 3rd and April the 9th, 2020 167 adults with COVID-19 were admitted to the Emergency Department (ED) (78 from Medicina cluster, 89 from Imola district). Data at ED presentation were collected;hospitalized patients were followed until death or discharge. RESULT(S): Medicina and Imola cohorts were similar in age, main comorbidities, clinical presentation, laboratory tests, arterial blood gas analysis (ABG), death and acute respiratory distress syndrome (ARDS) rates. Age, hypertension, diabetes, chronic obstructive pulmonary disease, dyspnea, body temperature, quickSOFA Score, elevated C-reactive protein (CRP), creatinine, urea, DELTA A-a O2, respiratory rate and FiO2 were associated with death and ARDS. Elevated Glasgow Coma Scale, diastolic blood pressure, oxygen peripheral saturation, P/F and pH were associated with patient survival and protective from ARDS. After the intervention in Medicina district, patients presenting at ED were younger and with long-lasting symptoms;CRP values were significantly lower, ABG and respiratory clinical parameters were less severely impaired. These differences did not affect the outcome. CONCLUSION(S): Since the results of our study are consistent with worldwide evidences, we suggest that the early insight of a small local SARS-CoV-2 outbreak can be representative and predictive of the subsequent course of the virus in wider areas. This must be kept in mind to manage next epidemic waves.Copyright © 2022 EDIZIONI MINERVA MEDICA.

Exposure to psychotropic medications and COVID-19 course after hospital admission: Results from a prospective cohort study.

OBJECTIVE: There is evidence of a bidirectional association between COVID-19 disease and psychiatric disorders. We aimed to assess whether exposure to psychotropic medications prior to hospitalization was associated with mortality or discharge within 30 days after hospital admission. METHODS: In this prospective study, we included all individuals with a laboratory-confirmed COVID-19 infection who were admitted to the Bologna University Hospital between 1st March 2020 and 31st January 2021. We collected data about pre-existing psychiatric disorders and the use of psychotropic medications at the admission. As univariate analyses, we estimated cumulative incidence functions for 30-day mortality and discharge stratifying by exposure to each of the psychotropic medication classes. Finally, we fitted Cox regression models to estimate cause-specific Hazard Ratios (HR) of 30-day mortality and discharge. Results were adjusted for sociodemographic (age, sex), clinically relevant variables (comorbidity, c-reactive protein levels, severity of disease at presentation, history of smoking, study period), and psychiatric variables (psychiatric disorder diagnosis, number of psychotropic medications). RESULTS: Out of a total of 1238 hospitalized patients, 316 were prescribed psychotropic medications at the time of admission. Among these, 45 (3.6%) were taking a first-generation antipsychotics (FGA) and 66 (5.3%) a second generation antipsychotic (SGA). Exposure to SGA was associated with increased rates of 30-day mortality (HR = 2.01, 95%CI = 1.02-3.97) and exposure to FGA was associated with decreased rates of 30-day discharge (HR = 0.55, 95%CI = 0.33-0.90). CONCLUSION: Patients with COVID-19 infection exposed to FGA and SGA may have worse COVID-19 infection outcomes.

Evaluation of breakthrough infections in solid organ transplant recipients: the prospective CONTRAST cohort

Background. Solid organ transplant (SOT) recipients are at higher risk than general population for complicated COVID-19 course. Moreover COVID-19 vaccination in this setting is associated with a suboptimal immune response. However, the impact of this finding on the risk of breakthrough infection (BI) in SOT recipients has to be yet determined. Methods. Single-center prospective longitudinal cohort of adult SOT recipients who received three doses of mRNA COVID-19 vaccine between February and December 2021 and were followed up to March 30 2022. Patients were tested for antibody response at several timepoints (1 st dose, 2 nd dose, 3+/-1 month after 1 st dose, and 1 month after 3 rd dose). Main endpoints were: i) BI defined as laboratory confirmed SARS-CoV2 infection diagnosed >=14 day after 2 nd dose;ii) positive antibody response (AbR) defined as anti-rapid binding domain titer >=5 U/ml determined by Elecsys Anti-SARS-CoV-2 ECLIA assay (Roche Diagnostics, CH), the last available determination before BI was considered. Results. Study cohort consists of 642 SOT (277 kidney, 191 liver, 144 heart, 37 lung) recipients: 63.9% males, median age 54 +/- 14.5 years. Of them, 111 (17.8%) developed BI, BI rates were 19.9%, 18.1%, 15.2% and 10.8% among liver, heart, kidney and lung transplant recipients, respectively. Positive-AbR was observed in 60% of all patients, but rates varied from 8.7% to 91.3% among patients with BI and without BI, respectively. Predictors of BI infection at multivariable analysis were liver (vs. other grafts) transplant (OR 2.98, 95%CI 1.47-6.03), mycophenolate (1.63, 0.92-2.88) and steroids (1.8, 1.05- 3.33), while positive-AbR (0.61, 0.35-1.04) and age (0.97, 0.95-0.99) were protective. On the other hand, liver transplant (1.94, 1.02-3.69), time from transplant (1.09, 1.05-1.21), and Moderna vaccine (2.32, 1.46-3.70) were associated with positive-AbR, while age (0.97, 0.95-0.98), heart transplant (0.56, 0.33-0.96), mycophenolate (0.65, 0.39-1.06) and steroids (0.39, 0.23-0.65) with lower probability of positive-AbR. Conclusion. Although associated with positive-AbR, liver transplant and younger age were also BI predictors, suggesting the importance of social factors and the controversial role of immune monitoring.

Post-Infection Irritable Bowel Syndrome in Sars-Cov-2 Patients: The Gi-Covid19 Study

Introduction: SARS-CoV-2 infection, known as COVID-19, may lead to persistent gastrointestinal dysfunction resembling aspects of post-infection disorders of gut-brain interaction (DGBI). However, the long-term consequences of COVID-19 on the gastrointestinal tract remain unclear. Aims & Methods: We aimed to evaluate the prevalence of gastrointestinal symptoms and post-infection disorders of gut-brain interaction (DGBI) up to 12 months after hospitalization and the factors associated with their presence. The GI-COVID19 is a prospective, multicenter, controlled study. Patients with and without COVID-19 diagnosis were assessed at hospital admission and followed up after 1, 6, and 12 months to assess gastrointestinal symptoms using the Gastrointestinal Symptoms Rating Scale, the Rome IV Diagnostic Questionnaire for Functional Gastrointestinal Disorders in Adults, and the hospital anxiety and depression scale. ClinicalTrials. gov number, NCT04691895. Result(s): The study included2183 hospitalized patients. After excluding patients with pre-existing gastrointestinal symptoms and/or surgery, a total of 883 patients (614 COVID-19 and 269 controls) were included in the primary analysis, of whom 435 COVID-19 and 188 controls completed 12 months of follow-up. At enrollment, gastrointestinal symptoms occurred more frequently in COVID-19 patients than in the control group (59.3% vs. 39.7%, P<0.001). Symptoms more frequently complained by COVID-19 patients at enrollment were nausea, diarrhea, loose stool, and urgency. At 1-month follow-up evaluation, nausea and acid regurgitation were significantly more prevalent in COVID-19 patients than in the control group (8.7% vs. 1.7%, P=0.015 and 8.4% vs. 2.1%, P=0.006, respectively). At 6 months, COVID-19 patients reported lower rates of flatus (17.6% vs. 19.1%, P=0.024), constipation (8.9% vs. 17.1%, P<0.001) and hard stools (9.6 vs. 17.2%, P=0.030) as compared with the control group. At 12 months, constipation and hard stools were significantly less prevalent in COVID-19 patients than in the control group (9.6% vs. 16%, P=0.019 and 10.9% vs. 17.7%, P=0.011, respectively). COVID-19 patients reported higher rates of DGBI during follow-up compared to controls (Table), although statistically significant differences were found only for irritable bowel syndrome (IBS) according to Rome III criteria (4.4% vs 1.1%, P=0.036) and Rome IV criteria (3.2% vs 0.5%, P=0.045). The rate of COVID-19 patients depressed at 6 months and with anxiety at 12 months was higher compared to controls (4.1% vs 2.7%, P=0.014 and 4.5% vs 1.1%, P=0.088, respectively). Factors significantly associated with IBS diagnosis were anamnestic allergies (OR 10.024, 95% CI 1.766-56.891, P=0.009), chronic intake of proton pump inhibitors (OR 4.816, 95% CI 1.447-16.025, P=0.010) and dyspnea (OR 4.157, 95% CI 1.336-12.934, P=0.014). Conclusion(s): Hospitalized COVID-19 patients complain less constipation and hard stools than control at 12 months after acute infection. COVID-19 patients are also more likely to develop IBS.

Management of vaccine-related issues during a pandemic emergency: activation of a referral center : Christian Cintori

Issue Vaccine hesitancy (VH) and the challenges faced by healthcare workers (HWs) in evaluating the complex risk-benefit ratio of vaccines’ threaten the effectiveness of vaccination policy. The threat is enhanced when new vaccines are adopted during a pandemic emergency. In Italy, the Emilia-Romagna Region (ERR) created a specialized referral board called Vax-Consilium (VC) to support and guide HWs. Description of the problem During a pandemic emergency, rapid and appropriate vaccine implementation is necessary to protect fragile individuals and to encourage vaccine adherence among exposed groups. Challenges in the realm of vaccination emerge, especially when dealing with patients with a complex medical history or previous vaccine adverse events. HWs were able to consult VC via a standardized digital form after obtaining the patient’s informed consent. After a multidisciplinary and evidence-based evaluation, VC provided a conclusive report on the individual vaccine risk-benefit analysis. No cost is charged to the patient. Results During the anti-COVID-19 vaccination campaign in 2021, 148 interrogations were submitted to VC: 121 were evaluated, whereas 27 were withdrawn by the HWs or rejected because of insufficient documentation. Mean patient age was 44 years. No absolute contraindication was found, whereas in 23 cases VC recommended immunization with a different vaccine. The disciplines most frequently involved were neurology, angiology and cardiology. Lessons VC implementation in EER proved highly effective. Indeed, during the pandemic, anti-COVID-19 vaccination coverage reached >90%. In addition, DTaP-polio-HBV-HIb and MMR vaccination coverage reached >95%. VC proved to be a high-quality public health service. Not only was citizens’ trust in the healthcare system enhanced and was VH reduced, but HWs knowledge improved even in cases not considered in national and international guidelines. Key messages • A specialized referral board (Vax-Consilium) could be an effective tool for enhancing citizens’ trust in vaccines. • A specialized referral board (Vax-Consilium) contributes to lowering VH and supporting HWs decision-making process.

METHYLPREDNISOLONE PULSES in HOSPITALIZED PATIENTS with SEVERE COVID-19 PNEUMONIA

Background: Pulse glucocorticoid therapy (> 250 mg of prednisone equivalent per day for 1 or a few days) is used in many immuno-inflammatory diseases for its quick and strong anti-inflammatory effect in emergency situations. It was used during in Severe Acute Respiratory Syndrome epidemics with no consistent data regarding its benefits. The efficacy and safety of this therapy associated to dexamethasone in coronavirus disease 2019 (Covid-19) pneumonia are unclear. Methods: We conducted a double-blind, randomized, placebo-controlled trial in hospitalized patients with COVID19-pneumonia. The study population included patients hospitalized for recent-onset Covid-19 pneumonia requiring supplemental oxygen in any delivery mode, except invasive mechanical ventilation, with PaO2/FiO2 between 100 and 300, and a C-reactive protein greater than 5 mg/dl. Patients were randomly assigned to receive 1 gram of methylprednisolone for 3 consecutive days or placebo in addition to standard dexamethasone. The primary outcome was the duration of the patient hospitalization, calculated as the time interval between randomization and hospital discharge without the need of supplementary oxygen. All-cause mortality, survival free from invasive ventilation and safety were also evaluated. Written informed consent was obtained from each patient or from the patient's legally authorized representative if the patient was unable to provide consent. Results: A total of 304 patients underwent randomization in 19 Italian sites between December 21, 2020, and March 10, 2021. Three patients retired the consent to the study one day after randomization, leaving 301 patients eligible for intention to treat analyses. 112 of 151 (74.2%) patients in the pulse methylprednisolone arm and 111 of 150 (74.0%) patients in the placebo arm were discharged from hospital without oxygen (p = 0.528) within 28 days from randomization. We did not observe any significant differences between pulse methylprednisolone and placebo arms in terms of admission to Intensive Care Unit with orotracheal intubation or death (19.9% versus 16.0% respectively;hazard ratio, 1.27;95%CI, 0.74-2.16), or in terms of overall mortality (9.3% versus 11.3% respectively;hazard ratio, 0.82;95%CI, 0.40-1.66). Serious adverse events occurred in 9 patients (6.0%) in the methylprednisolone pulse group and in 12 patients (8.0%) in the placebo group. Conclusion: Methylprednisolone pulse therapy in addition to dexamethasone was not of benefit in patients with COVID-19 pneumonia.

Enoxaparin in COVID-19 moderate to severe hospitalized patients (INHIXACOV19)

Background : COVID-19 (Coronavirus Disease 2019) is associated with High rates of thrombosis in hospitalized patients leading to varying pharmacologic thromboprophylaxis use based on rapidly changing societal guidance, institutional protocols from local expertise, and geographic patterns of practice. Aims : To assess the efficacy and safety of enoxaparin in hospitalized patients with moderate to severe COVID-19 infection. Methods : Phase II single-arm interventional prospective study including all patients treated with the study drug and an observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study. Each patient was followed-up for a minimum of 90 days after COVID19 diagnosis. Patients included in the interventional study received subcutaneous enoxaparin in a single daily dose of:60 mg once daily in case of body weight of 45 to 60 kg 80 mg per day in case of weight from 61 to 100 kg or 100 mg once daily in case of bodyweight >100 kg for 14 days, with dose adjustments on the basis of anti-factor Xa activity monitoring. Patients included in the observational cohort received standard thrombo-prophylaxis with subcutaneous enoxaparin 40 mg/die. Primary outcomes were all-cause in-hospital 30-day and 90 mortality rates. Secondary outcomes were the proportion of patients in the severe or critical stage of disease at the end of treatment, proportion of patients who developed major and non-major bleeding events and thromboembolic complications, time to first negative RT-PCR on nasofaringeal swab, reduction of viral load in blood. Results : Recruitment of 100 patients enrolled phase II single-arm interventional prospective study has been completed, while the recruitment of 200 patients in the observational prospective cohort study is ongoing. Conclusions : Full results will be available by June 2021.

