Lung damage in 
INTRODUCTION A century after the 1918–1920 influenza pandemic, the coronavirus disease 2019 (COVID‐19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) , has demonstrated the major impact of a viral illness on healthcare systems over a narrow time period. Understanding of SARS‐CoV‐2 infection has evolved since early 2020. The typical sequence of lung damage in severe SARS‐CoV‐2 infection starts with diffuse alveolar damage with the formation of hyaline membranes endothelial cell damage and, later progressing to a proliferative intermediate stage and finally resulting in fibrotic remodelling with impaired alveolar gas exchange. , , Vaccines have proven highly effective at preventing symptomatic disease in clinical trials and real‐world reports, , , and in reducing COVID‐19 mortality and hospitalizations. , However, knowledge gaps remain on the real contribution of SARS‐CoV‐2 infection on mortality and the effect of vaccination on containing the number of serious adverse events, including death. Available epidemiological studies assessing COVID‐19 mortality have primarily focused on early pandemic waves, leaving recent years relatively underexplored. The contribution of SARS‐CoV‐2 infection to death among patients deceased during index hospital admission and the potential role of vaccination in modulating the severity of COVID‐19‐induced lung injury have not been investigated in large and well‐characterized cohorts. Robust information on the pathological correlates of SARS‐CoV‐2 infection can be obtained almost exclusively from post‐mortem examination of patients. Over the last couple of years, we have investigated: (a) the hallmarks of advanced COVID‐19 pathology ; (b) the presence of myocardial injury and inflammation among patients deceased with severe SARS‐CoV‐2 infection ; and (c) the persistent SARS‐CoV‐2 infection in patients seemingly recovered from COVID‐19. Here, we present findings from post‐mortem analysis of hospitalized patients with COVID‐19 who died in the Province of Trieste (North East Italy), including (i) rates of in‐hospital mortality, (ii) contribution of COVID‐19 to death, (iii) histological extent of lung injury and (iv) impact of vaccination.   METHODS 2.1 Patients This was a single‐centre, prospective, observational analysis conducted at the Institute of Pathological Anatomy and Histology, Cattinara University Hospital of Trieste, Italy. Study population comprised consecutive in‐patients deceased at the University Hospitals in Trieste (Trieste, Italy) during the COVID‐19 pandemic (March 2020–December 2022) who had SARS‐CoV‐2 infection confirmed by real‐time polymerase chain‐reaction (RT‐PCR) tests on nasopharyngeal swab, and presented with symptoms and imaging data indicative of SARS‐CoV‐2‐related pneumonia. Clinical data, including age, gender, known comorbidities and therapies of patients hospitalized with evidence of COVID‐19 infection were collected. The final population included all patients referred for post‐mortem examination by all departments of the University Hospitals of Trieste (Trieste, Italy). Data on vaccination status, number of vaccine doses and type of vaccine were collected for a randomly selected sample of 508 patients. 2.2 Ethical approval This study was approved by the Joint Ethical Committee of the Regione Friuli Venezia Giulia, Italy (re. 0019072/P/GEN/ARCS). 2.3 Diagnostic PCR test Combined oropharyngeal and nasopharyngeal swabs were collected for RNA extraction, followed by SARS‐CoV‐2 genome quantitative real‐time PCR quantification using the Liferiver Novel Coronavirus (2019‐nCoV) Real Time Multiplex RT‐PCR Kit (#ZJ0010; Liferiver Bio‐Tech, San Diego, CA, USA). 2.4 Pathology Post‐mortem examination was conducted at the Institute of Pathological Anatomy and Histology, Cattinara University Hospital of Trieste, which is the only institute providing this service in the province of Trieste. Trieste has a long‐standing tradition of post‐mortem investigations and has achieved a remarkably high autopsy rate for over one century (around 60% of hospital deaths). For each case, full body autopsy was performed with deep characterization of all visceral organs. Post‐mortem evaluation was performed by the same pathologist (R.B.) and her team of expert technicians, minimizing operator‐dependent biases. The pathologist (R.B.) has performed approximately 800 autopsies/year (at least 100 acute respiratory distress syndromes [ARDS]/year) over the last 25 years. All procedures were performed by adequately trained operators in a negative pressure biosafety level 3 (BSL‐3) room. After identification of representative areas of tissue abnormalities at macroscopic examination, multiple samples were collected from each organ. At least 10 samples were collected from each lung for deep characterization