key: cord-315970-m5o962yw
authors: Di Ciaula, Agostino; Palmieri, Vincenzo O.; Migliore, Giovanni; Portincasa, Piero
title: COVID‐19, internists and resilience: the north‐south Italy outbreak.
date: 2020-06-01
journal: Eur J Clin Invest
DOI: 10.1111/eci.13299
sha: 
doc_id: 315970
cord_uid: m5o962yw

According to data from the World Health Organization, Italy has been particularly affected by the ongoing COVID‐19 pandemic. On April 1(st) 2020, Italy gained, at a world level, the highest number of total confirmed cases (n=110,574) and deaths (n=13,155) since the beginning of the outbreak. The number of cases raised exponentially, reaching a total of 227,364 infected subjects and 32,330 deaths on May, 20. The distribution of infected subjects and deaths, however, was not homogeneous, being respectively about 7‐times and 12‐times higher in northern‐ than in southern regions

According to data from the World Health Organization, Italy has been particularly affected by the ongoing COVID-19 pandemic. On April 1 st 2020, Italy gained, at a world level, the highest number of total confirmed cases (n=110,574) and deaths (n=13,155) since the beginning of the outbreak [1] . The number of cases raised exponentially, reaching a total of 227,364 infected subjects and 32,330 deaths on May, 20. The distribution of infected subjects and deaths, however, was not homogeneous, being respectively about 7-times and 12-times higher in northern-than in southern regions [2] .

Besides monitoring the outbreak, epidemiologic data should be analyzed to test the adequacy of strategies adopted to contain the pandemic, to better face the rising cases of COVID-19 in other countries, and to use lessons from this pandemic for future possible outbreaks. From a clinical point of view, evidence points to a multi-organ involvement secondary to the SARS-CoV-2 infection [3] . In this rapidly changing and novel context, the role of the specialist in internal medicine represents a winning factor for optimal management of critically ill adults with suspected or diagnosed COVID-19. The role of the internist provides a precious support to specialists working in different settings, namely emergency room (ER), infective disease, respiratory, and intensive care units (ICU).

Here, we analyze the main phases of the COVID-19 outbreak in Italy. In addition, while discussing some pathophysiological implications of this complex disease, we briefly describe the events that we experienced -following the COVID-19 outbreak-at our academic division of internal medicine in the largest regional hospital of Apulia.

Epidemiologic data were searched from public available databases from the World Health Organization [4] , and the Italian Ministry of Health [5] . The rates of infected subjects and deaths in Italy (whole country and regional level) per 100,000 residents were calculated considering the official number of residents derived from the National Institute of Statistics (ISTAT).

Correlations were tested using the Pearson coefficient and plotted using linear regression. Data updated to May 20, 2020.

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The spread of the COVID-19 pandemic is not homogenous worldwide. Most rapid and extensive outbreak occurs in a few countries (i.e. USA, Italy, Spain, China, Germany, France, Iran) [4] . In Italy, the first cases of infection (a couple of Chinese tourists) occurred on January 30, 2020 at the Italian Experimental Institute "Lazzaro Spallanzani" in Rome. Figure 1 summarizes the daily progression in the cumulative number of COVID-19 positive subjects and in the incidence of deaths related to COVID-19 in southern and northern Italy, since the start of the outbreak. Table 1 lists the containment strategies adopted by the central Government. The spread of infection followed divergent trends between northern and southern Italy.

Since the average incubation period for COVID-19 is 5-6 days and, in its early stages, the epidemic double in size every 7.4 days [6] , the initial outcome of the country lockdown was expected by two-three weeks. As shown in Figure 2 , this hypothesis was confirmed by the analysis of the absolute daily number of new cases of infection in northern and southern Italy. 

A total of 33,883,040 subjects live in northern Italian regions. The first COVID-19 case in a northern region was noticed in Codogno, a small town in Lombardy, 60 km south-east from Milan. In Codogno a local quarantine started on February 23. After two weeks (March 8), the whole northern Italy was quarantined. On the national "lockdown" day (March 12), in northern Italy there was a total of 14,335 infected patients and 997 COVID-19 related deaths. On May 20, infected subjects were 200,768 and the number of deaths increased to 29,876.

A total of 26,476,506 subjects live in southern Italian regions. The first three cases in this area occurred only five days after the first case in northern Italy. However, on the "lockdown" day, the total number of infected patients was 778, about 18-fold lower than in northern Italy. The COVID-19 related deaths were 19, about 52-folds lower than in northern Italian regions. On May 20, infected subjects were 26,596 and COVID-19 related deaths were 2,454, about 7-and 12-fold lower, respectively, than in northern Italy.

