One year of COVID-19: infection rates and symptoms in patients with inherited metabolic diseases followed by MetabERN.

BACKGROUND: Since the beginning of the COVID-19 pandemic, MetabERN has been monitoring the SARS-CoV-2 infection rates within its metabolic community. To gather data on the total number of cases and the severity of symptoms among IMD patients one year into the pandemic, an online survey was distributed among all MetabERN healthcare providers (HCP). Epidemiological analysis was performed by integrating the survey's data with the MetabERN database. RESULTS: Survey's respondents reported a total of 452 cases of COVID-19 among their IMD patients (213 paediatric and 239 adults). Considering the total number of patients followed by the respondents (n = 26,347), the registered prevalence of COVID-19 in the IMD population was of 1716 × 100,000. Italy emerged as the most affected country (25.4% of cases), followed by the United Kingdom (14.2% of cases). Most of the paediatric cases of COVID-19 displayed no or mild symptoms during the disease: 34% of HCP reported having asymptomatic patients in 75-100% of cases, while 37.5% reported mild symptoms in about a quarter of their patients. Similarly to paediatric cases, most adult IMD patients with COVID-19 were asymptomatic or had mild symptoms: about one third of respondents reported 75-100% asymptomatic patients and about 65% of HCP had between 0 and 50% of patients with mild symptoms. The majority of the respondents reported no deaths due to COVID-19 in adult and paediatric patients with IMDs. CONCLUSIONS: Most of MetabERN's IMD patients who got COVID-19 during the first year of the pandemic had mild symptoms and a positive outcome of the disease. However, fatal events were recorded in paediatric patients; this, together with the lack of information on the long-term effects of COVID-19 in IMDs, call for caution in the metabolic population.

Social and medical needs of rare metabolic patients: results from a MetabERN survey.

BACKGROUND: Many surveys have been performed over the years to assess the medical and social requirements of patients with a rare disease, but no studies have focused specifically on patients in Europe or with an inherited metabolic disease (IMD). To obtain a comprehensive overview of the social and psychological status and needs of IMD patients, especially in Europe, the European Reference Network for Hereditary Metabolic Disorders (MetabERN) has performed a dedicated survey among its metabolic patients. RESULTS: A total of 924 patients and caregivers responded to the questionnaire. Most participants were from 25 European countries, with Spain, Italy, and Germany being the most represented; only eight participants were extra-European. The survey showed that most social assistance services, from free educational/development services for those with intellectual disability to transition from childhood to adult care and job placement support, are available for a limited number of patients or are unknown to the majority of patients or their parents/caregivers. Similarly, psychological assistance for the patient or the parent/caregiver is available for a small fraction of respondents, despite the fact that the majority considers this type of support necessary for both the patient and the caregiver. In addition, for most IMD patients local specialised or emergency medical assistance is lacking, although national clinical pathways are defined, and medical professionals of reference are readily available when needed. Lastly, while most national health services in Europe cover all or part of the expenses for medications, medical devices, food supplements, dietary integrators, physiotherapy, and speech therapy, significant gaps in the economic support for healthcare and other expenses still exist. CONCLUSIONS: Overall, our survey reveals a widespread lack of social, psychological, and economic support for IMD patients in Europe. More needs to be done to provide daily assistance to IMD patients in order to alleviate the burden on caregivers and to allow patients to become independent and productive adults. Where support is actually available locally or nationally, most IMD patients are not aware of it, so an active dissemination of this information among the metabolic community is essential.

Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey.

Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called "transition." The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.

Development of a novel diagnostic algorithm to predict NASH in HCV-positive patients.

Non-alcoholic steato-hepatitis (NASH) is a severe disease characterised by liver inflammation and progressive hepatic fibrosis, which may progress to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests that in hepatitis C virus patients steatosis and NASH are associated with faster fibrosis progression and hepatocellular carcinoma. A safe and reliable non-invasive diagnostic method to detect NASH at its early stages is still needed to prevent progression of the disease. We prospectively enrolled 91 hepatitis C virus-positive patients with histologically proven chronic liver disease: 77 patients were included in our study; of these, 10 had NASH. For each patient, various clinical and serological variables were collected. Different algorithms combining squamous cell carcinoma antigen-immunoglobulin-M (SCCA-IgM) levels with other common clinical data were created to provide the probability of having NASH. Our analysis revealed a statistically significant correlation between the histological presence of NASH and SCCA-IgM, insulin, homeostasis model assessment, haemoglobin, high-density lipoprotein and ferritin levels, and smoke. Compared to the use of a single marker, algorithms that combined four, six or seven variables identified NASH with higher accuracy. The best diagnostic performance was obtained with the logistic regression combination, which included all seven variables correlated with NASH. The combination of SCCA-IgM with common clinical data shows promising diagnostic performance for the detection of NASH in hepatitis C virus patients.

Characterization of SCCA-IgM as a biomarker of liver disease in an Asian cohort of patients.

Viral hepatitis infection is a major global issue and a leading cause of liver disease and associated deaths. Over time, patients infected with hepatitis B (HBV) or C virus (HCV) develop cirrhosis and, eventually, hepatocellular carcinoma (HCC). For this reason, they need to be constantly monitored. Current Asian guidelines recommend the determination of serum alpha-fetoprotein (AFP) together with liver ultrasounds every six months to detect HCC nodules. However, both methods have several limitations, and other biomarkers have been studied for monitoring cirrhosis, including SCCA-IgM, an immune-complex formed by Squamous Cell Carcinoma Antigen and IgM. To date, SCCA-IgM has been validated as a novel biomarker for liver diseases only in European populations. The aim of our study was to analyze SCCA-IgM as a biomarker to monitor cirrhosis evolution in an Asian cohort of patients and to compare its performance to that of AFP. We analyzed the concentration of AFP and SCCA-IgM in serum samples obtained from a group of Asian adult patients with cirrhosis or HCC and a control group of patients admitted for gastrointestinal disorders. In untreated patients and similarly to AFP, SCCA-IgM levels were significantly higher in patients with cirrhosis compared to those with HCC. In addition, SCCA-IgM, but not AFP serological levels, were significantly lower in HCC patients who were treated with surgical resection compared to those who received a different therapy.

Clinical evaluation of the iXip index to reduce prostate re-biopsies.

BACKGROUND: Prostate biopsy is the gold standard for prostate cancer (PCa) diagnosis, but it's invasive and associated with adverse events. Novel reliable tumor biomarkers and accurate non-invasive tests are required to avoid biopsies. The immune complex PSA-IgM is a new marker for PCa, and it has been included in an algorithm to generate the diagnostic index iXip, which determines the probability of having PCa. In this study we evaluated the ability of iXip to reduce the number of repeat biopsies in patients with a previous negative biopsy and suspicious for PCa. PATIENTS AND METHODS: 219 patients referred for prostate rebiopsy were included in the study. Each patient underwent a trans-rectal ultrasound-guided prostate biopsy and prostate volume examination. Blood samples were collected before any prostatic manipulation to determine the serological levels of PSA-IgM and PSA. The iXip index was calculated as previously reported using an online calculator. RESULTS: iXip values in patients with a positive biopsy were significantly higher than the ones observed in negative patients (p-value = 0.001). Based on iXip values, patients were divided in five risk groups: those with iXip < 0.2 had 0% probability of having PCa. High values of the Gleason score (≥7) were observed mostly in patients with iXip 0.3-0.8. CONCLUSION: Our preliminary results show that iXip identifies a sub-group of patients who can safely avoid rebiopsy because they do not have PCa. The index is a promising tool that could reduce the number of unnecessary prostate biopsies and the relative clinical complications and expenses.

Circulating SCCA-IgM complex is a useful biomarker to predict the outcome of therapy in hepatocellular carcinoma patients.

INTRODUCTION: Hepatocellular carcinoma (HCC) develops in about 3-4% of cirrhotic patients every year. The squamous cell carcinoma antigen (SCCA) has been found elevated in liver cancer specimens by immunohistochemistry, and detected in complex with IgM (SCCA-IgM) in the serum of patients with HCC. The aim of this study was to evaluate the ability of serological SCCA-IgM levels to predict the efficacy of HCC therapy. MATERIALS AND METHODS: From April 2012 to April 2014, 131 patients with a new diagnosis of HCC were enrolled. The HCC diagnosis was made according to the EASL guidelines. The patients were staged and treated according to the BCLC Staging System: BCLC stages A and B were treated with locoregional therapy, and BCLC stage C was treated with Sorafenib. Response to therapy was evaluated according to the mRECIST criteria. Serum SCCA-IgM levels were determined by a commercially available ELISA kit at basal time (T0) and after one month of treatment (T1). RESULTS: At baseline and one month into therapy, SCCA-IgM levels were significantly lower (p value <.05) in patients who responded to therapy compared to those who did not respond (median SCCA-IgM level [25th + 75th percentile] at T0:115.1 AU/mL [50.0 + 174.4] vs. 149.1 AU/mL [111.3 + 198.8]; median SCCA-IgM level [25th + 75th percentile] at T1: 113.4 AU/mL [50.0 + 194.2] vs. 170.6 AU/mL [111.7 + 344.2]). CONCLUSION: Our study suggests that the SCCA-IgM determination could be helpful in predicting the response to therapy in patients with HCC.

A novel endothelial-derived anti-inflammatory activity significantly inhibits spontaneous choroidal neovascularisation in a mouse model.

BACKGROUND: Endothelial cells (EC) grown on collagen particles inhibit intimal hyperplasia in animal models when applied perivascularly, and this effect appears to be, at least in part, the result of EC-derived soluble factors that suppress local vascular inflammation. To elucidate the molecular basis of the therapeutic effects of EC grown on collagen particles, the anti-inflammatory activity of conditioned medium from these cells was characterized. METHODS: Human aortic EC (HAEC) and, for chromatin immunoprecipitation assays, human umbilical vein EC (HUVEC) were treated with tumor necrosis factor alpha (TNFα) in the presence of conditioned medium generated by HAEC grown on collagen particles (ECPCM), and the anti-inflammatory effects were evaluated by analysing the expression of the inflammation-related adhesion molecules E-selectin and vascular cell adhesion molecule-1 (VCAM-1). The therapeutic activity of ECPCM was studied using the mouse strain JR5558, which develops spontaneous choroidal neovascularisation (CNV) lesions driven by local inflammation. RESULTS: ECPCM significantly suppressed TNFα-induced expression of E-selectin and VCAM-1. ECPCM did not affect the mRNA stability of the two genes, but suppressed TNFα-induced binding of the p65 subunit of NF-kB transcription factor to E-selectin and VCAM-1 promoters. In vivo, systemic ECPCM treatment significantly reduced the CNV area and the recruitment of activated macrophages to the lesions. Characterization of the molecule responsible for the anti-inflammatory activity in ECPCM indicates that it is unlikely to be a protein and that it is not any of the better characterized EC-derived anti-inflammatory molecules. CONCLUSIONS: Medium conditioned by HAEC grown on collagen particles exhibits significant anti-inflammatory activity via inhibition of genes that mediate inflammatory responses in EC.