The epidemic curve, i.e. the graph showing the number of new cases of a disease as a function of time, is one of the most common forms of displaying the trend of a disease in a population. It and its shape provide valuable information about the course of an epidemic and can help answer important questions regarding the type of exposure, the route of spread of the disease, when exposure to the disease agent occurred, what the incubation period was, etc. [3] [4] [5] . Figure 1 shows the trend in the rate of SARS-COV-2 infections for the period February

2020-December 2021 in the Italian territory. The first phase of the epidemic was characterized by a highly localized transmission, thanks also to the preventive public health measures of “social distancing”, initially limited to some restricted areas and gradually extended to the whole of Italy since March 11, 2020 (“lockdown”). On the other hand, the second phase of the epidemic involves a longer period and a higher rate of positive people, reaching a significant decrease in June 2021. The phenomena resume sudden growth in the autumn months reaching an unprecedented peak in December 2021.

An important role in the case of a pandemic is played by the “Surveillance System”, whose purpose is to keep under control all the information necessary for public health, in order to decide the actions to control the problems that a disease may cause on the health of citizens. This is a crucial and delicate phase, the consequences of which have repercussions both on the mobilization of public health resources and on other public institutions and on the whole community.

Behind the social and economic crisis, the Italian National Health System (NHS) collapsed because of the exponential increase of hospitalized patients [6] [7] . It is quite evident, however, how the pandemic showed the limited economic resources made available by the NHS, which had to deal with the excessive burden placed on the shoulders of health workers (from doctors to nurses and other professional figures) in terms of working conditions [8] [9] . If we consider the data at the national level starting from February 2020 (Figure 1), we can clearly observe a trend of the epidemic based on four main peaks, in correspondence to the four pandemic waves. The first wave, unexpected and dramatic in many Italian realities, mostly affected Northern Italy and its intensity waned with the measures adopted to contain the epidemic and with the arrival of the summer period [10] . The second wave, which exploded at the end of September, had a considerably larger size and a national spread, arriving, in mid-December, with values that were slightly decreasing but returned to rise in January and February, remaining however higher than those reached in the first wave. The second wave was also biphasic, with a slight decrease in the first months of 2021 and then a new increase in the spring of 2021. During November and December 2021, there is an increase in positivity due to the Omicron variant. Figure 2 shows the trend of Intensive Care Unit (ICU) admissions in Italy during the four main pandemic waves. It shows the presence of spikes in ICU admissions at the start of the pandemic, then in autumn 2020 and spring 2021.

The trend of contagions has been monitored, especially by calculating the incidence and prevalence of cases, thanks to the data published daily by Civil Protection.

Among the factors that certainly influence the reading of numbers, so much higher than in the first wave, certainly include the spread of the epidemic throughout the Italian territory and the increased diagnostic capacity of the health service: in December 2021 values of over 1.5 million swabs per day were reached.

Figure 3 shows the trend of daily variations in the number of infected people (in brown) and in the number of swabs (in orange) performed in Italy in the period between February 2020 and December 2021; we emphasize that since January 2021 the molecular swabs have been added for SARS-COV-2 infection diagnosis.

The pandemic trend can also be reconstructed with the time series of patients in home isolation (Figure 4), patients admitted to ICU and hospitalized in Italy (Figure 5). These figures show that the number of patients in home isolation is significantly higher than those admitted to intensive care. The figures show that the number of patients in home isolation is significantly higher than those admitted to intensive care. Specifically, the comparison between the epidemic waves highlights that the first phase has seen the maximum peak of the number of patients hospitalized in intensive care, against a relatively small number of cases in home isolation. On the other hand, in the second wave an inversion of the trend of the curves was observed: although reaching very high values in hospitalizations, due to the national distribution of admissions, an increase in the values of home isolates is noted.

This trend is also observed in the third wave, which retraces the anterior phase of the pandemic. The period of spring 2021, turns out to be a pivotal point for the analysis of the fourth wave that we are still living. In fact, starting in January 2021, the mass vaccination campaign began, as well as restrictive measures for the community. From this moment on, in fact, we can observe a sudden decrease in admissions to ICUs and wards dedicated to COVID-19 patients. Only

with the arrival of the Omicron variant, we can speak of a real fourth wave. Admissions in ordinary hospitalization go up, even if halved compared to previous waves, but the number of positive patients in home isolation increases, a sign that, thanks to mass vaccination, hospitalization has been reduced.