of histopathological structural abnormalities. Samples were fixed in 10% buffered formalin for at least 50 h and then embedded in paraffin. One‐micron sections were processed for the following histological staining: haematoxylin–eosin, Azan Mallory, and Alcian Blue PAS (ABPAS). Images were acquired using a Leica DM2700 M light microscope. In each case, the histological presence and severity of lung injury was classified based on the ‘pneumonia severity score’ developed by our pathologist (R.B.) (Figure ): 0 = absence of inflammation; 1 = interstitial oedema, exudative alveolar damage; 2 = same as 1 plus mild alveolar epithelial exfoliative damage with mild interstitial or alveolar inflammation; 3 = marked interstitial, alveolar and perivascular inflammation; necrotic exfoliation of alveolar epithelium and vascular endothelium; reactive pneumocyte hyperplasia; presence of endoalveolar macrophages; microvascular damage; concomitant reduction in functional lung parenchyma, with stage II or III acute respiratory distress syndrome (ARDS); and possible bacterial or fungal superinfections. The predominant pattern of lung involvement was assessed in each histological slide, and the pneumonia severity score was assigned based on the average of the predominant patterns across all lung samples for each patient. 2.5 Contribution of COVID ‐19 to death Cases were carefully reviewed to assess the contribution of COVID‐19 infection to death. In all patients, hospital medical records were analysed for clinical assessment and presence and type of comorbidities. The cause of death was classified as: ‘caused by COVID‐19’, in the absence of any other relevant medical comorbidities; ‘COVID‐19‐related’ if other comorbidities were present, such as pulmonary or extra‐pulmonary diseases aggravated by impaired lung function due to COVID‐19 infection, and ‘associated with minor COVID‐19’, in the presence of mild lung injury (i.e. no histological features of pneumonia) which was considered as an accompanying feature not directly contributing to death. 2.6 Objectives The primary objective of the study was to determine the rate of in‐hospital mortality among patients with evidence of COVID‐19 infection on admission. The secondary objectives were to: (a) determine the contribution of COVID‐19 infection to death and (b) investigate the impact of vaccination on the presence and extent of lung injury on histological analysis status. 2.7 Statistical analysis Continuous variables were expressed as median with interquartile range (IQR) [25°; 75°] as data were not normally distributed according to the results of Kolmogorov–Smirnov test; categorical variables were expressed as absolute numbers and percentages. Differences between groups were evaluated using Mann–Whitney test for continuous variables, while chi‐squared ( χ 2 ) or Fisher's exact test was used for dichotomous variables. Univariable and multivariable binary logistic regression analysis was used to investigate parameters associated with death from COVID‐19. Each variable was first explored with univariable binary logistic regression analysis and those variables that were statistically significant predictors of outcome ( p value <.05) were entered into a multivariable model to determine which covariates were independently associated with death from COVID‐19. Possible collinearity among candidate predictors was assessed using variance inflation factors with threshold equal to 5. We defined a p < .05 as statistically significant. All statistical analyses were performed using IBM SPSS Statistics 24.0 package (New York, NY) statistical software version 20.   Patients This was a single‐centre, prospective, observational analysis conducted at the Institute of Pathological Anatomy and Histology, Cattinara University Hospital of Trieste, Italy. Study population comprised consecutive in‐patients deceased at the University Hospitals in Trieste (Trieste, Italy) during the COVID‐19 pandemic (March 2020–December 2022) who had SARS‐CoV‐2 infection confirmed by real‐time polymerase chain‐reaction (RT‐PCR) tests on nasopharyngeal swab, and presented with symptoms and imaging data indicative of SARS‐CoV‐2‐related pneumonia. Clinical data, including age, gender, known comorbidities and therapies of patients hospitalized with evidence of COVID‐19 infection were collected. The final population included all patients referred for post‐mortem examination by all departments of the University Hospitals of Trieste (Trieste, Italy). Data on vaccination status, number of vaccine doses and type of vaccine were collected for a randomly selected sample of 508 patients.   Ethical approval This study was approved by the Joint Ethical Committee of the Regione Friuli Venezia Giulia, Italy (re. 0019072/P/GEN/ARCS).   