Premature Mortality Excess Rates Before and During the COVID-19 Pandemic: A Comparative Analysis Conducted in Bihor County, Romania

Background: Estimating the excess of premature deaths (before the age of 75 years) and Potential Years of Life Lost allows ranking causes of death as an expression of the burden of disease in a population. We statistically analysed the impact of the coronavirus disease 2019 (COVID-19) pandemic on excess premature mortality in the total population and specifically, by sexes, compared to the pre-pandemic period, through Potential Years of Life Lost. Material and method: In this retrospective descriptive observational study, we counted excess of premature mortality in the years 2020, 2021, and 2022 by cause of death (cardiovascular diseases, cancer, digestive diseases, injury, COVID-19, and other causes) and by sexes compared to the period average from 2017-2019, based on the deaths registered in Bihor County (48,948 people). Results: Premature deaths due to COVID-19 (1,745 people of both sexes) contributed 71.3% to excess mortality, the population being similar for both sexes (71.4% in men and 71.2% in women). The Potential Years of Life Lost/death due to COVID-19 was 11.84 years for both sexes (11.76 years in men and 12.02 years in women). Potential Years of Life Lost/all-cause heath was lower during the pandemic (13.42 years for both sexes, 14.06 years for men and 12.32 years for women) compared to the pre-pandemic period (14.6 years for both sexes, 15.1 years for men and 13.5 years for women). Conclusions: The excess of premature mortality and decreased Potential Years of Life Lost/death during the pandemic, shows an increase in the proportion of deaths at ages closer to the established limit for premature mortality (75 years) compared to the pre-pandemic period.


Introduction
Recent WHO (World Health Organisation) data on COVID-19 showed over 774,000,000 confirmed cases and more than 7,000,000 deaths worldwide [1].In Europe, this condition led to death in over 2,250,000 cases.The highest number of new deaths in March 2024 was reported by Russia, followed by the United Kingdom and Sweden [1].In Romania, the last data showed over 68,000 deaths due to COVID-19 from the beginning of the pandemic until the end of December 2022, with the total number of deaths being above 67,000.When COVID-19 infection coexists with pre-existing comorbidities such as hypertension, cardiovascular disease, diabetes, chronic kidney disease, malignancy, or immune-related disorders, the associated mortality rate tends to be higher [2][3][4].
Potential Years of Life Lost (PYLL) is a measurement tool for premature mortality.PYLL considers both the number of deaths and the age at which the deaths occur, and it takes into account an individual, a group of people, or a population who died prematurely, prior to a selected age limit [5].Potential Life Years Lost are considered an indicator that can be used in health planning and that allows for the causes of death to be ranked [5].PYLL effectiveness is attested by the latest studies which show premature mortality [6], related to COVID-19, making it the only tool that can be used for understanding the burden of this virus.
From the beginning of the pandemic until 31.12.2022, on Romania's territory, 3,312,085 cases of infection with SARS-CoV-2 were registered [7].In the same time interval, according to existing data on Bihor Country, 92,483 cases of infection with SARS-CoV-2 were diagnosed, the infection with COVID-19 being the main cause of death in 2,919 cases [8].
Given the existing studies in specialized literature demonstrating that COVID-19 infection, along with various comorbid conditions, correlates with higher mortality rates [2][3][4], we considered it essential to conduct this study to investigate whether these comorbidities also influence the potential differences in the PYLL between pre-pandemic and pandemic periods.Therefore, the present study aims to identify potential differences in PYLL (total, sexes, excess) between the pre-pandemic period (2017-2019) and the pandemic period (2020-2022) using the database from Bihor County (Romania).

Materials And Methods
The study conducted is a retrospective, descriptive, observational epidemiological one.Data were collected from The National Statistical Database, "The Statistical Death Form", with anonymized data, being approved by The Research Ethical Committee Decision, number CEFMF/03/31.01.2021.The database includes all deaths that occurred in a time interval between January 2017 and December 2022, registered in Bihor County, Romania.For each case, we gathered information on date of birth, date of death, age, sex, address (place of residence), place of death, causes of death, main cause of death, and secondary causes of death.The inclusion criterion was set up by the age limit, 75 years old being the upper limit, which was established after thorough searches, according to more public organizations (WHO, Organization for Economic Cooperation and Development (OECD) and the European Commission); deaths situated below this age were considered premature deaths; no lower limit was established.For fairness and equality, we set the age limit for which a death is considered premature at the age of 75.According to the OECD and the European Commission, life expectancy at birth in Romania in 2019 was 75.6 years, and in 2020, it decreased to 74.2 years [9].According to WHO/EURO, life expectancy at birth in Romania is 75.4 years (both sexes), 79.1 years for women and 71.8 years for men [10].
The literature cites several ways in which PYLL can be obtained.One possible way to obtain PYLL is based on life table norms for years of life lost, which is the number of years lost by an "average" person in a given population [11].Another way for obtaining PYLL is by calculating the difference between the potential life limit and the age at death of an individual, which results in the PYLL if the individual dies before the potential life limit [12].The sum of potential life years lost by all individuals in a community represents the total PYLL in that community (country, county, locality).When we take into consideration the calculation of PYLL, adjustments can be applied by excluding from the calculation, the cases with certain associated comorbidities [11,13] or even deaths that occurred before the age of 1 year.To ensure data comparability, "transparency in documenting the exact method used to calculate years of life lost (YLL)" [13] should be ensured despite all existing and identifiable limitations.
Statistical analysis was performed using Microsoft Excel.From each year's mortality database, deaths under 75 years of age were extracted in a separate spreadsheet.Two additional columns have been introduced in the spreadsheet with deaths occurring at age <75 years: cause groups according to the International Statistical Classification of Diseases and Related Health Problems (ICD)-10) [14] and potential life years lost per death.Starting from ICD-10, six groups of causes of death were used in the study: Diseases of the circulatory system (I00-I99), Cancer (C00-C-48), Diseases of the digestive system (K00-K93), Injuries (S00-T98), COVID-19 (U71-U72), other (all codes not included in other groups).
The calculation of PYLL performed by our study involved the following formula: PYLL = 75 -Age at death (in years) The sum of PYLL values for all deaths provided the annual PYLL.In order to calculate the overall PYLL and classify it according to sexes and specific causes of death groups, while also determining the total number of deaths and the average age within each cause of death group, the PivotTable function was utilized for each studied year.
The Gross Rate of PYLL (annual) was obtained by using the formula: (PYLL/Population under 75 years old)X 100.000 For age groups under 75 years, for each year studied, data was provided from The National Institute of Statistics in Romania [15,16].The main result of the study was to establish the excess PYLL during the pandemic period (2020-2022) compared to the pre-pandemic reference period (2017)(2018)(2019).Subtraction between PYLL by cause and sex in each pandemic year and PYLL in the reference period represented excess PYLL.

Results
In our study 48,948 people were included: 25,242 men and 23,700 women, with a sex ratio of 106.50 (men/women=1.065).Figure 1 displays the percentage of premature deaths related to the total deaths for each year examined in our study.We observed a higher incidence of premature deaths during the pandemic years, the highest value being recorded in 2021 followed by 2020 and 2022, compared to the pre-pandemic period (Figure 1).The total and sexes-specific number of deaths and PYLL by cause of death in the studied population are presented in Table 1.The excess of premature deaths in the period 2020-2022 in the population of Bihor Country (Table 1) was 2,448 deaths (of which 54.66% in men and 45.34% in women) which led to a total of 22,923 potential years of life loss (of which 59.63% in men and 40.37% in women).When analysing the excess by causes of death in both sexes compared to the reference period, a decrease in the number of deaths from cancer (-34%) and injuries (-26.5%) was found, while the PYLL for these two causes registered a decrease for cancer (-120.3%)and an increase for injuries (98.5%).COVID-19 was the cause of death in 1.745 people of both sexes and contributed 71.3% to excess mortality, the proportion being similar between sexes (71.4% in men and 71.2% in women).
PYLL/causes of death for each year of the pandemic and comparison with the mean baseline are shown in Table 6 and Figure 3 (both sexes), Figure 4 (men) and Figure 5 (women).Compared to the analysed period prior to the pandemic, during the pandemic, there was a decrease of approximately 1 year in PYLL/death by all causes.By group of causes in the case of PYLL/death, there was a decrease during the pandemic compared to the reference period in the case of cardiovascular diseases and cancer, but also an increase in the case of digestive diseases and injuries.7).In the pre-pandemic period, malignancies and digestive diseases occupied the second and third positions in terms of the number of deaths, while in terms of PYLL, malignancies remained the second leading cause of death, with injuries ranking in the third place in 2017 and 2018, and digestive diseases in 2019.During the pandemic, COVID-19 was the third leading cause of death in 2020 and 2021; however, in 2022, the last year of the pandemic, the ranking of the top three causes of death looked similar to that of the pre-pandemic years, with COVID-19 not included among the top three causes of death.