The battle between Italian health workers and COVID-19 was characterized by moments of great criticality and resulted in a high number of infections and deaths [11] .

According to data reported by HHI, since the beginning of the pandemic, the infection of healthcare personnel is about 182,000. Figure 6 highlights that the rate of infection among health workers is in line with the increase of contagions of the entire population in all pandemic waves, although the highest percentage of deaths (40%) was recorded in the first pandemic wave and, precisely, in the interval March 2020-April 2020, a period in which health workers, faced with a completely unexpected event, found themselves unprepared and also suffered from the organization and management of protections, often following guidelines dictated by the WHO that were unclear and continuously changing.

On the other hand, the second pandemic wave was characterized by an increase in infections, which reached 25.3%, but also by a significant decrease in deaths (below 10%). These data highlight how the reshaping of healthcare management strategies has led to better preparation for the pandemic wave on the part of healthcare workers. The third and fourth wave, despite numbers of infections significantly higher than the first (only in the last weeks of December, the reports of health workers tested positive to COVID-19 are more than 15,000), have seen a complete cessation of deaths, all thanks to well-defined protocols against contagion and to vaccinations with “booster” dose. Growing fear of the possibility of contagion and illness marked, in a distinct way, the mind of

healthcare workers, showing a real challenge on their psychological and mental health impact [12] . This situation created many difficulties in balancing work, private and family life. For these reasons, the HHI has dictated some practical indications, drawn from the analysis of the literature, on the prevention of emotional stress in health workers [13] [14] .

We focused our attention on the mortality data, firstly analysing the Italian context and, then, comparing it with other foreign countries. In Figure 7 and Figure 8 we considered the total trend of deaths and deaths rates, respectively, recorded in Italy in the period ranged from February 2020 and December 2021 divided into the three geographical areas (as provided by ISTAT):

- NORTH (Lombardy, Piedmont, Liguria, Valle d’Aosta, Emilia Romagna, Friuli Venezia Giulia, Trento, Bolzano, Veneto);

- CENTER (Latium, Marche, Tuscany, Umbria);

- SOUTH (Abruzzo, Basilicata, Calabria, Campania, Molise, Puglia and the islands Sicily and Sardinia).

The North come out the most affected geographic extension, while the regions of Central and Southern Italy (although in the first pandemic wave they did not record a large incidence of mortality) since the fall of 2020 have totalled tens of thousands of deaths, due to the spread of the virus throughout the Peninsula.

As of December 31, 2021, the total number of deaths in Italy is 137,247 people.

In particular, analysing the curve in Figure 7, we can see that the epidemic diffusion during the first phase was characterized by an increase in deaths, mainly in the North of the country, with about 30 thousand deaths, against the few thousand that occurred in the Center and in the South. In the summer months,

the situation was rather uniform throughout the country, while a significant worsening occurred in the second pandemic wave. In the North, the curve of deaths continued to rise, while the scenario changed in the regions of the Center and the South; in the South, there were even more deaths than in the regions of the Center. The peak of deaths, as in the previous summer, has flattened out and this trend has continued even during the fall and winter of 2021 where, despite the impressive number of positive antigenic and molecular swabs, the number of victims caused by COVID-19 are, proportionally, very few. All this thanks to the vaccination campaign promoted by the spring of 2021 that has led Italy to be an example for other nations of the world. The analysis carried out on the three Italian macro-areas has highlighted how, in reference to the number of deaths and infected, each geographical area presents a different trend than the others. Subsequently, using the data provided by HHI and ISTAT, the COVID-19 mortality rate was calculated for the entire pandemic period. Figure 8 shows that, in all three macro-areas, the peak mortality rate reaches important numbers in the second wave, dating back to May 2020.