Diagnostic PCR test Combined oropharyngeal and nasopharyngeal swabs were collected for RNA extraction, followed by SARS‐CoV‐2 genome quantitative real‐time PCR quantification using the Liferiver Novel Coronavirus (2019‐nCoV) Real Time Multiplex RT‐PCR Kit (#ZJ0010; Liferiver Bio‐Tech, San Diego, CA, USA).   Pathology Post‐mortem examination was conducted at the Institute of Pathological Anatomy and Histology, Cattinara University Hospital of Trieste, which is the only institute providing this service in the province of Trieste. Trieste has a long‐standing tradition of post‐mortem investigations and has achieved a remarkably high autopsy rate for over one century (around 60% of hospital deaths). For each case, full body autopsy was performed with deep characterization of all visceral organs. Post‐mortem evaluation was performed by the same pathologist (R.B.) and her team of expert technicians, minimizing operator‐dependent biases. The pathologist (R.B.) has performed approximately 800 autopsies/year (at least 100 acute respiratory distress syndromes [ARDS]/year) over the last 25 years. All procedures were performed by adequately trained operators in a negative pressure biosafety level 3 (BSL‐3) room. After identification of representative areas of tissue abnormalities at macroscopic examination, multiple samples were collected from each organ. At least 10 samples were collected from each lung for deep characterization of histopathological structural abnormalities. Samples were fixed in 10% buffered formalin for at least 50 h and then embedded in paraffin. One‐micron sections were processed for the following histological staining: haematoxylin–eosin, Azan Mallory, and Alcian Blue PAS (ABPAS). Images were acquired using a Leica DM2700 M light microscope. In each case, the histological presence and severity of lung injury was classified based on the ‘pneumonia severity score’ developed by our pathologist (R.B.) (Figure ): 0 = absence of inflammation; 1 = interstitial oedema, exudative alveolar damage; 2 = same as 1 plus mild alveolar epithelial exfoliative damage with mild interstitial or alveolar inflammation; 3 = marked interstitial, alveolar and perivascular inflammation; necrotic exfoliation of alveolar epithelium and vascular endothelium; reactive pneumocyte hyperplasia; presence of endoalveolar macrophages; microvascular damage; concomitant reduction in functional lung parenchyma, with stage II or III acute respiratory distress syndrome (ARDS); and possible bacterial or fungal superinfections. The predominant pattern of lung involvement was assessed in each histological slide, and the pneumonia severity score was assigned based on the average of the predominant patterns across all lung samples for each patient.   Contribution of COVID ‐19 to death Cases were carefully reviewed to assess the contribution of COVID‐19 infection to death. In all patients, hospital medical records were analysed for clinical assessment and presence and type of comorbidities. The cause of death was classified as: ‘caused by COVID‐19’, in the absence of any other relevant medical comorbidities; ‘COVID‐19‐related’ if other comorbidities were present, such as pulmonary or extra‐pulmonary diseases aggravated by impaired lung function due to COVID‐19 infection, and ‘associated with minor COVID‐19’, in the presence of mild lung injury (i.e. no histological features of pneumonia) which was considered as an accompanying feature not directly contributing to death.   Objectives The primary objective of the study was to determine the rate of in‐hospital mortality among patients with evidence of COVID‐19 infection on admission. The secondary objectives were to: (a) determine the contribution of COVID‐19 infection to death and (b) investigate the impact of vaccination on the presence and extent of lung injury on histological analysis status.   Statistical analysis Continuous variables were expressed as median with interquartile range (IQR) [25°; 75°] as data were not normally distributed according to the results of Kolmogorov–Smirnov test; categorical variables were expressed as absolute numbers and percentages. Differences between groups were evaluated using Mann–Whitney test for continuous variables, while chi‐squared ( χ 2 ) or Fisher's exact test was used for dichotomous variables. Univariable and multivariable binary logistic regression analysis was used to investigate parameters associated with death from COVID‐19. Each variable was first explored with univariable binary logistic regression analysis and those variables that were statistically significant predictors of outcome ( p value <.05) were entered into a multivariable model to determine which covariates were independently associated with death from COVID‐19. Possible collinearity among candidate predictors was assessed using variance inflation factors with threshold equal to 5. We defined a p < .05 as statistically significant. All statistical analyses were performed using IBM SPSS Statistics 24.0 package (New York, NY) statistical software version 20.   