Two years of SARS-CoV-2 pandemic and COVID-19 in Lombardy, Italy.

Lombardy, the largest and most densely populated Italian region, was severely hit in February 2020 by the first pandemic wave of SARS-CoV-2 and associated COVID-19. Since then, additional infection waves spread in the region. The aim of this study was to compare the first with the subsequent waves using the administrative database of the Lombardy Welfare directorate. In the time frames of the four 2020-2022 waves, the absolute number of infected cases, sites of management and crude mortality rate associated with SARS-CoV-2 positivity were extracted from the database. Infected cases progressively increased in the region by approximately 5-fold in the second versus the first wave, 4-fold in the third and 20-fold during the most recent wave mainly associated with the omicron variant. The crude death decreased from 18.7% in the first to 2% in the second and third wave to reach a 0.3% nadir at the time of the fourth wave. This study confirms that in Lombardy outcomes of public health and health-care relevance such as deaths and number of hospitalizations declined dramatically across the four virus waves and reached very low values in 2022 when, at variance with the first three SARS-CoV-2 waves, the majority of infected cases had been previously vaccinated.

Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, and Sodium-Glucose Cotransporter-2 Inhibitors and COVID-19 Outcomes.

PURPOSE: It has been reported that dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a role in modulation of inflammation associated with coronavirus disease 2019 (COVID-19). This study assessed the effect of these drug classes on COVID-19-related outcomes. METHODS: Using a COVID-19 linkable administrative database, we selected patients aged ≥40 years with at least 2 prescriptions of DPP-4i, GLP-1 RA, or SGLT-2i or any other antihyperglycemic drug and a diagnosis of COVID-19 from February 15, 2020, to March 15, 2021. Adjusted odds ratios (ORs) with 95% CIs were used to calculate the association between treatments and all-cause and in-hospital mortality and COVID-19-related hospitalization. A sensitivity analysis was performed by using inverse probability treatment weighting. FINDINGS: Overall, 32,853 subjects were included in the analysis. Multivariable models showed a reduction of the risk for COVID-19 outcomes for users of DPP-4i, GLP-1 RA, and SGLT-2i compared with nonusers, although statistical significance was reached only in DPP-4i users for total mortality (OR, 0.89; 95% CI, 0.82-0.97). The sensitivity analysis confirmed the main results reaching a significant reduction for hospital admission in GLP-1 RA users and in-hospital mortality in SGLT-2i users compared with nonusers. IMPLICATIONS: This study found a beneficial effect in the risk reduction of COVID-19 total mortality in DPP-4i users compared with nonusers. A positive trend was also observed in users of GLP-1 RA and SGLT-2i compared with nonusers. Randomized clinical trials are needed to confirm the effect of these drug classes as potential therapy for the treatment of COVID-19.

Post-COVID condition: dispensation of drugs and diagnostic tests as proxies of healthcare impact.

With the goal to increase knowledge on the healthcare impact of the post-COVID-19 condition we exploited the administrative claims database of Lombardy, the largest Italian region and the first after China to be heavily hit by the SARS-CoV-2 pandemic in February-May 2020. We chose to employ the dispensation of drugs and diagnostic tests as proxies of the impact of the post-COVID condition in 46,574 cases who recovered from COVID-19 and were negative at PCR testing within June 20, 2020. Data were obtained throughout the 18-month post-negativization period until December 2021 and results on the use of drugs and diagnostic tests were compared with those accrued in the same cases during the pre-COVID period in July-December 2019. After an increase in the first semester after SARS-CoV-2 negativization (July-December 2020), trends in the dispensation of drugs according to the broad ATC classes and of diagnostic tests decreased or remained substantially stable. However, dispensation of drugs for acid related disorders (A02), diabetes (A10), heparins (B01AB), direct oral anticoagulants (B01AP), antipsychotics (N05A), antidepressants (N06A) and for obstructive airways diseases (R03) was still higher than in the pre-COVID period. These findings, based upon drug and diagnostic test dispensation as proxies of the healthcare impact of the post-COVID condition, show that in a substantial proportion of recovered cases the post-COVID condition is active and clinically relevant 18 months after the acute disease. The findings also provide indirect evidence of the body organs and systems more compromised in the post-COVID period.

Role of Sex and Age in Fatal Outcomes of COVID-19: Women and Older Centenarians Are More Resilient.

In the present paper, we have analysed the role of age and sex in the fatal outcome of COVID-19, as there are conflicting results in the literature. As such, we have answered three controversial questions regarding this aspect of the COVID-19 pandemic: (1) Have women been more resilient than men? (2) Did centenarians die less than the remaining older people? (3) Were older centenarians more resistant to SARS-CoV-2 than younger centenarians? The literature review demonstrated that: (1) it is women who are more resilient, in agreement with data showing that women live longer than men even during severe famines and epidemics; however, there are conflicting data regarding centenarian men; (2) centenarians overall did not die less than remaining older people, likely linked to their frailty; (3) in the first pandemic wave of 2020, centenarians > 101 years old (i.e., born before 1919), but not "younger centenarians", have been more resilient to COVID-19 and this may be related to the 1918 Spanish flu epidemic, although it is unclear what the mechanisms might be involved.

Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations.

Background: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications. Methods: Blood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection. Results: Blood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels. Discussion: The overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

Willingness to share contacts in case of COVID-19 positivity-predictors of collaboration resistance in a nation-wide Italian survey.

BACKGROUND: The unwillingness to share contacts is one of the least explored aspects of the COVID-19 pandemic. Here we report the factors associated with resistance to collaborate on contact tracing, based on the results of a nation-wide survey conducted in Italy in January-March 2021. METHODS AND FINDINGS: The repeated cross-sectional on-line survey was conducted among 7,513 respondents (mean age 45.7, 50.4% women) selected to represent the Italian adult population 18-70 years old. Two groups were defined based on the direct question response expressing (1) unwillingness or (2) willingness to share the names of individuals with whom respondents had contact. We selected 70% of participants (training data set) to produce several multivariable binomial generalized linear models and estimated the proportion of variation explained by the model by McFadden R2, and the model's discriminatory ability by the index of concordance. Then, we have validated the regression models using the remaining 30% of respondents (testing data set), and identified the best performing model by removing the variables based on their impact on the Akaike information criterion and then evaluating the model predictive accuracy. We also performed a sensitivity analysis using principal component analysis. Overall, 5.5% of the respondents indicated that in case of positive SARS-CoV-2 test they would not share contacts. Of note, this percentage varied from 0.8% to 46.5% depending on the answers to other survey questions. From the 139 questions included in the multivariable analysis, the initial model proposed 20 independent factors that were reduced to the 6 factors with only modest changes in the model performance. The 6-variables model demonstrated good performance in the training (c-index 0.85 and McFadden R2 criteria 0.25) and in the testing data set (93.3% accuracy, AUC 0.78, sensitivity 30.4% and specificity 97.4%). The most influential factors related to unwillingness to share contacts were the lack of intention to perform the test in case of contact with a COVID-19 positive individual (OR 5.60, 95% CI 4.14 to 7.58, in a fully adjusted multivariable analysis), disagreement that the government should be allowed to force people into self-isolation (OR 1.79, 95% CI 1.12 to 2.84), disagreement with the national vaccination schedule (OR 2.63, 95% CI 1.86 to 3.69), not following to the preventive anti-COVID measures (OR 3.23, 95% CI 1.85 to 5.59), the absence of people in the immediate social environment who have been infected with COVID-19 (1.66, 95% CI 1.24 to 2.21), as well as difficulties in finding or understanding the information about the infection or related recommendations. A limitation of this study is the under-representation of persons not participating in internet-based surveys and some vulnerable groups like homeless people, persons with disabilities or migrants. CONCLUSIONS: Our analysis revealed several groups that expressed unwillingness to collaborate on contact tracing. The identified patterns may play a principal role not only in the COVID-19 epidemic but also be important for possible future public health threats, and appropriate interventions for their correction should be developed and ready for the implementation.

Willingness to share contacts in case of COVID-19 positivity–predictors of collaboration resistance in a nation-wide Italian survey

Background The unwillingness to share contacts is one of the least explored aspects of the COVID-19 pandemic. Here we report the factors associated with resistance to collaborate on contact tracing, based on the results of a nation-wide survey conducted in Italy in January-March 2021. Methods and findings The repeated cross-sectional on-line survey was conducted among 7,513 respondents (mean age 45.7, 50.4% women) selected to represent the Italian adult population 18–70 years old. Two groups were defined based on the direct question response expressing (1) unwillingness or (2) willingness to share the names of individuals with whom respondents had contact. We selected 70% of participants (training data set) to produce several multivariable binomial generalized linear models and estimated the proportion of variation explained by the model by McFadden R2, and the model’s discriminatory ability by the index of concordance. Then, we have validated the regression models using the remaining 30% of respondents (testing data set), and identified the best performing model by removing the variables based on their impact on the Akaike information criterion and then evaluating the model predictive accuracy. We also performed a sensitivity analysis using principal component analysis. Overall, 5.5% of the respondents indicated that in case of positive SARS-CoV-2 test they would not share contacts. Of note, this percentage varied from 0.8% to 46.5% depending on the answers to other survey questions. From the 139 questions included in the multivariable analysis, the initial model proposed 20 independent factors that were reduced to the 6 factors with only modest changes in the model performance. The 6-variables model demonstrated good performance in the training (c-index 0.85 and McFadden R2 criteria 0.25) and in the testing data set (93.3% accuracy, AUC 0.78, sensitivity 30.4% and specificity 97.4%). The most influential factors related to unwillingness to share contacts were the lack of intention to perform the test in case of contact with a COVID-19 positive individual (OR 5.60, 95% CI 4.14 to 7.58, in a fully adjusted multivariable analysis), disagreement that the government should be allowed to force people into self-isolation (OR 1.79, 95% CI 1.12 to 2.84), disagreement with the national vaccination schedule (OR 2.63, 95% CI 1.86 to 3.69), not following to the preventive anti-COVID measures (OR 3.23, 95% CI 1.85 to 5.59), the absence of people in the immediate social environment who have been infected with COVID-19 (1.66, 95% CI 1.24 to 2.21), as well as difficulties in finding or understanding the information about the infection or related recommendations. A limitation of this study is the under-representation of persons not participating in internet-based surveys and some vulnerable groups like homeless people, persons with disabilities or migrants. Conclusions Our analysis revealed several groups that expressed unwillingness to collaborate on contact tracing. The identified patterns may play a principal role not only in the COVID-19 epidemic but also be important for possible future public health threats, and appropriate interventions for their correction should be developed and ready for the implementation.

Patient-Reported Symptoms and Sequelae 12 Months After COVID-19 in Hospitalized Adults: A Multicenter Long-Term Follow-Up Study.

