Excess Total Mortality in Italy: An Update to February 2023 with Focus on Working Ages.

BACKGROUND: Italy had a persistent excess of total mortality up to July 2022. This study provides updated estimates of excess mortality in Italy until February 2023. METHODS: Mortality and population data from 2011 to 2019 were used to estimate the number of expected deaths during the pandemic. Expected deaths were obtained using over-dispersed Poisson regression models, fitted separately for men and women, including calendar year, age group, and a smoothed function of the day of the year as predictors. The excess deaths were then obtained by calculating the difference between observed and expected deaths and were computed at all ages and working ages (25-64 years). RESULTS: We estimated 26,647 excess deaths for all ages and 1248 for working ages from August to December 2022, resulting in a percent excess mortality of 10.2% and 4.7%, respectively. No excess mortality was detected in January and February 2023. CONCLUSIONS: Our study indicates substantial excess mortality beyond those directly attributed to COVID-19 during the BA.4 and BA.5 Omicron wave in the latter half of 2022. This excess could be attributed to additional factors, such as the heatwave during the summer of 2022 and the early onset of the influenza season.

Bronchoscopy in the post-acute phase of COVID-19: an observational study.

BACKGROUND: Bronchoscopy is a useful technique adopted in the management of patients with COVID-19. 10-40% of COVID-19 survivors experience persistent symptoms. A comprehensive description of the utility and safety of bronchoscopy in the management of patients with COVID-19 sequelae is lacking. The aim of the study was to evaluate the role of bronchoscopy in patients with suspected post-acute sequelae of COVID-19. METHODS: An observational, retrospective study was carried out in Italy. Patients requiring bronchoscopy for suspected COVID-19 sequelae were enrolled. RESULTS: 45 (21, 46.7%, female) patients were recruited. Bronchoscopy was more frequently indicated for patients with a previous critical disease. The most frequent indications were tracheal complications, mostly performed in patients who were hospitalized during the acute phase than treated at home (14, 48.3% VS. 1, 6.3%; p-value: 0.007) and persistent parenchymal infiltrates, more frequent in those treated at home (9, 56.3% VS. 5, 17.2%; p-value: 0.008). 3 (6.6%) patients after the first bronchoscopy required higher oxygen flow. Four patients were diagnosed with lung cancer. CONCLUSION: Bronchoscopy is a useful and safe technique in patients with suspected post-acute sequelae of COVID-19. The severity of acute disease plays a role in the rate and indications of bronchoscopy. Endoscopic procedures were mostly performed for tracheal complications in critical, hospitalized patients and for persistent lung parenchymal infiltrates in mild-moderate infections treated at home.

Excess mortality in Italy in 2020 by sex and age groups accounting for demographic changes and temporal trends in mortality.

BACKGROUND: Differences between total deaths registered during the Covid-19 pandemic and those registered in a previous reference period is a valid measure of the pandemic effect. However, this does not consider demographic changes and temporal trends in mortality. OBJECTIVE: To estimate the excess mortality in 2020 in Italy considering demographic changes and temporal trends in mortality. METHODS: We used daily mortality and population data for the 2011-2019 period to estimate the expected deaths in 2020. Expected deaths were estimated, separately by sex, through an over-dispersed Poisson regression model including calendar year and age group as covariates, a smooth function of the year's week, and the logarithm of the population as offset. The difference between observed and expected deaths was considered a measure of excess mortality. RESULTS: In 2020, 746,146 deaths occurred in Italy. We estimated an excess mortality of 90,725 deaths (95% CI: 86,503-94,914), which became 99,289 deaths after excluding January and February, when mortality was lower than expected. The excess was higher among men (49,422 deaths) than women (41,303 deaths) and it was mostly detected at ages ≥80 (60,224 deaths) and ages 65-79 (25,791 deaths), while among the population aged 25-49 and 50-64 we estimated an excess of 281 and 4764 deaths, respectively. CONCLUSIONS: After considering demographic changes and temporal improvement in mortality the excess deaths in 2020 still remains above 90,000 deaths. More important, considering these factors, the excess at ages <80 years is revised upwards, while the excess at older ages is revised downwards.

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS).