Discussion
The impact of COVID-19 on overall mortality is well-studied.The highest number of deaths due to COVID-19 was reported in 2021 [1].The use of PYLL to assess the impact of the COVID-19 pandemic on the population is described in the literature in numerous studies [5,8,11,[17][18][19].In a time interval situated between the beginning of the pandemic and the end of March, in Bulgaria the burden of the COVID-19 pandemic was quantified as "12.57, 12.02 and 12.51 years of life lost overall, for males, and for females, respectively, based on the PYLL metric" [8].In an international comparison made for the period between the beginning of the pandemic and August 2020, "the average PYLL per death was 8.7 years, with substantial variation ranging from 2.7 years in Australia to 19.3 PYLL in Ukraine" [5].For the whole year 2020, they have been identified as "countries with an average PYLL ≥13 are Estonia, Lithuania, Serbia, and Bulgaria, compared to values in the 7 to 9.5 years range for countries such as Switzerland, Sweden, and Belgium" [17].An Australian study comparing the 2009 H1N1 flu epidemic with the 2020 winter COVID-19 pandemic, shows that, although the crude death rate in-hospital was similar and due to the demographic differences of the affected patients, in-hospital deaths due to H1N1 influenza caused 11 times more PYLLs compared to COVID-19, in critically ill patients [18].Starting from the calculation of PYLL using age limits of 70, 75, and 80 years and comparisons between Italy, Germany, and the USA of the PYLL indicators for COVID-19, a study carried out in 2000 recommends setting the age limit at 80 years for calculating the impact of COVID-19 at the population level [19].The study carried out in Hungary, regarding a period from the beginning of the pandemic until May 12, 2021, "showed 10.5 years of life lost for each death" [11] for COVID-19 cases.
There are many studies quantifying excess mortality and PYLL by cause of death in the pandemic years of 2020 and 2021 [20][21][22].Globally, more than 20.500.000 years of life were lost because of COVID-19, this information being provided by a study developed on 81 countries in a time interval between 2015 and 2020 [23].Using data from the Swedish National Patient Register, one study [20] estimated the impact of the COVID-19 pandemic on age and gender-specific excess mortality and PYLL in Sweden for the year 2020 and the first five months of 2021 by comparison with relevant mortality data recorded between 2017-2019.
Another study, referring to the year 2020, estimates weekly excess of all-cause mortality in Norway and Sweden, Years of Life Lost (YLL) assigned to COVID-19 in Sweden, and the significance of the change in mortality [21].By measuring years of life lost (YLL) imputable to the pandemic, directly or indirectly, comparing mortality across geographic and socioeconomic groups, another study performed in England and Wales [12] showed that in the first COVID-19 pandemic year, strong socioeconomic and geographic inequalities came to become a reality and the most deprived areas reported the highest number of PYLL.To the best of our knowledge, no studies have been performed regarding the impact of COVID-19 on premature mortality and excess PYLL for the entire pandemic period (2020-2022).Data provided by our study regarding the entire pandemic period showed that only in Bihor County, Romania, 20,921 years of lives were lost because of COVID-19 disease.
According to a recent study (Williams G. et al, 2022) [24], Romania did not furnish information regarding sex distribution during the pandemic.The study we conducted provided information about this aspect, so in Bihor County, Romania, men were more affected compared to women by COVID-19, and PYLL in cases of males was higher compared with females.Despite the geographical limitation of our study to Bihor County, Romania, it provides high-quality data for future investigations.This is significant since, to the best of our knowledge, there exists no other demographic dataset that can provide substantial source of information on PYLL across both pre-pandemic and pandemic periods.

Limitations of the study
We acknowledge the limitations of using PYLL (setting the norm for which PYLL is equal to zero, recording deaths from a specific cause, interpreting results, focusing on deaths, and ignoring the quality of life), but most authors recommend using this indicator.Another limitation of this study could be the rectitude of cause of death coding.

Conclusions
The data obtained demonstrate that in the studied population (deaths from Bihor County, Romania) there was an excess of premature mortality during the pandemic (2020-2022) compared to the pre-pandemic period (2017-2019) and in the case of men the excess was higher in both number of deaths and PYLL compared to women.Much of the excess of premature mortality is attributed to COVID-19, even if throughout the analysed period, cardiovascular diseases represented the main cause of death.In the last year of the pandemic (2022) the hierarchy of causes of premature mortality was similar to the pre-pandemic years.When analysing PYLL/death by group causes, a decrease in cardiovascular diseases and malignancies was observed during the COVID-19 pandemic compared with a pre-pandemic period, but conversely, an increase was noted in digestive diseases and injuries.The excess of premature deaths in the pandemic period and the decrease in PYLL/death express a higher proportion of deaths at ages close to the defined cutoff of 75 years.Additional investigations will be conducted into PYLL and excess of premature mortality regarding the COVID-19 pandemic nationwide in Romania.

FIGURE 2 :
FIGURE 2: Gross rate of PYLL in the studied population PYLL: Potential Years of Life Lost

TABLE 1 : Excess of premature deaths and PYLL, total and by cause, compared with premature deaths and PYLL from 2017-2019, total and by gender
PYLL: Potential Years of Life Lost, NA: Data not available, n: number, %: percentage, CVD: Cardiovascular disease Premature mortality data leading to mean baseline for the years 2017-2019 are presented in Table2.The results obtained when calculating the PYLL indicators and the difference from the average baseline are presented in Table3(for the year 2020),Table4(for the year 2021) and Table5(for the year 2022).Causes of

TABLE 5 : Indicators of premature mortality in 2022 and the difference (excess) from the mean baseline in the studied population
PYLL: Potential Years of Life Lost, NA: Data not available, n: number, %: percentage, CVD: Cardiovascular disease, COVID-19: Coronavirus disease 2019