In most southern regions, travelers were obliged to inform the local authorities upon their arrival to track possible newly diagnosed infections. Thus, before the whole country was on lockdown, Accepted Article the containment measures in southern Italy were only on a voluntary basis (i.e., social isolation was advised).

In Apulia (southern Italy, about 4 million inhabitants), the regional authorities estimated that at least 16,545 subjects travelled from northern Italy from February 29 to March 14. In this region, the incidence of infected subjects increased from 0.1 (February 29) to 109.4 per 100,000 residents (May 20) being, on the same day, slightly higher than the rate observed in southern Italy (100.5 per 100,000 residents). This value, however, remained about 6-fold lower than the incidence recorded in northern Italy (i.e., 592.5 per 100,000 residents). On May 20, a total of 4,407 confirmed cases and 478 COVID-19 related deaths were recorded in Apulia [7] . The median age of infected subjects was 56 years, and about 80% of deaths were recorded in subjects with 70 or more years of age. At a regional level, a total of 1,535 patients were isolated at home, and 25% of cases were admitted in COVID-19 dedicated hospitals [7] . Of note, only a minority of patients had a severe (16%) or critical (3%) clinical presentation [7] . The majority of patients remained asymptomatic (37%) or had a non-critical clinical presentation (44%) requiring, after an initial triage, home isolation or clinical management in non-intensive care units.

Following the COVID-19 outbreak, the local Apulian government firstly increased the number of available beds in the units of intensive care, pneumology, and infectious diseases across the Region. Afterwards, the local health care system was re-modulated by creating "COVID-19" and "non-COVID-19" dedicated hospitals. The Policlinico, the second largest Hospital in southern Italy, hosts about 1,550 beds, with all medical specialties. It is the main hospital in Bari (capital city of Apulia), with a population of 320,257 inhabitants, raising to 750,000 inhabitants in the urban area and to 1.3 million inhabitants in the metropolitan area. Before the outbreak, the Clinica Medica "A. Murri" was a typical academic division of Internal Medicine in the tertiary referral hospital (i.e., 20 beds with 800 admissions/year, 800 day services/year, and 6,000 outpatients, including an active ultrasound service). All non-urgent outpatient activities, however, had been 

This article is protected by copyright. All rights reserved hours, the medical and paramedical staff from both divisions (including residents in Geriatrics and Internal Medicine) were properly trained in the correct use of personal protection devices. The staff was therefore re-located in the so-called "grey zone" equipped with up to 64 beds, occupying the whole 5th floor of the "Asclepios" block, a 5-floor building entirely dedicated to COVID-19 patients (Figure 4) . As internists, our specific mandate was the screening of a wide range of (noncritical, non-surgical) patients received from the ER, and suspected of having COVID-19

infection. The division was quickly arranged to accommodate COVID-19 positive, negative or suspected subjects, with clear separate pathways (dedicated rooms, corridors, elevators, doors, routes). After admission, patients not requiring ICU support are assessed and immediately transferred to a room with single bed, where they undergo the nasopharyngeal swab to obtain a specimen for testing by RT-PCR. If negative, a second test is repeated 24h later, at the local laboratory of public health [8] . Confirmed negative patients are either transferred to specific COVID-19 negative wards or discharged, with a nasopharyngeal swab repeated (outpatient basis) 2 weeks later. Persistently positive patients are managed accordingly. One option is the transfer to other COVID-19 positive wards in the "Asclepios" block, depending on the clinical evolution. A second option is the transfer to post-acute facilities in the territory. A third option (if asymptomatic), is to be placed in quarantine at home, after being full instructed about isolation requirements. Two weeks later, a special hospital unit will perform two nasopharyngeal swabs at home, with intervals of 24 hours. This organization facilitates the initial management of non-COVID-19 and COVID-19-related clinical presentations, while decreasing the burden of patients entering other COVID-19 dedicated wards. On April 24, a total of 330 patients had already been screened at our unit.

COVID-19 infection may remain asymptomatic [9] in a still undefined number of patients.

Otherwise, a 3-stage classification system of increasing severity has been proposed for COVID-19 infection, namely stage I (early infection), stage II (pulmonary phase), and stage III (hyperinflammation phase) [10] . Thus, the clinical symptoms range from fever, dry cough, headache to dyspnea, fatigue, to ARDS, shock, and cardiac failure [10, 11] . The multi-organ involvement secondary to SARS-CoV2 infection is therefore a possibility.

