Evaluation of Frequency of CMV Replication and Disease Complications Reveals New Cellular Defects and a Time Dependent Pattern in CVID Patients.

PURPOSE: Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and failure of specific antibody production due to B-cell defects. However, studies have documented various T-cell abnormalities, potentially linked to viral complications. The frequency of Cytomegalovirus (CMV) replication in CVID cohorts is poorly studied. To address this gap in knowledge, we set up an observational study with the objectives of identifying CVID patients with active viraemia (CMV, Epstein-Barr virus (EBV)), evaluating potential correlations with immunophenotypic characteristics, clinical outcome, and the dynamic progression of clinical phenotypes over time. METHODS: 31 CVID patients were retrospectively analysed according to viraemia, clinical and immunologic characteristics. 21 patients with non CVID humoral immunodeficiency were also evaluated as control. RESULTS: Active viral replication of CMV and/or EBV was observed in 25% of all patients. CMV replication was detected only in CVID patients (16%). CVID patients with active viral replication showed reduced HLA-DR+ NK counts when compared with CMV-DNA negative CVID patients. Viraemic patients had lower counts of LIN-DNAMbright and LIN-CD16+ inflammatory lymphoid precursors which correlated with NK-cell subsets. Analysis of the dynamic progression of CVID clinical phenotypes over time, showed that the initial infectious phenotype progressed to complicated phenotypes with time. All CMV viraemic patients had complicated disease. CONCLUSION: Taken together, an impaired production of inflammatory precursors and NK activation is present in CVID patients with active viraemia. Since "Complicated" CVID occurs as a function of disease duration, there is need for an accurate evaluation of this aspect to improve classification and clinical management of CVID patients.

Notch4 regulatory T cells and SARS-CoV-2 viremia shape COVID19 survival outcome.

BACKGROUND: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear. METHODS: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome. RESULTS: Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection. CONCLUSIONS: The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.

Brain cortical assessment by MRI in fetuses with left congenital diaphragmatic hernia.

OBJECTIVE: To evaluate fetal brain development using MRI (magnetic resonance imaging) in CDH (congenital diaphragmatic hernia). METHODS: 52 isolated left CDH and 104 control fetuses were imaged using MRI. Brain morphometry (Biparietal diameter-BPD, brain fronto-occipital diameter-BFOD, third ventricle, posterior ventricles, transcerebellar diameter-TCD, anteroposterior and craniocaudal cerebellar vermis diameter-AP and CC) and cortical structures (bilateral cingulate fissure-CF, insular fissure-IF, insular depth - ID) were compared with controls using Mann-Whitney test. RESULTS: Median gestational age at MRI (p = 0.95)and the median biparietal diameter (p = 0.737) were comparable. Among morphometric parameters, only the brain fronto-occipital diameter was significantly smaller in CDH (p = 0.001) and the third ventricle was significantly greater in CDH (<0.0001). Among cortical structures, the cingulate and insular fissures were significantly deeper in CDH fetuses (p < 0.0001) as the insular depth ID was smaller in CDH (p < 0.03). CONCLUSIONS: CDH fetuses have a smaller fronto-occipital diameter, reduced insular depth, deeper cingulate and insular fissure, and greater third ventricle width as compared to controls. These findings suggest that left CDH may have an impact on fetal brain development with an overall reduction in brain volume.

Intrafetal Laser Therapy Is a Feasible Treatment for Different Fetal Conditions: A Systematic Review.