Focusing our attention on the data from the first pandemic wave , we can see that the North has much higher numbers of positive subjects and a higher percentage of deaths in relation to the number of infected compared to Central and Southern Italy. The Cox and Stuart test, applied to the trends of deaths recorded in the three Italian territorial divisions, allowed us to state that the trends are characterized by a significant increase (North P = 0.021; Center P = 0.035 and South P = 0.018). The comparison of proportions allowed to identify the presence of significant differences between the macro-areas; in Table 1 the results (difference, 95% confidence interval (C.I.) and p-value) show a significantly higher percentage of COVID-19 deaths in the North than in the other Italian areas (P < 0.001), while the Center and the South show similar conditions in relation to the examined variable (P = 0.222).

The same analysis was carried out for the percentage of deaths in the second pandemic wave (September 2020 and May 2021) in the three macro-areas. Italy showed a percentage decrease in the number of deaths rates (Figure 8). In particular, the application of Cox and Stuart test for trend provided the results: North P = 0.002; Center P = 0.008 and South P = 0.014 from which we can deduce that all decreases are statistically significant.

The results reported in Table 1 show that, in the second pandemic wave, the comparison of the death ratios significantly differs for all Italian geographical areas (P < 0.0001).

*95% CI: 95% Confidence Interval. In bold, statistically significant p-value.

The third wave, although characterised by a short period, represents the first real response to the mass vaccinations that, since the beginning of the year 2021, have involved the entire Italian territory. Specifically, the p-values obtained (P < 0.001) show a significantly higher percentage of COVID-19 deaths in the North than in the other Italian areas (Table 1). In fact, it is possible to observe that Central Italy maintains a lower percentage of deaths than the North (P < 0.0001) and the South (P < 0.0001); North and South show similar proportions in the third pandemic wave (P = 0.856). In the fourth wave that we are still experiencing, the trend of death rates is characterized by a decrease in all three Italian areas. Comparing the deaths ratio, we can note there were highly significant differences between North vs Center (P < 0.0001), between Center vs South (P < 0.0001) and, also, between North vs South (P = 0.0004).

In the world the pandemic has taken on uneven distribution values, especially in terms of the increase in deaths, temporally and geographically. Very high numbers have been recorded in both infections and deaths; the lethality rate still assumes high values, being the most indicative measure of a country’s ability to cure. The first wave, in Europe, mainly affected Italy and Spain, increasing deaths by 40% and 50%, respectively, in the first months of the pandemic. Specifically, analyzing some of the major European countries, we can highlight that, after a year since the start of the pandemic and different ways of dealing with the emergency from the social and health point of view, the rates of deaths and infections due to COVID-19 were still high and, unfortunately, destined to increase due to the manifestation of new variants of the virus.

This trend continues throughout the year 2021, showing a uniform growth in all the analyzed countries. As of December 31, 2021, Italy has more than 6,125,683 infected people and a total of 137,247 deaths, or 2.24%. Focusing our attention on some foreign countries, we specifically found that:

- Germany has 6,816,907 infections and a percentage of deaths on infected people of 1.59%, equal to 108,352 deaths;

- Spain has 5,534,520 infected persons and 1.60% of these infected persons have died (88,794 deaths);

- France has 8,582,736 infected and 125,533 deaths, equal to 1.46%;

- Belgium has 1,999,127 infected and 27,594 deaths, equal to 1.38%;

- Albania has 205,777 infections and 3166 deaths, equal to 1.53%;

- England has 11,361,387 infections and 147,218 deaths with a lethality rate of 1.30%;

- India has 34,746,838 infections and 477,554 deaths with a lethality rate of 1.37%;

- Iran has 6,170,979 infections and 131,083 deaths, equal to 2.12;

- USA counts 50,846,941 infected and 806,437 deaths, equal to 1.60%;

- Brazil has 617,803 deaths and 22,213,762 infected, with a rate of 2.78%.

Figure 9 and Figure10 show the trends of deaths recorded both in Italy and in the examined foreign countries. All trends show a more or less accentuated increase, the variation of which can be attributed to the different pandemic containment strategies implemented in the various nations. The application of z-test (Table 2) allows to highlight the existence of highly significant differences (P < 0.0001) between Italy and all the other States examined in this study. Specifically, Italy has a higher mortality rate than all the countries examined, with the exception of Brazil, with respect to which it has a significantly lower rate.