Gastrointestinal symptoms (i.e. diarrhea, nausea, vomiting, and abdominal pain) may be observed early [12, 13] . About half of patients show elevation of liver tests, ALT, AST and GGT during

This article is protected by copyright. All rights reserved disease progression, and liver injury is possible in severe cases of COVID-19, possibly due to a direct viral infection of vascular endothelium, cholangiocytes, to immune-mediated inflammation or to drug hepatotoxicity [14] . Diabetes mellitus can increase the risk linked with COVID-19 infection, negatively affecting the progression and prognosis of the disease [15, 16] . Furthermore, relationships exist between COVID-19 and myocardial injury [17] , heart failure [17] , vascular inflammation, myocarditis, cardiac arrhythmias [18] , and hypoxic encephalopathy [19] . (ii) Extra-pulmonary systemic hyperinflammation syndrome (in the minority of infected patients):

the "cytokine storm" is associated with increased cytokine levels (IL-2, IL-6, IL-7, IL-10 and TNFα), granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, tumour necrosis factor-α, lymphopenia (in CD4+ and CD8+ T cells), decreased IFNγ expression in CD4+ T cells [23] [24] [25] .

D-dimer , Troponin and N-terminal pro B-type natriuretic peptide (NT-proBNP) can also increase, together with altered coagulation function [26] [27] [28] in those patients with more severe disease [10] .

Available epidemiologic evidence also point to more severe clinical presentations and higher risk of death in the elderly and/or in fragile patients with several co-morbidities [29] [30] [31] [32] .

In this context, the internist is typically trained to manage the complexity of systemic diseases, and to coordinate a multidisciplinary approach in the case of severe presentation.

The spread of COVID-19 has rapidly reached a pandemic dimension within few weeks, imposing a rapid remodulation of health systems to contain and adequately face the outbreak. The management of the disease also requires the transmission of adequate, evidence-based information and optimal decision-making [33] .

This article is protected by copyright. All rights reserved Italy was the first European country extensively affected by the outbreak, with national control measures (air traffic embargo) adopted the same day of the first diagnosed case in Rome, and with strict control measures (lockdown) about two weeks after the first local outbreak was noticed in northern Italy. The critical analysis of the ongoing Italian scenario, will help to manage the spread of the pandemic in other countries, and also to face the outbreak by optimizing the locally available resources.

Italy extends for a length of approximately 1,300 Km, and a different pandemic burden occurred in southern vs. northern Italy, as also observed in other geographical areas at a global level [4] .

The difference in population density between northern and southern Italy (210.3 and 187.8 residents/Km 2 , respectively) seems too small to fully explain the divergent epidemiologic burden of COVID-19 in these two areas. Thus, geographical differences in the incidence of infected subjects and COVID-19 related deaths point to the existence of possible specific and local environmental factors which need to be urgently identified, and that can play a major role in determining the spread and the outcomes of the infection. Besides economic, socio-cultural and lifestyle-related factors, a role is possible for climate change variations [34, 35] , air pollution [36] [37] [38] , and the effects of endocrine disrupting chemicals on the onset and progression of several comorbidities [39] able to influence the individual vulnerability to COVID-19 [29] [30] [31] [32] .

At a world level, a 1°C temperature rise above pre-industrial levels is linked with new and emerging infectious diseases [34] . There might be relationships between climate change, marked reduction in biodiversity, and transfer by species-crossing (from wild species to humans) of several viruses, namely Ebola, SARS Coronavirus 1, Middle East Respiratory Syndrome (MERS) Coronavirus, Nipah virus and Hendra virus [40, 41] . Climate changes are also associated with increased incidence of respiratory infections [34, 35] . A study evaluating the effects of temperature on mortality in 306 communities from 12 country/regions, described Italy as one of the countries with the highest temperature-related mortality risk [42] .

An analysis on 66 administrative regions in Italy, Spain, France and Germany showed that longterm exposure to nitrogen dioxide, a common air pollutant mainly produced by anthropogenic processes, may be one of the most important contributors to fatality caused by SARS-CoV-2 infection. This effect occurs mainly when the air concentrations of this pollutant are combined with downwards airflow which prevent efficient dispersion [36] . Some regions in northern Italy (mainly Lombardy and Emilia Romagna) are among the most polluted European geographical

This article is protected by copyright. All rights reserved areas and, at the same time, have the highest world level of virus lethality [37] . Positive associations have been also described between newly COVID-19 confirmed cases and short-term exposure to particulate matter (i.e. PM2.5, PM10), nitrogen dioxide, and ozone [38] .

Lastly, individual outcomes from COVID-19 are strongly dependent on the presence of comorbidities [29] [30] [31] [32] . Chronic exposure to both air pollutants and endocrine disruptors introduced with contaminated food and beverages or through dermal contact, might play a role in increasing individual vulnerability and frailty, mainly in elderly subjects [39, 43] .