RESULTS 3.1 Study population We identified 1235 patients with SARS‐CoV‐2 infection who died in the Cattinara and Maggiore University Hospitals of Trieste, Italy during the study period (318 patients in 2020, 532 patients in 2021, 385 patients in 2022). These patients accounted for 20% ( n = 318/1584) of all patients deceased in 2020, 29.8% ( n = 532/1788) in 2021 and 23.1% ( n = 385/1665) in 2022. Median age at death was 83 [77–89] years and increased over time, from 83 [77–89] years in 2020 to 86 [79–92] years in 2022. Women were 44% ( n = 544) of all patients and were older than men at the time of death: 86 [80–91] years in women versus 81 [75–87] years in men ( p < .001). Figure shows the distribution of in‐hospital mortality in patients with SARS‐CoV‐2 infection compared to the official data on global mortality during the pandemic from the Italian National Institute of Statistics (ISTAT) for the province of Trieste. A sudden increase in mortality was identified from November–December 2020 to March–April 2021 (first peak) and from December–January 2021 to January–February 2022 (second peak). The first peak lasted longer than the second peak, with a higher number of deaths. When analysing the shape of the distribution of death, there was a rapid decline in the months following the second peak. The in‐hospital mortality curve of SARS‐CoV‐2 patients in Trieste hospitals paralleled the overall mortality trend in the province's ISTAT registry. 3.2 Characterization of clinical profile and lung histology of COVID ‐19 patients Complete body autopsies were performed in 1038 cases, achieving a total post‐mortem examination coverage of 84% of all patients deceased with SARS‐CoV‐2 infection during the study period. Data of 508 cases randomly selected among the 1038 patients were reviewed for deep histological characterization: 122 autopsies for 2020, 234 for 2021 and 152 for 2022. Among the 508 patients, median age at death was 81 [74–88] years and 63.2% ( n = 321) were men. Major comorbidities were present in 92% ( n = 504) of patients. The most common types of comorbidities were cardiovascular (64.4%, n = 327), followed by lung disorders (26%, n = 132), cancer (18.1%, n = 92), neurological diseases (17.3%, n = 88), kidney disease (14.6%, n = 74), autoimmune disorders (14.4%, n = 673), infectious disease (12.2%, n = 62), gastrointestinal disorders (9.8%, n = 50) and haematological conditions (4.3%, n = 122). The presence of ≥3 major comorbidities was found in 18.5% ( n = 94) of patients. Table and Figure show the presence and extent of lung tissue damage in the group of 508 patients. Histological analysis revealed absence of inflammation (pneumonia score = 0) in 10.4% ( n = 53) of cases (3.3% in 2020, 8.1% in 2021 and 19.7% in 2022), pneumonia score 1 in 12.2% ( n = 61) of cases (9.8% in 2020, 10.3% in 2021 and 17.1% in 2022), pneumonia score 2 in 32.1% ( n = 163) of cases (26.2% in 2020, 32.9% in 2021 and 35.5% in 2022), and pneumonia score 3 in 45.3% ( n = 231) of cases (60.7% in 2020, 48.7% in 2021 and 27.6% in 2022). Robust reproducibility among different operators for the assessment of the pneumonia score was confirmed with sensitivity analysis (kappa of .933, Table ). 3.3 Impact of comorbidities, vaccination and extent of lung injury on contribution of COVID to in‐hospital mortality The contribution of COVID‐19 to death is show in Table . Among the 508 cases, SARS‐CoV‐2 infection was (a) the cause of death in 90 patients, (b) contributing to death with other major comorbidities in 304 patients and (c) an accompanying feature leading only to a mild form of lung involvement (i.e. not significantly contributing to death) in 114 patients. There was a progressive reduction over time in the number of cases in which SARS‐CoV‐2 infection was the cause of death (23.8% in 2020, 20.9% in 2021 and 7.9% in 2022), and that was paralleled by a progressive increase in the number of cases in which SARS‐CoV‐2 infection was conferring only mild symptoms and not directly contributing to death. Univariable binary logistic regression analysis identified a number of parameters associated with death related to SARS‐CoV‐2 infection (Table ). On multivariable analysis, sex (male) (OR 2.80, p < .001), year of death (OR .38 for 2022, p = .003, model A), vaccination (any dose) (.20, p < .001, model B), cardiovascular disorders (OR 2.40, p = .001), autoimmune disorders (OR 14.1, p < .001) and lung disorders (OR 2.51, p = .003) were independently associated with death related to SARS‐CoV‐2 infection. For all the variables included in the multivariable Cox regression model, variable inflation factor was <3.5. Table shows the distribution of pneumonia score according to the vaccination status of the 508 patients. A total of 172 patients were vaccinated at least with two doses. All patients were vaccinated with Pfizer BioNTech (BNT162b2) COVID‐19 vaccine: 93% were triple‐vaccinated and 7% were double‐vaccinated. Compared to unvaccinated patients, the presence of pneumonia severity score 1 was greater (20.9% vs. 7.7%, p < .001) and that of pneumonia severity score 3 lower among vaccinated patients (26.2% vs. 55.1%, p < .001).   Study population We identified 1235 patients with SARS‐CoV‐2 infection who died in the Cattinara and Maggiore University Hospitals of Trieste, Italy during the study period (318 patients in 2020, 532 patients in 2021, 385 patients in 2022). These patients accounted for 20% ( n = 318/1584) of all patients deceased in 2020, 29.8% ( n = 532/1788) in 2021 and 23.1% ( n = 385/1665) in 2022. Median age at death was 83 [77–89] years and increased over time, from 83 [77–89] years in 2020 to 86 [79–92] years in 2022. Women were 44% ( n = 544) of all patients and were older than men at the time of death: 86 [80–91] years in women versus 81 [75–87] years in men ( p < .001). Figure shows the distribution of in‐hospital mortality in patients with SARS‐CoV‐2 infection compared to the official data on global mortality during the pandemic from the Italian National Institute of Statistics (ISTAT) for the province of Trieste. A sudden increase in mortality was identified from November–December 2020 to March–April 2021 (first peak) and from December–January 2021 to January–February 2022 (second peak). The first peak lasted longer than the second peak, with a higher number of deaths. When analysing the shape of the distribution of death, there was a rapid decline in the months following the second peak. The in‐hospital mortality curve of SARS‐CoV‐2 patients in Trieste hospitals paralleled the overall mortality trend in the province's ISTAT registry.   Characterization of clinical profile and lung histology of COVID ‐19 patients Complete body autopsies were performed in 1038 cases, achieving a total post‐mortem examination coverage of 84% of all patients deceased with SARS‐CoV‐2 infection during the study period. Data of 508 cases randomly selected among the 1038 patients were reviewed for deep histological characterization: 122 autopsies for 2020, 234 for 2021 and 152 for 2022. Among the 508 patients, median age at death was 81 [74–88] years and 63.2% ( n = 321) were men. Major comorbidities were present in 92% ( n = 504) of patients. The most common types of comorbidities were cardiovascular (64.4%, n = 327), followed by lung disorders (26%, n = 132), cancer (18.1%, n = 92), neurological diseases (17.3%, n = 88), kidney disease (14.6%, n = 74), autoimmune disorders (14.4%, n = 673), infectious disease (12.2%, n = 62), gastrointestinal disorders (9.8%, n = 50) and haematological conditions (4.3%, n = 122). The presence of ≥3 major comorbidities was found in 18.5% ( n = 94) of patients. Table and Figure show the presence and extent of lung tissue damage in the group of 508 patients. Histological analysis revealed absence of inflammation (pneumonia score = 0) in 10.4% ( n = 53) of cases (3.3% in 2020, 8.1% in 2021 and 19.7% in 2022), pneumonia score 1 in 12.2% ( n = 61) of cases (9.8% in 2020, 10.3% in 2021 and 17.1% in 2022), pneumonia score 2 in 32.1% ( n = 163) of cases (26.2% in 2020, 32.9% in 2021 and 35.5% in 2022), and pneumonia score 3 in 45.3% ( n = 231) of cases (60.7% in 2020, 48.7% in 2021 and 27.6% in 2022). Robust reproducibility among different operators for the assessment of the pneumonia score was confirmed with sensitivity analysis (kappa of .933, Table ).   Impact of comorbidities, vaccination and extent of lung injury on contribution of COVID to in‐hospital mortality The contribution of COVID‐19 to death is show in Table . Among the 508 cases, SARS‐CoV‐2 infection was (a) the cause of death in 90 patients, (b) contributing to death with other major comorbidities in 304 patients and (c) an accompanying feature leading only to a mild form of lung involvement (i.e. not significantly contributing to death) in 114 patients. There was a progressive reduction over time in the number of cases in which SARS‐CoV‐2 infection was the cause of death (23.8% in 2020, 20.9% in 2021 and 7.9% in 2022), and that was paralleled by a progressive increase in the number of cases in which SARS‐CoV‐2 infection was conferring only mild symptoms and not directly contributing to death. Univariable binary logistic regression analysis identified a number of parameters associated with death related to SARS‐CoV‐2 infection (Table ). On multivariable analysis, sex (male) (OR 2.80, p < .001), year of death (OR .38 for 2022, p = .003, model A), vaccination (any dose) (.20, p < .001, model B), cardiovascular disorders (OR 2.40, p = .001), autoimmune disorders (OR 14.1, p < .001) and lung disorders (OR 2.51, p = .003) were independently associated with death related to SARS‐CoV‐2 infection. For all the variables included in the multivariable Cox regression model, variable inflation factor was <3.5. Table shows the distribution of pneumonia score according to the vaccination status of the 508 patients. A total of 172 patients were vaccinated at least with two doses. All patients were vaccinated with Pfizer BioNTech (BNT162b2) COVID‐19 vaccine: 93% were triple‐vaccinated and 7% were double‐vaccinated. Compared to unvaccinated patients, the presence of pneumonia severity score 1 was greater (20.9% vs. 7.7%, p < .001) and that of pneumonia severity score 3 lower among vaccinated patients (26.2% vs. 55.1%, p < .001).   DISCUSSION In this study we analysed a large cohort of in‐patients with SARS‐CoV‐2 infection who deceased in the province of Trieste, all of whom were assessed by post‐mortem examination. The findings showed that: (i) the contribution of SARS‐CoV‐2 infection to in‐hospital mortality progressively declined over time from 23.8% in 2020 to 7.9% in 2022; (ii) vaccination status was independently associated with death related to SARS‐CoV‐2 infection after adjusting for other known predictors, and (iii) across the study period, 45.3% of patients had a pneumonia score 3 (i.e. severe lung injury); this percentage was higher among unvaccinated as opposed to vaccinated patients (55.1% vs. 26.2%, respectively). The trend of in‐hospital mortality among patients with SARS‐CoV‐2 infection in the province of Trieste progressively decreased over time and was similar to that of the Italian territory during the pandemic. These results are in line with a recent UK study analysing trends in absolute and relative COVID‐19‐related mortality risks between March 2020 and August 2022. That study demonstrated a substantial decrease in COVID‐19‐related deaths from 4.48 deaths during wave one (March–May 2020) to .67 death per 1000 person‐years during wave five (June–August 2022). Of note, the absolute COVID‐19‐related death rates did not decrease over time for people with lower vaccination coverage and impaired immune response. When comparing the mortality curves of the COVID‐19 pandemic to other great pandemics in the past such as the influenza pandemic between 1918 and 1920, it is noteworthy that COVID‐19 appears to have a lower case‐fatality rate. The mortality curve of the influenza pandemic had a normal distribution achieving the peak and then progressively decreasing, while the mortality curve of COVID‐19 pandemic achieved a peak followed by a plateau and an asymmetric descending branch. The flattening of the epidemiological curve is likely a consequence of multiple factors, including the adoption of restrictive lockdown measurements, use of personal protective equipment, rapid development and deployment of effective vaccines and administration of antiviral therapies for patients diagnosed with COVID‐19 at high risk of progressing to severe disease. The clinical phenotype of deceased in‐patients has changed over time. In this study cohort, patients deceased in 2020 and mid‐2021 were younger, had lower number of comorbidities and more severe lung injury due to SARS‐CoV‐2 infection compared to those deceased in 2022. The dynamic changes in clinical and pathological characteristics of in‐patients at death are largely associated to the adoption of these effective measures. Recent European data published by the World Health Organization reported a reduction in the risk of death due to SARS‐CoV‐2 infection by 57% following the start of the vaccination campaign back in December 2020. The most consistent reduction was observed among in the age range 60–69 (54% reduction), 70–79 (57% reduction), and over 80 years (62% reduction), representing ~1.4 million lives saved among all subjects aged 25 years or older. Under‐vaccination represents an emerging risk factor for severe COVID‐19 outcomes. A recent UK study reported a proportion of under‐vaccinated subjects ranging from 32.8% in Wales to 49.8% in Northern Ireland, with >7000 preventable hospitalizations and deaths. In the present study, vaccination status was an independent predictor of death related to SARS‐CoV‐2 infection, even after adjusting for other known predictor of death. In particular, being vaccinated was associated with a consistent reduction—around 80%—in the risk of death from SARS‐CoV‐2 infection. The impact of COVID‐19 vaccination in reducing mortality and morbidity rates worldwide is well established, but autopsies represent the gold standard in determining the cause of death after SARS‐CoV‐2 infection. In the present