INTRODUCTION: Over the past years, intrafetal laser (IFL) therapy has been increasingly used in the management of various prenatal conditions. The aim of our research was to clarify the effectiveness and safety of this technique. METHODS: A systematic review of the literature was carried out using MEDLINE/PubMed over a period of 20 years (2001-2021). RESULTS: A total of forty-one articles were selected in the literature search, including 194 cases of twin reversed arterial perfusion (TRAP) sequence, 56 cases of bronchopulmonary sequestrations (BPSs), 5 cases of placental chorioangiomas (PCA), 11 cases of sacrococcygeal teratoma (SCT), and 103 cases of embryo reduction (ER) managed using IFL. In TRAP sequence, perfusion of the acardiac twin was successfully disrupted in all cases. However, preterm premature rupture of membranes (P-PROMs) occurred in 6 out of 79 pregnancies (7.5%), and preterm birth (PTB) occurred in 36 out of 122 pregnancies (29.5%). In BPS, IFL was successfully performed in all cases with no significant fetal-maternal complications. The rates of P-PROM and PTB were, respectively, 3.2% and 12.5%. All PCA IFL-treated cases resulted in successful pregnancy outcomes; no cases of P-PROM were reported, but the rate of PTB reached a peak of 60% due to complications such as severe fetal growth restriction and fetal Doppler abnormalities. In SCT cases, complete cessation of blood flow was achieved in 4 patients (36.4%); P-PROM occurred in 2 cases (18.2%), whereas the rate of PTB was 87.5%. In ER, no intraoperative or major maternal complications were described in the literature. Rates of miscarriage and PTB differed between initial trichorionic triamniotic and dichorionic triamniotic triplet pregnancies. CONCLUSION: Our analysis suggests that IFL is a safe and feasible technique for the management of different fetal conditions. However, the overall risk of PTB, and its related morbidity and mortality, ranges from 12.5% in BPS to 87.5% in SCT IFL-treated cases. This information could aid in decision-making during prenatal counseling. However, final perinatal outcome depends on the severity of the disease itself.

Tranexamic acid adverse reactions: a brief summary for internists and emergency doctors.

Tranexamic acid (TXA) is a synthetic lysine analogue that is well known as antifibrinolytic agent. It can reduce blood loss in clinical use, especially in conditions where fibrinolysis or hyperfibrinolysis are involved, such as trauma or surgery. Moreover, TXA has been approved as second-line prophylactic therapy for hereditary angioedema and further data have been published about a possible use of TXA as maintenance treatment for nonhistaminergic angioedema and treatment for episodes of bradykinin-mediated angioedema induced by ACE inhibitors. TXA can be administered through several routes: orally, topically, or intravenously. Although, it is a drug with a very high safety profile, in few cases hypersensitivity reactions have been described occurring with different clinical manifestations. Ethamsylate can be an alternative in TXA sensitized patients. In this brief article we describe TXA adverse reactions and current protocols which have been proposed to help clinicians to diagnose TXA hypersensitivity.

Fetal Doppler Parameters at Term in Pregnancies Affected by Gestational Diabetes: Role in the Prediction of Perinatal Outcomes.

OBJECTIVE: The timing of delivery for women affected by gestational diabetes (GDM) is still controversial. Good clinical practice often suggests offering induction of labor at term in order to reduce the complications associated with this condition, while recent evidence supports expectant management. Fetal Doppler parameters represent a validated tool for testing fetal well-being at term and can select pregnancies that need increased surveillance. The aim of the present study was to evaluate the role of fetal Doppler parameters at term for the prediction of pregnancy outcomes in patients affected by GDM. METHODS: Prospective cohort study in a single center. Evaluation of umbilical artery (UA) PI, middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR) and umbilical-to-cerebral ratio (UCR) at > 37 weeks of gestation in singleton, morphologically normal pregnancies affected by GDM, was performed in order to estimate the association between ultrasound measurements at term and perinatal outcome. Regression linear analysis was used to estimate the association between fetal Doppler parameters and neonatal pH, neonatal Apgar score, neonatal weight and a composite adverse outcome. The receiver operating characteristic (ROC) curve was used to estimate the possible predictive value of the above association. RESULTS: Our results on 130 women showed MCA PI to be the best predictor of perinatal outcomes in terms of low Apgar score at the 1st minute (p = 0.00), pH (p = 0.02) and composite adverse outcome (p = 0.05). UCR showed a significant correlation with neonatal pH (p = 0.02). No significant correlations for UA PI and CPR MoMs have been demonstrated in our population. However, the small sample size is a limitation of the study. CONCLUSION: Evaluation of MCA Doppler and eventually UCR at term can be a useful tool to discriminate pregnancies affected by GDM that can benefit from IOL before 41 weeks in order to reduce complications related to this condition.

Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound: A Systematic Review and Meta-Analysis.

BACKGROUND: Prenatal diagnosis of coarctation of the aorta (CoA) is still challenging and affected by high rates of false-positive diagnoses. The aim of this study was to ascertain the strength of association and to quantify the diagnostic accuracy of different ultrasound signs in predicting CoA prenatally. METHODS: Medline, Embase, CINAHL, and Cochrane databases were searched. Random-effects and hierarchical summary receiver operating characteristic model meta-analyses were used to analyze the data. RESULTS: Seven hundred ninety-four articles were identified, and 12 (922 fetuses at risk for CoA) articles were included. Mean mitral valve diameter z score was lower (P<0.001) and the mean tricuspid valve diameter z score was higher in fetuses with CoA than in those without CoA (P=0.01). Mean aortic valve diameter z score was lower in fetuses with CoA than in healthy fetuses (P≤0.001), but the ascending aorta diameter, expressed as z score or millimeters, was similar between groups (P=0.07 and 0.47, respectively). Mean aortic isthmus diameter z scores measured either in sagittal (P=0.02) or in 3-vessel trachea view (P<0.001) were lower in fetuses with CoA. Conversely, the mean pulmonary artery diameter z score, the right/left ventricular and pulmonary artery/ascending aorta diameter ratios were higher (P<0.001, P=0.02, and P=0.02, respectively) in fetuses with CoA in comparison with controls, although aortic isthmus/arterial duct diameter ratio was lower in fetuses with CoA than in those without CoA (P<0.001). The presence of coarctation shelf and aortic arch hypoplasia were more common in fetuses with CoA than in controls (odds ratio, 26.0; 95% confidence interval, 4.42-153; P<0.001 and odds ratio, 38.2; 95% confidence interval, 3.01-486; P=0.005), whereas persistent left superior vena cava (P=0.85), ventricular septal defect (P=0.12), and bicuspid aortic valve (P=0.14) did not carry an increased risk for this anomaly. Multiparametric diagnostic models integrating different ultrasound signs for the detection of CoA were associated with an increased detection rate. CONCLUSIONS: The detection rate of CoA may improve when a multiple-criteria prediction model is adopted. Further large multicenter studies sharing the same imaging protocols are needed to develop objective models for risk assessment in these fetuses.

Clinical Characteristics of Systemic Lupus Erythematosus in Caucasians and Latin American Hispanics: Data from a Single Tertiary Center.

Background: Different studies report that systemic lupus erythematosus (SLE) tends to have a more aggressive course in Hispanic patients. In this study, we analysed epidemiologic, clinical, and laboratory characteristics in a cohort of Hispanic and Caucasian lupus patients in the context of Italian health service, which provides free access to care to all citizens, thus mitigating the impact of socioeconomic factors that negatively influence the course of the disease in ethnic minorities. Methods: This single-center retrospective study was conducted at the San Martino Hospital "Lupus Clinic" in Genoa, Italy. Patients ≥18 years with a confirmed diagnosis of SLE and definite ethnicity (Hispanic or Caucasian) were recruited. Results: A total of 126 patients (90 Caucasians and 36 Hispanics) were enrolled. We compared epidemiologic characteristics, clinical features, autoantibodies profile, and treatment options without evidencing any statistically significant difference between the two groups, except for disease duration, which was higher in the Caucasian group (20.4 years versus 14.2 years in the Hispanic group, P=0.002) and SLICC damage index, which was greater in Caucasian patients (2.11 versus 1.88 in Hispanics, P=0.037), but this difference was no longer significant after correction for disease duration (P=0.096). Conclusions: In our cohort, Hispanic ethnicity is not associated with worse disease features and outcomes. Therefore, we speculated that socioeconomic factors, in particular, free access to healthcare, might be more relevant in influencing the course of the disease than genetic background.