Further analyses are therefore required to adequately identify the major environmental determinants regulating the spread of SARS-CoV-2 infection, and the prognosis of COVID-19.

Italian epidemiological data confirm the efficacy of early and stringent measures of primary prevention, as observed in China [44] . About two weeks after the drastic containment measures legally imposed by the lockdown, a trend towards a reduction of new cases clearly emerged in the whole country.

In the absence of vaccines or specific therapeutics of confirmed efficacy, the only useful tool to govern and limit the epidemic remains the social distancing, quarantine, community containment and all other public health measures aimed at the primary prevention [45, 46] . In addition, we should be aware that rapid and aggressive outbreaks can easily originate from care homes for elderly people. A worrying aspect emerges from a last study showing that rapid and widespread transmission of SARS-CoV-2 occurred in skilled nursing facility, where more than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission [47, 48] . The problem involves the residents, their family members and medical, nurse personnel if protection protocols are poorly implemented [49] .

The Italian National Health System was established with the Law N. 833, on December 23, 1978. This law was based on the equity of care and underlined the precious role of primary prevention, parallel to adequate health assistance and rehabilitation. As clinicians working in the public healthcare system, we argue that the system should be prepared to limit everywhere morbidity and mortality deriving from this and future pandemics. In the most affected regions (northern Italy, mainly Lombardy) serious concerns existed about the effective capacity of the national health system to adequately face the burden of disease. This capacity was challenged by the total and simultaneous number of cases, in particular of those requiring intensive care. In this respect, systemic resources required to adequately manage such a critical situation might be insufficient

This article is protected by copyright. All rights reserved (i.e. personnel, number of available beds, overcrowding, intensive care facilities) [50, 51] . The structural limits deriving from insufficient resources has also generated ethical concerns regarding the prioritization of patients to be treated (i.e. younger patients prioritized over the elderly), and the equity of care [52] . A prospective data collection of critical care bed number in European countries from July 2010 to July 2011 showed a marked variability between countries. Italy had 12.5 critical care beds per 100,000 capita of population, a number slightly over the continental average (11.5) but about half than that of Germany, the European country with the highest value (29.2) . Of note, several EU countries downsized their curative bed capacity in the past 10 years Furthermore, evidence show that outcomes are strongly dependent on age (i.e. worst outcome in the elderly), on the extent of fragile patients and on the presence of co-morbidities [29] [30] [31] [32] . In the next future, severe health damage from further similar outbreaks could be strongly prevented by measures focusing on successful aging and healthspan, rather than merely on increasing lifespan. This approach should include a better management of all the environmental factors affecting noncommunicable diseases, thus contributing to primary prevention of diseases and to decreased frailty, as well as to increased number of years lived without diseases or disability [43] . 

This article is protected by copyright. All rights reserved "The discipline of Internal Medicine is involved in scientific and educational activity, as well as dedicated health care in the field of medical pathophysiology, instrumental and functional medical semeiology, medical methodology, evidence-based medicine, general clinical medicine and medical therapy, with specific aspects of emergency medicine, geriatrics and gerontology, allergology and clinical immunology; further fields of interests include clinical and metabolic aspects of vascular diseases, clinical nutrition, sport medicine, and thermal medicine"

In this complex scenario, and according to our experience, internists are called to serve prevention measures, front-line selection of patients, management of the disease and complications, tight coordination with other specialties, according to specific requirements. In our opinion, this is an outstanding example of professional resilience to sudden, and unexpected events which endanger the public health.

The SARS-CoV-2 infection became an unprecedented clinical challenge. The rapid pandemic spread has strongly stressed the national policies and health systems worldwide, highlighting critical issues and capacity of resilience.

The dramatic experience deriving from the COVID-19 pandemic should be maximized to adequately manage the present outbreak in other countries, but also to provide useful tools for future, potential pandemics. An additional goal should be the improvement of the overall health systems, oriented to adequately fulfill public needs.

The best approach derives from a combination of public health measures aimed at primary prevention, an adequate allocation of financial resources needed to efficiently face public health needs (in terms of personnel, processes, and tools), and an appropriate clinical management of affected individuals. This last goal, in particular, relies on the evidence that the infection by SARS-Cov-2 generates a complex and systemic disease, with multi-organ involvement. In this context, specialists in internal medicine play an undisputed pivotal role.

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This article is protected by copyright. All rights reserved [2] . Dots and lines indicate the incidence of cases per 100,000 residents in southern and northern Italian regions. 

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This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved