Report on the new coronavirus Covid-19 pandemic in Italy

Background Sars-CoV-2 is a coronavirus associated with human severe acute respiratory disease named Covid-19, �rst reported in China on December 2019. World Health Organization declared Covid-19 a pandemic on March 20, 2020. This report aims to outline the Italian outbreak characteristics. Italy, as one of �rst most affected area outside Asian continent, could give experiences to the other countries. Methods Data on positive cases and Covid-19 patients made available by Italian Health Authorities were reanalyzed and described. Results Up to April 18, 2020 Italy recorded 175,925 Sars-CoV-2 positive cases (10.68% among health care professionals) and 23,227 Covid-19 deaths. Covid-19 patients median age was 62 years. Male/female ratio was 1.00. Median time between symptoms and diagnosis was 6 days. Between hospitalized patients, the 10% needed intensive care. Median age at death was 80 years, with differences between sexes. Apparent lethality rate was 13.2%. At least one concomitant medical condition was present in 96.4% of patients who died. Discussion The number of Italian positive cases could be higher and the Italian lethality rate could be lower. The presence of asymptomatic people, known to be a vehicle for Covid-19 also for serious cases, could made slower the decrease of infection and distance the end of the novel coronavirus epidemic.

Background Sars-CoV-2 is a coronavirus associated with human severe acute respiratory disease named Covid-19, rst reported in China on December 2019.World Health Organization declared Covid-19 a pandemic on March 20, 2020.This report aims to outline the Italian outbreak characteristics.Italy, as one of rst most affected area outside Asian continent, could give experiences to the other countries.
Methods Data on positive cases and Covid-19 patients made available by Italian Health Authorities were reanalyzed and described.
Results Up to April 18, 2020 Italy recorded 175,925 Sars-CoV-2 positive cases (10.68% among health care professionals) and 23,227 Covid-19 deaths.Covid-19 patients median age was 62 years.Male/female ratio was 1.00.Median time between symptoms and diagnosis was 6 days.Between hospitalized patients, the 10% needed intensive care.Median age at death was 80 years, with differences between sexes.Apparent lethality rate was 13.2%.At least one concomitant medical condition was present in 96.4% of patients who died.
Discussion The number of Italian positive cases could be higher and the Italian lethality rate could be lower.The presence of asymptomatic people, known to be a vehicle for Covid-19 also for serious cases, could made slower the decrease of infection and distance the end of the novel coronavirus epidemic.

Background
Sars-CoV-2 is a coronavirus associated with human severe acute respiratory disease named Covid-19, rst reported in Wuhan, Hubei province in China on December 12, 2019 1 .Up to January 20, 2020, 282 con rmed cases of Covid-19 were reported from four countries including China (278 cases), Thailand (2 cases), Japan (1 case) and the Republic of Korea (1 case) 2 .Up to January 23, 2020, 581 cases were reported in Thailand, Japan, Hong Kong Special Administrative Region, Taipei Municipality, China, Macau Special Administrative Region, United States of America and the Republic of Korea.All these Covid-19 patients had travel history to Wuhan 2 .Up to January 27, 2020 globally 2,798 con rmed cases were reported for novel coronavirus and for the rst time Covid-19 cases were reported also in the European region (France rst and then in Germany) 2 .On January 31, 2020 when globally 9,826 cases of Covid-19 acute respiratory disease were con rmed, the rst two cases were reported in Italy; both had travel history to Wuhan City 2 .The rst Italian Covid-19 case due by local transmission, was reported on February 21, 2020, in Codogno, a city belonging to the province of Lodi, at the boundaries between the province of Lodi and the province of Cremona, in the region of Lombardia, in the North of Italy.In no time the number of Covid-19 cases increased considerably and Italy was soon the rst most suffering country outside the Asian continent.Covid-19 cases started to be reported also by other countries worldwide.The World Health Organization (WHO) on March 11, 2020 declared Covid-19 a pandemic, pointing to the over 118,000 cases of the coronavirus illness in over 110 countries and territories around the world and the sustained risk of further global spread 2 .As of March 11, South-East Asia, Europe, America, West Paci c, East Mediterranean, and African regions were affected by the spread of Covid-19 epidemic, for a total of 167 countries worldwide 2 .Up to March 17, 2020 more than two million (2,074,529) Sars-CoV-2 cases and 139,378 Covid-19 deaths were globally reported 2 .Worldwide level WHO risk assessment was classi ed as very high 2 .This report aims to pointed out data and patients characteristics from Italian epidemic.Italy, as one of the rst most affected regions could give experiences to other countries.

Methods
Data source.Italian data about Covid-19 were made available by Italian Health Authorities "Protezione Civile" and "Istituto Superiore di Sanità".In detail, "Protezione Civile" daily updated and made available online the number of tests made to evaluate the presence of Sars-CoV-2 infection, the number of Covid-19 positive cases, the numbers of hospitalized, intensive care and homecare Covid-19 patients and the number of Covid-19 deaths by region and overall in Italy 3 .Daily updated number of positive cases by provinces was made available as well 3 ."Istituto Superiore di Sanità" weekly updated and published online cases and deaths distribution by age and by sex, disease incubation time and descriptive statistics about patients who died (symptoms, comorbidities, treatment, hospitalization time and complications) 4 .Data analysis Cumulative data obtained from previously listed references were reanalyzed and described in this report.Lethality was calculated as the ratio between deaths and positive cases and cumulative incidence as the ratio between positive new cases and Italian inhabitants, according to last census 5 .For the observation time, crude and age standardized incidence rates were calculated as well 5,6 .STATA 15 (Texas, USA) was used as statistical analysis software.

Italian Covid-19 cases
Overall the number of Italian Sars-CoV-2 positive cases was increasing but the exponential phase, that mark out the rst epidemic phase of a virus infection, seemed de nitively distance from data.The grow factor, based on number of cases and not on virus reproduction number, was lower than 1 since March 20, 2020.Figure 1 shows the daily increase of new positive Covid-19 cases in Italy.Considering the daily increase, we should consider both the test's execution time and the number of swabs daily made.The number of Sars-CoV-2's RNA evaluation tests changed in time and increased from 2.07/1000 Italian inhabitants on March 15 (18.14% positive) to 8.40/1000 on March 31 (13.70% positive) and it was 18.51/1000 on April 15, 2020 (6.10% positive) 3,5 .It should be considered that available tests' number was swabs' number.Taking into consideration con rmation's and repeat's tests, it should be reasonable a number of people who were tested that was about the 70% of the swabs' number.
Up to April 18, 2020 according to o cial data, Italy recorded 175,925 Sars-CoV-2 positive cases, 10.68% among health care professionals 3,4 .The age and sex distribution of cases is reported in Table 1, incidence is reported as well.Median age was 62 years (0-100 range) 4 and overall male/female ratio was 1.00.The different behavior in more aged people was probably due to the higher number of women aged more than 90s (male female ratio equal to 0.37, according to last census 5 ).Between health care professional Covid-19 patients, median age at diagnosis was 48 years and male/female ratio was 0.47 4 .
From available literature the estimated mean incubation time of Covid-19 was 5.5 days and symptoms occurred by 11.5 days in the 97.5% of infected people 7 .Italy reported a median time between symptoms and diagnosis equal to 3 days for cases recorded on February 20-29 (1,614 cases analyzed), 5 days for cases recorded on March 1-10 (9,732 analyzed), 6 days for cases recorded on March 11-20 (27,679 analyzed) and 7 days for cases recorded between March 21 and April 9 (46,236 analyzed) 4 .
Overall 25.74% of positive cases were hospitalized 3 .During hospitalization patients were treated by antibiotics (84%), antivirals (56%) and corticosteroids (35%) 4 .The 19.6% of patients was concomitant treated with all of these medications 4 .On April 18, 2020 the 9.85% of all Covid-19 hospitalized patients received intensive care 3 .Detail on hospitalization status and number of patients who needed intensive care is reported in Figure 2.

Italian Covid-19 deaths
Up to April 18, 2020 according to o cial data, Italy recorded overall 23,227 Covid-19 deaths 3 .Considering the daily deaths increase, reported in Figure 2, we should also considered the disease progression time.
The age and sex distribution of patients who died is reported in Table 1 4 , lethality rate is reported as well.On April 18, 2020 Italian lethality rate was equal to 13.2%, 0.4% among health care professionals 3,4 .Overall lethality increased with age, especially in male patients.Median age at death was 80 years (range 0-100; IQR 73-86), with differences between sexes (83 for women and 79 for men) 4 .
Between who died, most common symptoms before hospitalization were fever (76.0%), dyspnea (72.0%), cough (38.0%) diarrhea (6.0%) and hemoptysis (1.0%) 4 .The 5.9% of patients did not experienced any symptom at hospital admission 4 .Median time between presence of symptoms and death was 10 days; between hospitalization and death 5 days, and was 4 days longer if patient was moved to intensive care unit 4 .
Most common complications that nally lead to patient's death were acute respiratory distress syndrome (96.7%), acute kidney injury (22.9%), superinfection (12.4%) and acute myocardial injury (9.5%) 4 .Figure 1.Positive Covid-19 cases, daily increase since February 24, 2020 (up to April 18, 2020) 3 ; as absolute number (N, continuous blue line, in dotted blue line its 6 days moving average) and as percentage (%, brown line).As reported by Italian Authorities in their newsletter, data were daily updated and we should considered a possible delay in data communication by regions due to a such high number of tests performed a day 4 3 .In this area the districts of Cremona, Lodi, Bergamo, Brescia and Milano were the most affected cities and according to last o cial data, their cumulative incidence values were equal to 1,51%, 1.18%, 0.95%, 0.93% and 0.48% respectively 3,5 .
Codogno and the around area, for a total of 10 municipalities in the province of Lodi, at the boundary of the province of Cremona (Codogno, Castiglione d'Adda, Casalpusterlengo, Fombio, Maleo, Somaglia, Bertonico, Terranova dei Passerini, Castelgerundo and San Fiorano), were quarantined and de ned "red zone" since February 23, 2020 8 .Up to March 5, 2020 this area reached 5,830 laboratory-con rmed Sars-CoV-2 cases 3 .As reported, the quarantine strategy pointed out a valid approach to slowdown the spread of the infection and no positive new cases were recorded on March 10, 2020 in Codogno, where the 99.94% of inhabitants followed the restriction policies 9 .
Due to the increase of cases outside this area, Lombardia and all Italy, was quarantined from March 8, 2020 and a strengthening of restriction policies was made on March 20, 2020 8 .Increase of cases across the most affected cities in Lombardia is reported in Figure 3; Italy compared to Lombardia is reported as well (Figure 4).The effects of restriction policies should considered also disease incubation time.From o cial data 3 , the apparent Covid-19 lethality rate seemed to be higher than in other most affected countries, as China for example.This was probably due to two main consideration: the high rate of old people in Italy and the Italian recommendations to evaluate a positive case.About rst consideration, data could be analyzed using standardized rates, but a longer observation time and shared guidelines among countries should be needed to take advantage from a such type of epidemiological indicator in a scenario of virus infection.About second observation, according to the decree of February 25, 2020 (updated on April 3, 2020 12 ) in Italy the presence of viral RNA was evaluated in very suspected Covid-19, symptomatic ILI (In uenza-Like Illness) and SARI (Severe Acute Respiratory Infections) cases 13 , not considering the asymptomatic cases.This observation was important for the estimation of the number of Sars-CoV-2 positive subjects and so for the lethality attributed to Covid-19 in Italy.The epidemiological study, unique in Italy, set up in Vo' Euganeo, the city that recorded the rst Covid-19 case in Veneto (the most affected Italian region, after Lombardia and Emilia Romagna); showed the presence of asymptomatic people.All inhabitants of Vo' Euganeo at the beginning of Covid-19 epidemic, between February 29 and March 5, Page 6/11 2020, were test for the presence of Sars-CoV-2's RNA.Seventy/2,778 subjects were positive, 14/70 subjects were hospitalized and 1/14 died 14 .We would have seen for Vo' Euganeo, as positive people 14 symptomatic cases and considering the one death that occurred in Vo' Euganeo, the rst Covid-19 death that occurred in Italy; as lethality rate 1/14 (7.1%) rather than the rate 1/70 (1.4%).It could be reasonable that the number of Italian positive cases could be higher and the Italian lethality rate could be lower.On the other hand, some deaths could been not considered, especially among old people who died at home or at elderly residences without the awareness of their Sars-CoV-2 status, as locally reported.Overall Italy counts 3,420 elderly residences (19.8% in Lombardia) 15 .On April 14, 1,082/3,420 elderly residences answered the survey conducted by Italian health authority "Isituto Superiore di Sanità" 15 16 .In the last week of February (all causes) deaths increase was higher than 20% in Lodi again (+117.1%),Bergamo (+30.6%) and Cremona (+22.1%) 16.In last week of February there was an increase of (all causes) deaths also for other two provinces in Lombardia, Pavia (+38.8%), and Como (+38.1%) 16.
Overestimating deaths (hypothesis of deaths increase entirely due to Covid-19), and considering 2.3% as a more plausible value of lethality

Conclusion
Since the Covid-19 outbreak began, Italy made many efforts: quarantine and national restrictive policies, new healthcare professionals hiring and fast building of new camp hospitals and intensive care units; in a fast race against time and virus.Even if slower, the increase of Covid-19 did not stop and restriction policies, that prevented both much further deaths and the spread of infection in Central and South Italy; could be not su cient.Asymptomatic subjects, people without information about their positive status and without symptoms, could be themselves unaware vehicles for Covid-19, also for serious cases 17 .They could made slower the decrease of infection and distance the end of the novel coronavirus epidemic.Italy really never stopped and two months later the detection of the rst local Covid-19 case, the Italian government was planning the economic recovery.Many new kits to make faster the evaluation of the presence of virus's RNA in the blood, or make possible the evaluation of immunoglobulins against Sars-CoV-2 or digital tools for contact tracing were or are under validation; and the e ciently organization of district medicine to plan a "Phase 2 of epidemic" that will have to be safe and clever to restart the economy without restart the epidemic.In the meantime new hopes arose from experimental trials with past and new drugs 18 , in a worldwide war against a such challenging submicroscopic nonliving molecule named Sars-CoV-2.

Figure 4 .
Figure 4. Cumulative Sars-CoV-2 cases, by day in Lombardia and overall in Italy since February 24, 2020 (up to April 18, 2020) 3 .Positive Sars-CoV-2 cases (dark lines) and hospitalized Covid-19 patients (light lines) in Italy (without cases recorded in Lombardia, blue lines) and in Lombardia (red lines) on a semilogarithmic scale.Legend: "Positive cases" includes both hospitalized and homecare Covid-19 patients; "Hospitalized" includes patients admitted to all hospital wards.

1 Positive
Figures

Figure 2 Distribution
Figure 2

Table 1 .
4 We should also considered the execution time of test needed to evaluate the presence of virus's RNA.Positive cases diagnosed and number of deaths recorded overall, by age and by sex since February 21, 2020 (up to April 16, 2020); information about sex was missing in 380 cases4.Number of Italian inhabitants available at last census 5 was used to calculate cumulative incidence and crude Figure2.Distribution of Covid-19 Italian cases by hospitalization status and exitus since February 24, 2020 (up to April 18, 2020)3.Homecare Covid-19 patients, recovered cases or cases still positive that were dismissed from hospital are not included in this graph.As reported by Italian Authorities in their newsletter the number of deaths were deaths occurred in patients who tested positive for Sars-CoV-2's RNA, independently from pre-existing diseases4.
rate.Eurostat 2013 standard population 6 was used to calculate age standardized rate.Legend: "Unk" is for unknown, "Cum Inc" is for cumulative incidence, "Crude Inc Rate" is for crude incidence rate; "Age Std Inc Rate" is for age standardized incidence rate.Both incidence rates are monthly incidence rate for the observation time period, x100,000); "M" was for male ,"F" female.Focus on Lombardia, the region where the Italian Covid-19 outbreak beganItaly is organized in 19 regions and 2 autonomous provinces and the most affected Italian area was the region of Lombardia, in the North of Italy.Up to April 18, 2020 Lombardia recorded 65,381 Covid-19 cases (37.2% of all cases), and 12,050 related deaths (51.9% of all deaths) 15According to the survey's report, between February 1 and April 14, 6,773 deaths occurred (49.7% between March 16 and March 31, 45.0% in Lombardia): 364/6,773 were o cially positive Covid-19 deaths and 2,360/6,773 were people who died because of u like symptoms15.In the January 1, 2020 and according to ISTAT mortality data (all causes deaths) released on April 17, in Lombardia the weekly deaths increase was over than 20% same week in previous years (mean 2015-2019) since the 3 rd week of February only in the province of Lodi (+23.0%) 1; in Lombardia the number of positive people could be higher than o cial data, reaching in the most affected cities a cumulative incidence value about 20%, even greater for a lesser lethality rate.We should however considered that available data are temporary data and available knowledge on Covid-19 is temporary knowledge.Globally, on April 18, 2020 Sars-CoV-2 is a relatively new coronavirus and Covid-19 is a relatively new disease.Data should be reanalyzed when new knowledge will be available, before delineate a strong hypothesis about more reasonable number of positives Sars-CoV-2 cases and Covid-19 deaths and evaluate differences between countries.