An innovative technological infrastructure for managing SARS-CoV-2 data across different cohorts in compliance with General Data Protection Regulation.

Background: The ORCHESTRA project, funded by the European Commission, aims to create a pan-European cohort built on existing and new large-scale population cohorts to help rapidly advance the knowledge related to the prevention of the SARS-CoV-2 infection and the management of COVID-19 and its long-term sequelae. The integration and analysis of the very heterogeneous health data pose the challenge of building an innovative technological infrastructure as the foundation of a dedicated framework for data management that should address the regulatory requirements such as the General Data Protection Regulation (GDPR). Methods: The three participating Supercomputing European Centres (CINECA - Italy, CINES - France and HLRS - Germany) designed and deployed a dedicated infrastructure to fulfil the functional requirements for data management to ensure sensitive biomedical data confidentiality/privacy, integrity, and security. Besides the technological issues, many methodological aspects have been considered: Berlin Institute of Health (BIH), Charité provided its expertise both for data protection, information security, and data harmonisation/standardisation. Results: The resulting infrastructure is based on a multi-layer approach that integrates several security measures to ensure data protection. A centralised Data Collection Platform has been established in the Italian National Hub while, for the use cases in which data sharing is not possible due to privacy restrictions, a distributed approach for Federated Analysis has been considered. A Data Portal is available as a centralised point of access for non-sensitive data and results, according to findability, accessibility, interoperability, and reusability (FAIR) data principles. This technological infrastructure has been used to support significative data exchange between population cohorts and to publish important scientific results related to SARS-CoV-2. Conclusions: Considering the increasing demand for data usage in accordance with the requirements of the GDPR regulations, the experience gained in the project and the infrastructure released for the ORCHESTRA project can act as a model to manage future public health threats. Other projects could benefit from the results achieved by ORCHESTRA by building upon the available standardisation of variables, design of the architecture, and process used for GDPR compliance.

Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort.

Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively). Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials. Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.

Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections: The ORCHESTRA Prospective Cohort Study.

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p < 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05-0.27, p < 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08-5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03-1.08, p < 0.001), and male gender (aOR:1.97, 95%CI: 1.04-3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p < 0.001) in immunocompromised and elderly patients >75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.

Initial treatment of diabetes in Italy. A nationwide population-based study from of the ARNO Diabetes Observatory.

BACKGROUND AND AIMS: To investigate diabetes treatment initiation and continuation in the next sixth months in newly diagnosed Italian subjects. METHODS AND RESULTS: We analyzed administrative claims of 11,300,750 Italian residents. Subjects with incident diabetes were identified by glucose lowering drug prescriptions, disease-specific co-payment exemptions and hospital discharge codes occurring in 2018 but not in 2017. Incident cases were 65,932 of whom 91.4% received the prescription of a glucose lowering drug. Among the latter, those receiving a prescription of a noninsulin medication but no insulin were 84.8%, those receiving a prescription of insulin only were 9.4%, and those receiving prescriptions of both insulin and noninsulin drugs were 5.8%. Metformin was the most frequently drug initially prescribed in noninsulin treated subjects (~85%) and sulphonylurea receptor (SUR) agonists collectively ranked as second (~13%). Lispro (35%) and glargine (34%) were the most frequently prescribed molecules in subjects who were insulin treated. Differences in prescriptions were found in age categories, with increased use of SUR agonists across decades. In the first six months, as many as 50% of noninsulin treated patients continued with the initial drug, ~15% added a second agent, ~5% switched to another medication, and ~30% discontinued any glucose lowering treatment. CONCLUSIONS: These data document that current guidelines are often neglected because prescriptions of SUR agonists as first agent are still quite common and insulin is prescribed more than expected. They point out the urgent need to improve the dissemination and implementations of guidelines in diabetes care.

Incidence of diabetes mellitus in Italy in year 2018. A nationwide population-based study of the ARNO Diabetes Observatory.

BACKGROUNDS AND AIMS: To assess incidence of diabetes in Italy in 2018 by the use of administrative claims from several million residents. Differences in rates in men and women across decades of age were investigated. Incident rates of insulin or noninsulin treated subjects were also examined. METHODS AND RESULTS: We analyzed administrative healthcare claims of 11,300,750 subjects monitored by the ARNO Diabetes Observatory. Incident cases of diabetes were identified by glucose lowering drug prescriptions, disease-specific co-payment exemptions and hospital discharge codes related to diabetes occurring in 2018 but not in 2017. We identified 697,208 subjects with ascertained diabetes. Incident cases were 65,932, with a rate of 5.83 per 1000 person-years (p-y). Incidence of drug-treated diabetes (n = 60,271) was 5.33 per 1000 p-y. Subjects receiving only insulin prescriptions were 5652 (rate 0.50 per 1000 p-y) and those receiving only prescriptions of noninsulin medications were 51,085 (rate 4.52 per 1000 p-y). Incidence rates progressively increased across decades until age 80 and then dropped by 25-30%. Overall, incident rates were generally higher in women aged 11-40 and in men aged ≥51. CONCLUSIONS: Recent cases represented ~10% of the population of diabetic subjects. Incidence of noninsulin-treated diabetes was almost 10-fold higher than incidence of insulin-treated diabetes. Substantial differences in incidence rates were observed in men and women of several decades of age: women more affected in adolescence and young adult age, men more affected in mature and advanced age. These data provide further understanding on the epidemiological burden of the disease in Italy.

A view on the quality of diabetes care in Italy and the role of Diabetes Clinics from the 2018 ARNO Diabetes Observatory.