INTRODUCTION: Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking. METHODS: We conducted a multi-center, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. PRIMARY OUTCOME: reduction in 28-day mortality. SECONDARY OUTCOMES: mechanical ventilation-free days at 28 days, need for ICU referral, length of hospitalisation, need for tracheostomy, changes in PaO2:FiO2 ratio, C-reactive protein levels and WHO clinical progression scale at days 3, 7, and 14. RESULTS: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35[10.4%] versus 41[12.1%]; p=0.49), nor in the median mechanical ventilation-free days (23[14] versus 24[16]; p=0.49). ICU referral was necessary in 41[12.2%] versus 45[13.2%]; p=0.68 and tracheostomy in 8[2.4%] versus 9[2.6%]; p=0.82. Survivors in the methylprednisolone group required a longer median hospitalisation (15[11] versus 14[11] days; p=0.005) and experienced an improvement in C-reactive protein levels, but not in PaO2:FiO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified timepoints. CONCLUSION: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared to conventional dexamethasone in COVID-19 pneumonia.

Vitamin D in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients with non-invasive ventilation support.

BACKGROUND: Vitamin D (VitD) deficiency has been reported to be associated with respiratory tract infection. In this work we evaluated the concentration of VitD in COVID-19 patients experiencing acute respiratory infections of different levels of severity excluding those who underwent invasive respiratory support. METHODS: The levels of serum VitD and C-reactive protein (CRP) were analyzed in 118 consecutive hospitalized COVID-19 patients (74M, 44F), confirmed with rRT-PCR. Of these patients with ventilation support 52 (44.1%) received oxygen via nasal cannula, oxygen mask or an oxygen mask with a reservoir, 48 (40.7%) were on a continuous positive airway pressure device (CPAP) and 18 (15,3%) on non-invasive mechanical ventilation (NIMV). RESULTS: The median values (range) of VitD and of CRP were 15.1 ng/mL (1.3-73.3) and 14.2 mg/L (5.0-151.2), respectively. A negative correlation from VitD levels and those of CRP (correlation coefficient - 0.259: P=0.005) was observed. VitD levels in O2 support patients were significantly higher than in both CPAP and NIMV patients. No statistical differences were found for CRP levels (P=0.834) among the three type of oxygen support. Fewer patients with O2 support had VitD <30 ng/mL and <20 ng/mL than CPAP and NIMV patients. There were no relationships between VitD and the three classes of IgM (P=0.419) and of IgG (P=0.862) SARS-CoV-2 antibodies values. The behavior was the same for CRP. CONCLUSIONS: Our study shows that a significant proportion of COVID-19 patients have a VitD deficiency and that this condition is more frequent in CPAP and in NIMV patients.

Exploring the Role of Immune System and Inflammatory Cytokines in SARS-CoV-2 Induced Lung Disease: A Narrative Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 19 (COVID-19). COVID-19 can manifest with a heterogenous spectrum of disease severity, from mild upper airways infection to severe interstitial pneumonia and devastating acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection may induce an over activation of the immune system and the release of high concentrations of pro-inflammatory cytokines, leading to a "cytokine storm", a recognized pathogenetic mechanism in the genesis of SARS-CoV-2-induced lung disease. This overproduction of inflammatory cytokines has been recognized as a poor prognostic factor, since it can lead to disease progression, organ failure, ARDS and death. Moreover, the immune system shows dysregulated activity, particularly through activated macrophages and T-helper cells and in the co-occurrent exhaustion of lymphocytes. We carried out a non-systematic literature review aimed at providing an overview of the current knowledge on the pathologic mechanisms played by the immune system and the inflammation in the genesis of SARS-CoV-2-induced lung disease. An overview on potential treatments for this harmful condition and for contrasting the "cytokine storm" has also been presented. Finally, a look at the experimented experimental vaccines against SARS-CoV-2 has been included.

Acute Improvements of Oxygenation with Cpap and Clinical Outcomes in Severe COVID-19 Pneumonia: A Multicenter, Retrospective Study.