analysis, COVID‐19 was significantly less frequently the leading cause of death or a severe contributory factor to the fatal outcome in recent years as opposed to beginning of the pandemic. This is the first analysis to provide data on the association of vaccination status with the extent and severity of lung injury, with histological evidence of milder lung involvement in patients with SARS‐CoV‐2 infection following vaccination compared to the pre‐vaccination era. Noteworthy, these findings support the efficacy of vaccination not only in reducing mortality but also in mitigating severe lung injury, resulting in a reduction in the risk of developing chronic lung diseases, recurrent infections and end‐stage lung diseases requiring transplantation. This has important implications for public health strategies and vaccine advocacy. In‐patients deceased in 2020 were not vaccinated and exhibited a more severe lung injury on post‐mortem examination, consistent with pneumonia score 2 and 3. Following the development of effective vaccines and conduction of a nation‐wide vaccination campaign in Italy, the proportion of vaccinated patients substantially increased to 84.5% coverage of fully vaccinated population over 12 years old in November 2021. Of note, the study population deceased in 2022 mostly comprised vaccinated patients and demonstrated a substantially lower pneumonia severity score which argues strongly for a protective effect of COVID‐19 vaccination on SARS‐CoV‐2 infection in the lung. Beside vaccination, other factors have reasonably played a role for the improved outcomes including attenuation of viral pathogenicity, development of effective antiviral treatments with the ability of preventing severe disease, and different SARS‐CoV‐2 variants which may be associated with variable severity of lung involvement. In a recent autopsy study of 117 patients deceased with SARS‐CoV‐2 infection, the typical histological features of COVID‐19‐related lung injury were detected independently of the disease‐causing virus variant, albeit they were significantly less common and less severe among patients infected by omicron variants compared to other variants. In that series, the omicron variant was associated with a milder disease course and low lethality. Our results provide a further reason to perform COVID‐19 vaccination, especially among patients with multiple comorbidities, which is to reduce the extent and severity of lung damage in the event of SARS‐CoV‐2 infection. Future research with longitudinal studies to assess the long‐term impact of COVID‐19 vaccination on lung health and the significance of other organs affected by SARS‐CoV‐2 infection is required. The present data need to be interpreted within the limitations of the study. Full clinical characterization for the full cohort of 1235 in‐patients with SARS‐CoV‐2 infection was not available, partly due to the difficulties in collecting relevant data during the pandemic. Histological characterization of extent and severity of lung injury was performed in a randomly selected sample of 508 patients and was not available in the full cohort. The results of the study have not been externally validated, but inter‐operator variability for assessing the pneumonia severity score was low (Table ). Finally, cases for deep pathological assessment were randomly selected by the operator (R.B.) and no algorithm was employed for randomization. This might have introduced a selection bias.   CONCLUSION The contribution of SARS‐CoV‐2 infection to in‐hospital mortality has progressively declined over time, from 23.8% in 2020 to 7.9% in 2022. Vaccination status was an independent predictor of death related to SARS‐CoV‐2 infection after adjusting for other known independent predictor of adverse outcomes. COVID‐19 vaccination was associated with a lower pneumonia severity score at post‐mortem examination, suggesting that the benefits of vaccination extend beyond reduction of mortality rates. In the absence of histological data on the contribution of COVID‐19 to death, these data may inform on the impact of vaccination in mitigating lung damage induced by SARS‐CoV‐2.   R.B.: performed autopsies and histological analysis, study concept and design, data interpretation, review and editing final draft. A.P.: supervised the study, data interpretation, study concept and design, and drafted and edited the manuscript. M.P.: analysed histology. G.S.: supervised the study. A.I.: collected data. E.B.: collected data. F.Z.: analysed histology. M.G.: data evaluation. C.C.: data evaluation. G.B.: clinical data collection. A.T.: clinical data collection. F.S.: analysed histology; study concept and design, data interpretation. All authors approved the final version of the manuscript.   The authors declare no conflict of interest.   Data S1:   