BACKGROUNDS AND AIMS: To investigate relevant indicators of quality of care in a large population-based sample of people with diabetes representative of clinical practice in Italy in 2018. METHODS AND RESULTS: We analyzed data from 11,300,750 subjects. All administrative healthcare claims collected in 2018 were scrutinized to identify subjects with diabetes and investigate several indicators of quality of care. Subjects with diabetes were identified by anti-hyperglycemic drug prescriptions, disease-specific co-payment exemption and hospital discharge codes. Indicators of quality of care pertained to monitoring (HbA1c, creatinine, lipid profile, microalbuminuria, eye examination, ECG, ultrasonography of carotid and lower limb arteries) and diabetes treatment (anti-hyperglycemic agents in subjects with cardiovascular disease, CVD). Subjects attending and nonattending Diabetes Clinics were compared. We identified 697,208 individuals with diabetes. HbA1c was assessed at least once in the year in 62.7%, creatinine in 62.3%, total cholesterol in 59.6%, microalbuminuria in 34.3%. Frequency of eye examination was 8.2%, ECG 23.5%, carotid ultrasonography 14.3%, lower limb ultrasonography 7.6%. Among anti-hyperglycemic drugs, SGLT-2 inhibitors were prescribed to ~5% and GLP-1 receptor agonists to ~5% although the proportion of subjects with CVD was ~45%. Subjects attending Diabetes Clinics had higher figures for all these monitoring and treatment indicators. CONCLUSIONS: The implementation of national and international guidelines regarding disease monitoring and treatment is far from being satisfactory, especially among subjects nonattending Diabetes Clinics. Further efforts and investments are needed for better disseminating guidelines, more efficaciously engaging healthcare professionals and more strongly empowering the healthcare system to improve diabetes care.

Clinical burden of diabetes in Italy in 2018: a look at a systemic disease from the ARNO Diabetes Observatory.

INTRODUCTION: Diabetes is a highly prevalent disease worldwide and represents a challenge for patients and healthcare systems. This population-based study evaluated diabetes burden in Italy in 2018 by assessing all aspects of outpatient and hospital care. RESEARCH DESIGN AND METHODS: We investigated data of 11 300 750 residents in local health districts contributing to ARNO Diabetes Observatory (~20% of Italian inhabitants). All administrative healthcare claims were analyzed to gather information on access to medical resources. Subjects with diabetes, identified by antihyperglycemic drug prescriptions, disease-specific copayment exemption and hospital discharge codes, were compared with age, sex and residency-matched non-diabetic individuals. RESULTS: We identified 697 208 subjects with ascertained diabetes, yielding a prevalence of 6.2% (6.5% in men vs 5.9% in women, p<0.001). Age was 69±15 (mean±SD). As compared with non-diabetic subjects, patients with diabetes received more prescriptions of any drugs (+30%, p<0.001), laboratory tests, radiologic exams and outpatient specialist consultations (+20%, p<0.001) and were hospitalized more frequently (+86%, p<0.001), with a longer stay (+1.4 days, p<0.001). Although cardiovascular diseases accounted for many hospital discharge diagnoses, virtually all diseases contributed to the higher rate of hospital admissions in diabetic subjects (235 vs 99 per 1000 person-years, p<0.001). Healthcare costs were >2-fold higher in subjects with diabetes, mainly driven by hospitalizations and outpatient care related to chronic complications rather than to glucose-lowering drugs, diabetes-specific devices, or metabolic monitoring. CONCLUSIONS: The burden of diabetes in Italy is particularly heavy and, as a systemic disease, it includes all aspects of clinical medicine, with consequent high expenses in all areas of healthcare.

Impact of hospitalizations for bronchiolitis in preterm infants on long-term health care costs in Italy: a retrospective case-control study.

PURPOSE: Bronchiolitis is an acute inflammatory injury of the bronchioles, and is the most frequent cause of hospitalization for lower respiratory tract infections in preterm infants. This was a retrospective, observational, case-control study conducted in Italy, based on administrative database analysis. The aim of this study was to evaluate differences in health care costs of preterm infants with and without early hospitalization for bronchiolitis. PATIENTS AND METHODS: Preterm infants born in the period between January 1, 2009 and December 31, 2010 and hospitalized for bronchiolitis in the first year of life were selected from the ARNO Observatory database and observed for the first 4 years of life. These preterm infants were compared (paired 1-3) with preterm infants who were not hospitalized for bronchiolitis in the first year of life and with similar characteristics. Only direct health care costs reimbursed by the Italian National Health Service were considered for this study (drugs, hospitalizations, and diagnostic/therapeutic procedures). RESULTS: Of 40,823 newborns in the accrual period, 863 were preterm with no evidence of prophylaxis, and 22 preterm infants were hospitalized for bronchiolitis (cases) and paired with 62 controls. Overall, cases had 74% higher average cost per infant in the first 4 years of life than controls (18,624€ versus 10,189€, respectively). The major cost drivers were hospitalizations, accounting for >90% in both the populations. The increase in total yearly health care cost between cases and controls remained substantial even in the fourth year of life for all cost items. A relevant increase in hospitalizations and drug consumption linked to respiratory tract diseases was noted in infants hospitalized for bronchiolitis during the entire follow-up period. CONCLUSION: Preterm infants hospitalized for bronchiolitis in the first year of life were associated with increased resource consumption and costs throughout the entire period of observation; even in the fourth year, the difference versus paired controls was relevant.