It is not known if the degrees of improvement in oxygenation obtained by CPAP can predict clinical outcomes in patients with COVID-19 pneumonia. This was a retrospective study conducted on patients with severe COVID-19 pneumonia treated with CPAP in three University hospitals in Milan, Italy, from March 2020 to March 2021. Arterial gas analysis was obtained before and 1 h after starting CPAP. CPAP failure included either death in the respiratory units while on CPAP or the need for intubation. Two hundred and eleven patients (mean age 64 years, 74% males) were included. Baseline median PaO2, PaO2/FiO2 ratio (P/F), and the alveolar-arterial (A-a) O2 gradient were 68 (57−83) mmHg, 129 (91−179) mmHg and 310 (177−559) mmHg, respectively. Forty-two (19.9%) patients died in the respiratory units and 51 (24.2%) were intubated. After starting CPAP, PaO2/FiO2 increased by 57 (12−113; p < 0.001) mmHg, and (A-a) O2 was reduced by 68 (−25−250; p < 0.001) mmHg. A substantial overlap of PaO2, P/F, and A-a gradient at baseline and during CPAP was observed in CPAP failures and successes; CPAP-associated improvements in oxygenation in both groups were similar. In conclusion, CPAP-associated improvements in oxygenation do not predict clinical outcomes in patients with severe COVID-19 pneumonia.

Updated estimates of excess total mortality in Italy during the circulation of the BA.2 and BA.4-5 Omicron variants: April-July 2022.

BACKGROUND: The impact of new lineages and sub-lineages of Omicron on total and excess mortality is largely unknown. This study aims to provide estimates of excess mortality during the circulation of the Omicron variant in Italy updated to July 2022. METHODS: Over-dispersed Poisson regression models, fitted separately for men and women, on 2011-2019 mortality data were used to estimate the expected number of deaths during the Covid-19 pandemic. The excess deaths were then obtained by the difference between observed and expected deaths and computed at all ages and at working ages (25-64 years). RESULTS: Between April and June 2022, we estimated 9,631 excess deaths (+6.3%) at all ages (4,400 in April, 3,369 in May, 1,862 in June) and 12,090 in July 2022 (+23.4%). At working ages, the excess was 763 (+4.9%) in April-June 2022 and 679 (+13.0%) in July 2022. CONCLUSIONS: Excess total mortality persisted during the circulation of different lineages and sub-lineages of the Omicron variant in Italy. This excess was not limited to the elderly population but involved also working age individuals, though the absolute number of deaths was small. The substantial excess found in July 2022 is, however, largely attributable to high temperatures. At the end of the year, this may translate into 30 to 35,000 excess deaths, i.e. over 5% excess mortality. This reversed the long-term trend toward increasing life expectancy, with the relative implications in social security and retirement schemes.

No excess mortality among working-age Italians during the Omicron wave of Covid-19.

BACKGROUND: This study provides updated estimates of the excess deaths in Italy with a focus on the working-age population. METHODS: Over-dispersed Poisson regression models, fitted on 2011-2019 mortality data, and including terms for age, calendar year and a smooth function of the week of the year, were used to estimate the expected number of deaths during the Covid-19 pandemic. The excess deaths were then obtained by the difference between observed and expected deaths and reported according to the pandemic periods defined by the predominant circulating variant of SARS-CoV-2. RESULTS: Around 170,700 excess deaths at all ages were estimated between March 2020 and March 2022 in Italy with most of the excess occurring during the pre-Delta and Delta period, and 2930 excess deaths (+2.5%) during the Omicron wave. The excesses among the working age population were: 10,425 deaths (+11.8%) during the pre-Delta period, 2460 (+9.4%) during the Delta wave, 283 (+2.2%) during the transition period to Delta. Mortality was lower than expected during the Omicron wave (-6.1%). CONCLUSIONS: Over the periods preceding the Omicron wave, Covid-19 caused around 12,800 excess deaths among individuals of working age, accounting for over 10% excess death. This excess was no longer observed during the Omicron wave.

Excess total mortality during the Covid-19 pandemic in Italy: updated estimates indicate persistent excess in recent months.