Objective: Our knowledge on the long-term consequences of COVID-19 is still scarce despite the clinical relevance of persisting syndrome. The aim of this study was to analyze patient-reported outcomes, including assessment by specific questionnaires of health impairment and symptoms. Methods: This is a prospective, observational and multicenter cohort study coordinated by Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico di Milano and Istituto di Ricerche Farmacologiche Mario Negri IRCCS including eight hospitals located in North and Central Italy. A telephone interview to assess rehospitalization, access to health care resources, general health status subjective evaluation, and symptoms was performed at 12 months after the discharge in patients admitted to hospital because of COVID-19 from February 2020 to the end of May 2020. Results: Among the 776 patients discharged alive, 44 (5.7%) died, 456 subjects (58.8%) completed the questionnaire and 276 (35.6%) were not reachable or refused to join the telephone interview. The mean age of the study population was 59.4 years (SD 14.1), 69.8% of individuals needed oxygen support during hospitalization and 10.4% were admitted to ICU. Overall, 91.7% of participants reported at least one symptom/sequela at 12 months. Exertional dyspnea (71.7%), fatigue (54.6%), and gastrointestinal symptoms (32.8%) were the most reported ones. Health issues after discharge including hospitalization or access to emergency room were described by 19.4% of subjects. Female and presence of comorbidities were independent predictors of whealth impairment and presence of ≥2 symptoms/sequelae after 12 months from hospitalization for COVID-19. Conclusions: Patient-reported symptoms and sequelae, principally dyspnea and fatigue, are found in most individuals even 12 months from COVID-19 hospitalization. Long-term follow-up based on patient-centered outcome can contribute to plan tailored interventions.

Impact of the post-COVID-19 condition on health care after the first disease wave in Lombardy.

BACKGROUND: Lombardy was affected in the early months of 2020 by the SARS-CoV-2 pandemic with very high morbidity and mortality. The post-COVID-19 condition and related public health burden are scarcely known. SETTING AND DESIGN: Using the regional population administrative database including all the 48,932 individuals who survived COVID-19 and became polymerase-chain-reaction negative for SARS-CoV-2 by 31 May 2020, incident mortality, rehospitalizations, attendances to hospital emergency room, and outpatient medical visits were evaluated over a mid-term period of 6 months in 20,521 individuals managed at home, 26,016 hospitalized in medical wards, and 1611 in intensive care units (ICUs). These data were also evaluated in the corresponding period of 2019, when the region was not yet affected by the pandemic. Other indicators and proxies of the health-care burden related to the post-COVID condition were also evaluated. MAIN RESULTS: In individuals previously admitted to the ICU and medical wards, rehospitalizations, attendances to hospital emergency rooms, and out-patient medical visits were much more frequent in the 6-month period after SARS-CoV-2 negativization than in the same prepandemic period. Performances of spirometry increased more than 50-fold, chest CT scans 32-fold in ICU-admitted cases and 5.5-fold in non-ICU cases, and electrocardiography 5.6-fold in ICU cases and twofold in non-ICU cases. Use of drugs and biochemical tests increased in all cases. CONCLUSIONS: These results provide a real-life picture of the post-COVID condition and of its effects on the increased consumption of health-care resources, considered proxies of comorbidities.

Prognostic value of copeptin and mid-regional proadrenomedullin in COVID-19-hospitalized patients.

BACKGROUND: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality. METHODS: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC). RESULTS: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001). CONCLUSIONS: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.

COVID-19 mortality in Lombardy: the vulnerability of the oldest old and the resilience of male centenarians.

Italy was the first European nation to be affected by COVID-19. The biggest cluster of cases occurred in Lombardy, the most populous Italian region, and elderly men were the population hit in the hardest way. Besides its high infectivity, COVID-19 causes a severe cytokine storm and old people, especially those with comorbidities, appear to be the most vulnerable, presumably in connection to inflammaging. In centenarians inflammaging is much lower than predicted by their chronological age and females, presenting survival advantage in almost all centenarian populations, outnumber males, a phenomenon particularly evident in Northern Italy. Within this scenario, we wondered if: a) the COVID-19 mortality in centenarians was lower than that in people aged between 50 and 80 and b) the mortality from COVID-19 in nonagenarians and centenarians highlighted gender differences.We checked COVID-19-related vulnerability/mortality at the peak of infection (March 2020), using data on total deaths (i.e. not only confirmed COVID-19 cases). Our conclusion is that excess mortality increases steadily up to very old ages and at the same time men older than 90 years become relatively more resilient than age-matched females.