Estimation of lifetime costs for patients receiving a transplant: the case of liver transplantation related to hepatitis B in Italy.

Introduction: In Italy, post-liver transplant (LT) hepatitis B virus (HBV) reinfection prophylaxis is frequently based on a combined regimen of anti-HBV immunoglobulin (HBIG) and oral antivirals. However, little information is available at the national level on the cost of LT and the contribution of HBV prophylaxis. This study aimed to quantify the direct healthcare cost for adult patients undergoing LT for HBV-related disease over a lifetime horizon and from the perspective of a National Healthcare Service. Methods: A pharmaco-economic model was implemented with a 4-tiered approach consisting of 1) preliminary literature research to define the research question; 2) pragmatic literature review to retrieve existing information and inform the model; 3) micro-simulated patient cycles; and 4) validation from a panel of national experts. Results: The average lifetime healthcare cost of LT for HBV-related disease was €395,986. The greatest cost drivers were post-transplant end-stage renal failure (31.9% of the total), immunosuppression (20.6%), and acute transplant phase (15.8%). HBV reinfection prophylaxis with HBIG and antivirals accounted for 12.4% and 6.4% of the total cost, respectively; however, lifetime HBIG prophylaxis was only associated with a 6.6% increase (~€422 k). Various sensitivity analyses have shown that discount rates have the greatest impact on total costs. Conclusion: This analysis showed that the burden of LT due to HBV is not only clinical but also economic.

An epidemiological investigation of high-risk infants for Respiratory Syncytial Virus infections: a retrospective cohort study.

BACKGROUND: Respiratory Syncytial Virus (RSV) infections may lead to severe consequences in infants born preterm with breathing problems (such as bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS)) or congenital heart diseases (CHD). Since studies investigating the influence of different gestational age (WGA) and concomitant specific comorbidities on the burden of RSV infections are scarce, the present study aimed to better characterize these high-risk populations in the Italian context. METHODS: This retrospective, longitudinal and record-linkage cohort study involved infants born between 2017 and 2019 in Lazio Region (Italy) and is based on data extracted from administrative databases. Each infant was exclusively included in one of the following cohorts: (1) BPD-RDS (WGA ≤35 with or without CHD) or (2) CHD (without BPD and/or RDS) or (3) Preterm (WGA ≤35 without BPD (and/or RDS) or CHD). Each cohort was followed for 12 months from birth. Information related to sociodemographic at birth, and RSV and Undetermined Respiratory Agents (URA) hospitalizations and drug consumption at follow-up were retrieved and described. RESULTS: A total of 8,196 infants were selected and classified as 1,084 BPD-RDS, 3,286 CHD and 3,826 Preterm. More than 30% of the BPD-RDS cohort was composed by early preterm infants (WGA ≤ 29) in contrast to the Preterm cohort predominantly constitute by moderate preterm infants (98.2%), while CHD infants were primarily born at term (83.9%). At follow-up, despite the cohorts showed similar proportions of RSV hospitalizations, in BPD-RDS cohort hospitalizations were more frequently severe compared to those occurred in the Preterm cohort (p<0.01), in the BPD-RDS cohort was also found the highest proportion of URA hospitalizations (p<0.0001). In addition, BPD-RDS infants, compared to those of the remaining cohorts, received more frequently prophylaxis with palivizumab (p<0.0001) and were more frequently treated with adrenergics inhalants, and glucocorticoids for systemic use. CONCLUSIONS: The assessment of the study clinical outcomes highlighted that, the demographic and clinical characteristics at birth of the study cohorts influence their level of vulnerability to RSV and URA infections. As such, continuous monitoring of these populations is necessary in order to ensure a timely organization of health care system able to respond to their needs in the future.