Pre-Existing HBV and HCV Infections Do Not Affect COVID-19-Related Outcomes: An Observational Retrospective Study

Background: A better understanding of the interaction between SARS-CoV-2 infection and HBV or HCV hepatitis is very important. Objectives: We aimed at determining the prevalence and the impact of pre-existing HBV and HCV infections in patients with COVID19. Methods: We conducted a retrospective study and included all the subjects positive for SARS-CoV-2 from March to May 2020. We evaluated the prevalence of chronic HBV and HCV infections and performed a matched cohort analysis to compare COVID-19-related outcomes between patients with and without infections due to HBV or HCV. Results: Among 606 subjects, 12 cases (2%) had positive HBsAg, and 6 cases (0.99%) presented detectable HCV RNA. We recognized 80 individuals positive for SARS-CoV-2 with negative markers for HBV and HCV suitable for the matched analysis. No statistical differences in mechanical ventilation and mortality rates were found (P = 0.27 and P = 0.80, respectively). Moreover, individuals with viral hepatitis were more likely to be admitted to the Intensive Care Unit in comparison to those without HBV or HCV infections (29% vs. 15%). The median time of virus clearance was 27.5 days, with no difference between the two groups. Conclusions: In our cohort, the pre-existing viral liver infection did not have any impact on the clinical and virological evolution of COVID-19.

Clinical experience with therapeutic dose of Low-Molecular-Weight Heparin

A 71-year old gentleman with history of arterial hypertension treated with valsartan presented on was hospitalized at the Infectious Diseases Unit, University of Bologna (Italy) for severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2) and received treatment with hydroxychloroquine 200mg bid (400 mg bid the first day), azithromycin 400 mg qd, thrombotic prophylaxis with enoxaparin 4000 UI qd and Venturi mask oxygen delivering FiO2 of 31%. The case highlights the high frequency of coagulopathy in patients with moderate to severe cases of SARS-CoV-2 associated disease (COVID-19). After one week the patient significantly improved and the daily dose of enoxaparin was reduced and definitively discontinued four days later. The case highlights the high frequency of coagulopathy in patients with moderate to severe cases of SARS-CoV-2 associated disease (COVID-19). Considering the available information we believe that LMWH may represent a promising treatment for COVID-19 but further well-designed trials are needed to address these points.

Negative impact of hyperglycaemia on tocilizumab therapy in Covid-19 patients.

Tocilizumab (TCZ) is used for treating moderate-to-severe Covid-19 pneumonia by targeting interleukin-6 receptors (IL-6Rs) and reducing cytokine release. Yet, in spite of this therapy, patients with vs. patients without diabetes have an adverse disease course. In fact, glucose homoeostasis has influenced the outcomes of diabetes patients with infectious diseases. Of the 475 Covid-19-positive patients admitted to infectious disease departments (University of Bologna, University Vanvitelli of Napoli, San Sebastiano Caserta Hospital) in Italy since 1 March 2020, 31 (39.7%) hyperglycaemic and 47 (60.3%) normoglycaemic patients (blood glucose levels ≥140mg/dL) were retrospectively evaluated at admission and during their hospital stay. Of note, 20 (64%) hyperglycaemic and 11 (23.4%) normoglycaemic patients had diabetes (P<0.01). At admission, hyperglycaemic vs. normoglycaemic patients had fivefold higher IL-6 levels, which persisted even after TCZ administration (P<0.05). Intriguingly, in a risk-adjusted Cox regression analysis, TCZ in hyperglycaemic patients failed to attenuate risk of severe outcomes as it did in normoglycaemic patients (P<0.009). Also, in hyperglycaemic patients, higher IL-6 plasma levels reduced the effects of TCZ, while adding IL-6 levels to the Cox regression model led to loss of significance (P<0.07) of its effects. Moreover, there was evidence that optimal Covid-19 infection management with TCZ is not achieved during hyperglycaemia in both diabetic and non-diabetic patients. These data may be of interest to currently ongoing clinical trials of TCZ effects in Covid-19 patients and of optimal control of glycaemia in this patient subset.

Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. OBJECTIVES: To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions. SOURCES: Inductive PubMed search for publications relevant to the topic. CONTENT: The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer. IMPLICATIONS: Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials. Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.