BACKGROUND: New releases of daily mortality data are available in Italy; the last containing data up to 31 January 2022. This study revises previous estimates of the excess mortality in Italy during the Covid-19 pandemic. METHODS: Excess mortality was estimated as the difference between the number of registered deaths and the expected deaths. Expected deaths in March-December 2020, January-December 2021 and January 2022 were estimated separately by sex, through an over-dispersed Poisson regression model using mortality and population data for the period 2011-2019. The models included terms for calendar year, age group, a smooth function of week of the year and the natural logarithm of the population as offset term. RESULTS: We estimated 99,334 excess deaths (+18.8%) between March and December 2020, 61,808 deaths (+9.5%) in 2021 and 4143 deaths (+6.1%) in January 2022. Over the whole pandemic period, 13,039 excess deaths (+10.2%) were estimated in the age group 25-64 years with most of the excess observed among men [10,025 deaths (+12.6%) among men and 3014 deaths (+6.3%) among women]. CONCLUSIONS: Up to 31 January 2022, over 165 thousand excess deaths were estimated in Italy, of these about 8% occurred among the working age population. Despite high vaccination uptake, excess mortality is still observed in recent months.

Real World Estimate of Vaccination Protection in Individuals Hospitalized for COVID-19.

Whether vaccination confers a protective effect against progression after hospital admission for COVID-19 remains to be elucidated. Observational study including all the patients admitted to San Paolo Hospital in Milan for COVID-19 in 2021. Previous vaccination was categorized as: none, one dose, full vaccination (two or three doses >14 days before symptoms onset). Data were collected at hospital admission, including demographic and clinical variables, age-unadjusted Charlson Comorbidity index (CCI). The highest intensity of ventilation during hospitalization was registered. The endpoints were in-hospital death (primary) and mechanical ventilation/death (secondary). Survival analysis was conducted by means of Kaplan-Meier curves and Cox regression models. Effect measure modification by age was formally tested. We included 956 patients: 151 (16%) fully vaccinated (18 also third dose), 62 (7%) one dose vaccinated, 743 (78%) unvaccinated. People fully vaccinated were older and suffering from more comorbidities than unvaccinated. By 28 days, the risk of death was of 35.9% (95%CI: 30.1-41.7) in unvaccinated, 41.5% (24.5-58.5) in one dose and 28.4% (18.2-38.5) in fully vaccinated (p = 0.63). After controlling for age, ethnicity, CCI and month of admission, fully vaccinated participants showed a risk reduction of 50% for both in-hospital death, AHR 0.50 (95%CI: 0.30-0.84) and for mechanical ventilation or death, AHR 0.49 (95%CI: 0.35-0.69) compared to unvaccinated, regardless of age (interaction p > 0.56). Fully vaccinated individuals in whom vaccine failed to keep them out of hospital, appeared to be protected against critical disease or death when compared to non-vaccinated. These data support universal COVID-19 vaccination.

One-year cognitive follow-up of COVID-19 hospitalized patients.

BACKGROUND AND PURPOSE: Cognitive dysfunction has been observed following recovery from COVID-19. To the best of our knowledge, however, no study has assessed the progression of cognitive impairment after 1 year. The aim was to assess cognitive functioning at 1 year from hospital discharge, and eventual associations with specific clinical variables. METHODS: Seventy-six patients (aged 22-74 years) who had been hospitalized for COVID-19 were recruited. Patients received neuropsychological assessments at 5 (n = 76) and 12 months (n = 53) from hospital discharge. RESULTS: Over half (63.2%) of the patients had deficits in at least one test at 5 months. Compared to the assessment at 5 months, verbal memory, attention and processing speed improved significantly after 1 year (all p < 0.05), whereas visuospatial memory did not (all p > 0.500). The most affected domains after 1 year were processing speed (28.3%) and long-term visuospatial (18.1%) and verbal (15.1%) memory. Lower PaO2 /FiO2 ratios in the acute phase were associated with worse verbal long-term memory (p = 0.029) and visuospatial learning (p = 0.041) at 5 months. Worse visuospatial long-term memory at 5 months was associated with hyposmia (p = 0.020) and dysgeusia (p = 0.037). CONCLUSION: Our study expands the results from previous studies showing that cognitive impairment can still be observed after 1 year. Patients with severe COVID-19 should receive periodic cognitive follow-up evaluations, as cognitive deficits in recovered patients could have social and occupational implications.

Excess total mortality in 2021 in Italy was about one third of that observed in 2020.

BACKGROUND: Italy was severely hit by the Covid-19 pandemic with an excess of around 90,000 total deaths in 2020. Comparable data in 2021 are needed for monitoring the effects of the interventions adopted to control its spread and reduce the burden. This study estimates the excess mortality in Italy in the first eight months of 2021, with a focus on the working age population. METHODS: Excess mortality was estimated as difference between the number of registered deaths and the expected deaths. Expected deaths in March-December 2020 and January-August 2021 were estimated separately by sex, through an over-dispersed Poisson regression model using mortality and population data for the period 2011-2019 (before the Covid-19 outbreak). The models included terms for calendar year, age group, a smooth function of week of the year and the natural logarithm of the population as offset term.  Results: In the first eight months of 2021, we estimated 34,599 excess deaths (+7.9% of the expected deaths), of these 3667 were among individuals of working age (25-64 years). In this age group, mortality was 8.2% higher than expected with higher excesses among men (2972 deaths, +10.7%) than women (695 deaths, +4.1%). CONCLUSIONS: The excess deaths in the first eight months of 2021 account for about one third of that registered in 2020. Current data indicate that around 5000 excess deaths are expected by the end of the year, leading to a total excess for 2021 of around 40 thousand deaths. Despite the absence of influenza in January-March 2021, a relevant excess was also observed among the working age population.

Feasibility and Clinical Outcomes of a Step Up Noninvasive Respiratory Support Strategy in Patients with Severe COVID-19 Pneumonia.

The best noninvasive respiratory strategy in patients with Coronavirus Disease 2019 (COVID-19) pneumonia is still discussed. We aimed at assessing the rate of endotracheal intubation (ETI) in patients treated with continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV) if CPAP failed. Secondary outcomes were in-hospital mortality and in-hospital length of stay (LOS). A retrospective, observational, multicenter study was conducted in intermediate-high dependency respiratory units of two Italian university hospitals. Consecutive patients with COVID-19 treated with CPAP were enrolled. Thoraco-abdominal asynchrony or hemodynamic instability led to ETI. Patients showing SpO2 ≤ 94%, respiratory rate ≥ 30 bpm or accessory muscle activation on CPAP received NIV. Respiratory distress and desaturation despite NIV eventually led to ETI. 156 patients were included. The overall rate of ETI was 30%, mortality 18% and median LOS 24 (17-32) days. Among patients that failed CPAP (n = 63), 28% were intubated, while the remaining 72% received NIV, of which 65% were intubated. Patients intubated after CPAP showed lower baseline PaO2/FiO2, lower lymphocyte counts and higher D-dimer values compared with patients intubated after CPAP + NIV. Mortality was 22% with CPAP + ETI, and 20% with CPAP + NIV + ETI. In the case of CPAP failure, a NIV trial appears feasible, does not deteriorate respiratory status and may reduce the need for ETI in COVID-19 patients.

Link between serum lipid signature and prognostic factors in COVID-19 patients.

Although the serum lipidome is markedly affected by COVID-19, two unresolved issues remain: how the severity of the disease affects the level and the composition of serum lipids and whether serum lipidome analysis may identify specific lipids impairment linked to the patients' outcome. Sera from 49 COVID-19 patients were analyzed by untargeted lipidomics. Patients were clustered according to: inflammation (C-reactive protein), hypoxia (Horowitz Index), coagulation state (D-dimer), kidney function (creatinine) and age. COVID-19 patients exhibited remarkable and distinctive dyslipidemia for each prognostic factor associated with reduced defense against oxidative stress. When patients were clustered by outcome (7 days), a peculiar lipidome signature was detected with an overall increase of 29 lipid species, including-among others-four ceramide and three sulfatide species, univocally related to this analysis. Considering the lipids that were affected by all the prognostic factors, we found one sphingomyelin related to inflammation and viral infection of the respiratory tract and two sphingomyelins, that are independently related to patients' age, and they appear as candidate biomarkers to monitor disease progression and severity. Although preliminary and needing validation, this report pioneers the translation of lipidome signatures to link the effects of five critical clinical prognostic factors with the patients' outcomes.