COVID-19 impact on the decision process of the Italian Medicine Agency: a quantitative assessment.

Background: Since the COVID-19 pandemic has placed more attention on drugs' approval process and the importance of rapid decision-making in the healthcare sector, it is crucial to assess how time to market (TTM) of drugs varied. Objective: To estimate the impact of the COVID-19 pandemic on TTM of drugs in Italy. Methods: An IQVIA database was used to retrieve information on drugs that obtained positive opinion from the Committee for Medicinal Products for Human Use between January 2015 and December 2021. The available observations were divided into three groups (Pre COVID, Partially COVID, and Fully COVID) according to the timing of their negotiation process. Differences in average TTM among the three groups were analyzed in three steps: (1) descriptive statistics; (2) univariate analysis; (3) multivariate analysis, using a matching estimator. Results: A total of 363 unique combinations of molecule and indication met the inclusion criteria: 174 in the Pre COVID group, 69 in the Partially COVID group, and 123 in the Fully COVID group. Descriptive statistics and univariate analysis found a statistically significant difference in TTM among the three periods, with average TTM increasing during the pandemic (+136 days, p = 0.00) and then decreasing afterward (-23 days, p = 0.09). In the matching analysis, results for the Partially COVID period were confirmed (+108 days, p = 0.00) while results for the Fully COVID period lost significance but maintained a negative sign. Conclusions: The results suggest that after an adjustment phase in the Partially COVID period, a return to the status quo was reached.

Patients with multiple sclerosis: a burden and cost of illness study.

BACKGROUND: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease negatively impacting patients' physical, psychological and social well-being with a significant economic burden. OBJECTIVES: The study estimates MS burden and cost of illness in Italy from a societal perspective in 2019. METHODS: Information on the impact of the disease on daily activities, symptoms, employment, resource utilization and the role of caregivers was collected through questionnaires completed by 944 patients and caregivers. Results were stratified according to both disease severity and payer. Mean costs and overall costs were extrapolated from the sample to the Italian MS population considering published distribution of severity. RESULTS: The study showed a great impact of the disease on daily and work activities increasing with the disability. The overwhelming burden of fatigue emerged. Mean annual costs were estimated at €39,307/patient (€29,676, €43,464 and €53,454 in mild, moderate and severe cases, respectively). Direct healthcare costs were the major component (€21,069), followed by indirect costs (€15,004). The overall cost of the disease in Italy was €4.8 billion. The National Healthcare System (NHS) sustained most of the costs (80%), most notably direct healthcare costs, while patients paid almost all non-healthcare expenses. CONCLUSIONS: This study confirmed that MS carries a substantial burden to patients and society, highlighting the need for awareness of this disease.

Comparison of mediastinal shift angles obtained with ultrasound and magnetic resonance imaging in fetuses with isolated left sided congenital diaphragmatic hernia.

OBJECTIVES: To compare ultrasound (US) and magnetic resonance imaging (MRI) in the assessment of mediastinal shift angles (MSAs) in fetuses affected by isolated left congenital diaphragmatic hernia (CDH). The use of MRI-MSA and US-MSA as prognostic factor for postnatal survival in fetal left CDH was also explored. METHODS: This was an observational study of 29 fetuses with prenatally diagnosed isolated left CDH, assessed with both US and MRI examinations between January 2015 and December 2018. The US-MSA measurements performed within 2 weeks from the MRI assessment were considered for the analysis. The primary outcome was the postnatal survival rate. RESULTS: No significant difference between US and MRI MSAs was detected (p = .419). Among the 29 cases, there were 21 alive infants, for an overall postnatal survival rate of 72.41%. After stratifying for postnatal survival, the best cutoffs with the highest discriminatory power in terms of sensibility and specificity were 42.1° for the US-MSA and 39.1° for the MRI-MSA. The performance of MRI-MSA in predicting postnatal survival was close to that of US-MSA in terms of sensitivity (62.5 versus 50.0%), specificity (80.9 versus 90.5%), positive predictive value (55.6 versus 66.7%), negative predictive value (85.0 versus 82.6%) and accuracy (75.9 versus 79.3%). There was no statistically significant difference between the two modalities (p > .05 for all). CONCLUSIONS: MRI and US can be interchangeably used for the assessment of MSA in prenatally diagnosed isolated left CDH. Moreover, MSA measured by both US and MRI was confirmed to be correlated with perinatal outcome in terms of survival.

Fetal cardiac dimensions in congenital diaphragmatic hernia: relationship with gestational age and postnatal outcomes.

OBJECTIVE: To serially assess fetal cardiac dimensions in congenital diaphragmatic hernia (CDH) and their relation to disease severity. STUDY DESIGN: Retrospective analysis of CDH cases and matched controls. Mitral (MVd) and tricuspid (TVd) valve diameters, left (LV) and right (RV) ventricular length and area, Z-scores, were serially assessed at 24-26, 30-32, and 35-37 weeks gestational age (GA). RESULTS: In CDH cases MVd, MVd Z-score, and LV area were significantly reduced at 24-26 and 35-37 weeks GA. TVd, TVd Z-score, and RV area were significantly reduced at 24-26 weeks. RV area Z-score increased with advancing GA. MVd and MVd Z-score were significantly lower at 24-26 weeks GA in CDH who had a combined outcome of death and/or ECMO. CONCLUSIONS: LV hypoplasia in CDH is characterized by reduced MVd from 24 weeks GA. MVd, and the ratio of mitral and tricuspid valve diameters at later gestations, may be potential predictors of disease severity.

Systemic Sclerosis and Vaccinations: A Register-Based Cohort Study about Seasonal Influenza and Streptococcus pneumoniae Vaccination Rate and Uptake from Liguria Regional Center, Northwest Italy.

Systemic sclerosis (SSc) is the connective tissue disease with the highest mortality and patients with chronic inflammatory immune-mediated diseases are at high risk of acquiring infections as they are often treated with immunosuppressive or biological drugs. This study, conducted among the patients followed by our clinical immunology, part of the Internal Medicine Department in the Ospedale Policlinico San Martino, Genoa, northwest Italy, has set itself the primary objective of analyzing the vaccine uptake and the vaccination coverage against both seasonal influenza and S. pneumoniae in a cohort of patients with SSc. We evaluated the influenza and pneumococcal vaccination rate among various subgroups of patients and the source of the recommendation for vaccination. We evaluated the vaccination rate changes between the two years considered in our study. We also calculated a binomial logistic regression between vaccination acceptance and clinical and demographics characteristics of the patients to evaluate the adjusted odds ratio (OR) of each factor on vaccination. The vaccination coverage that resulted was significantly higher than in other similar studies. Age over 65 years old, interstitial lung disease, and ongoing immunosuppressive therapy were significantly related with acceptance to both vaccinations using univariate analyses, but the multivariate logistic regression found a significant correlation only with the age and therapy factors.

Oral misoprostol versus intravaginal dinoprostone for labor induction: a comparison study.

BACKGROUND: Induction of labor (IOL) is one of the most common procedures performed in obstetrics, accounting for about the 20% of deliveries in the developed countries and it still represents a challenge to obstetricians. The aim of this study is the comparison between two techniques for IOL: oral misoprostol and Propess®. METHODS: A retrospective study has been carried out in a single tertiary referral center. Clinical maternal, fetal and neonatal information was recorded. RESULTS: A total of 863 women were included. the vaginal delivery (VD) rate was significantly higher in the misoprostol group. The cesarean section rate was comparable between groups. Adverse events and neonatal outcomes were comparable between groups. CONCLUSIONS: Misoprostol shows a higher VD rate with fewer patients needing a second type of induction and a shorter time to the onset of active labor and to VD.