Parallel epidemics, or nearly so: Certainties and uncertainties about SARS-CoV-2 in Italy

Abstract

Between the end of the second and the beginning of the following century BC, the Greek philosopher Plutarch wrote “The parallel lives”, a series of twin biographies, each of which comparing a Greek and Roman prominent figure as for life events, vices and virtues. Now that our world is facing SARS-CoV-2 pandemics with its relevant country-specific timing and evolution pattern characteristics, we feel like repeating Plutarch’s parallelism experiment by analyzing factors eventually influencing its expression in different and far afield countries and by trying a head-to-head comparison between two main Italian regions. The history of COVID-19 pandemics is contributed to by a series of events occurring between the end of 2019 and the beginning of 2020 caused by SARS-CoV-2 virus infection, starting in Wuhan, China, and spreading throughout the world thereafter [1China’s first confirmed Covid-19 case traced back to November 17, in South China Morning Post, 13 marzo 2020 https://www.scmp.com/news/china/society/article/3074991/coronavirus-chinas-first-confirmed-covid-19-case-traced-back.Google Scholar, 2Coronavirus, il primo caso il 17 novembre: la ricostruzione che mette in difficoltà le autorità cinesi, Il Corriere della Sera, 14 marzo 2020.Google Scholar]. Event sequence The first COVID-19 infection case, referring to a 55-year-old man in Hubei province, was recorded on November 17, 2019 [1China’s first confirmed Covid-19 case traced back to November 17, in South China Morning Post, 13 marzo 2020 https://www.scmp.com/news/china/society/article/3074991/coronavirus-chinas-first-confirmed-covid-19-case-traced-back.Google Scholar, 2Coronavirus, il primo caso il 17 novembre: la ricostruzione che mette in difficoltà le autorità cinesi, Il Corriere della Sera, 14 marzo 2020.Google Scholar]. In the very beginning the agent was not identified as a new type of coronavirus, so that the news was reported by the Chinese government only on January 13, 2020 [[3]https://www.corriere.it/salute/20_marzo_14/coronavirus-primo-caso-17-novembre-ricostruzione-che-mette-difficolta-autorita-cinesi-87e75646-65e3-11ea-a287-bbde7409af03.shtmlGoogle Scholar]. Immediately after the epidemics became apparent so that Hubei province and the town of Wuhan were isolated and some 60 million people underwent a strict, army-secured quarantine which guaranteed the outbreak switch-off in about two months. Italy recorded its first COVID-19 pandemic event on January 31, 2020, when two tourists coming from China were found to be virus-positive in Rome [[4]WHO DECLARES 2019-NCOV ARD ‘PUBLIC HEALTH EMERGENCY OF INTERNATIONAL CONCERN’; PHIL GOV’T ISSUES TRAVEL BAN. Press Release 31 January, 2020. https://www.doh.gov.ph/doh-press-release/who-declares-2019-nCoV-ARD-public-health-emergency-of-international-concernGoogle Scholar]. On February 20, new outbreaks were detected in Codogno, Lodi province, Lombardy region, in terms of 16 infected people, summing up to 60 on the following day and causing the first deaths soon after [5Conte G. I primi due casi di coronavirus confermati in Italia. Il 2 febbraio l'evacuazione degli italiani da Wuhan, su ANSA, 31 gennaio 2020. https://www.ansa.it/canale_saluteebenessere/notizie/sanita/2020/01/30/conte-primi-due-casi-di-coronavirus-confermati-in-italia.-il-2-febbraio-levacuazione-degli-italiani-da-wuhan-_3698a086-c24e-470e-bba0-ef010daf4705.htmlGoogle Scholar, 6Coronavirus: 14 casi in Lombardia, due positivi ai primi test in Veneto, in la Repubblica, 21 febbraio 2020. https://www.repubblica.it/cronaca/2020/02/21/news/coronavirus_casi_veneto-249192220/Google Scholar, 7Due casi di coronavirus confermati dai primi due test a Padova, in Il Mattino (Padova), 21 febbraio 2020. https://www.ilmattino.it/primopiano/cronaca/coronavirus_padova_contagiati_veneto_ultime_notizie-5066356.htmlGoogle Scholar, 8Coronavirus, in isolamento Castiglione d’Adda, Codogno, Casalpusterlengo e altri 7 comuni, in Corriere della Sera (Milano), https://milano.corriere.it/notizie/cronaca/20_febbraio_21/coronavirus-castiglione-d-adda-codogno-isolamento-non-uscite-casa-non-andate-pronto-soccorso-4b0597ee-548e-11ea-9196-da7d305401b7.shtmlGoogle Scholar]. The patient identified as Case 1 was a 38-year old man from Codogno having respiratory tract infection signs. His wife and a close friend were also found COVID-19-positive [[5]Conte G. I primi due casi di coronavirus confermati in Italia. Il 2 febbraio l'evacuazione degli italiani da Wuhan, su ANSA, 31 gennaio 2020. https://www.ansa.it/canale_saluteebenessere/notizie/sanita/2020/01/30/conte-primi-due-casi-di-coronavirus-confermati-in-italia.-il-2-febbraio-levacuazione-degli-italiani-da-wuhan-_3698a086-c24e-470e-bba0-ef010daf4705.htmlGoogle Scholar] so that 13 municipalities in Lombardy and one in Veneto were immediately isolated to fulfil contagion containment procedures [[9]Matarese L. Coronavirus, obiettivo isolare il focolaio, in L'Huffington Post, 21 febbraio 2020. https://www.huffingtonpost.it/entry/coronavirus-obiettivo-isolare-il-focolaio_it_5e5036cbc5b629695f5a77f8Google Scholar]. Fig. 1, Fig. 2, Fig. 3 depict the evolution pattern of the epidemic in Italy throughout April 18, 2020 showing some slight positive signals, despite an overall long-lasting trend.Fig. 2New day-to-day (in yellow) SARS-CoV-2 swab-positive patients (left panel), death cases (right panel) and moving average of healed individuals on a continuous 5-day basis (middle panel, in blue) as of April 18, 2020 (Source: Data from the Ministry of Health processed by the ISS, modified). [[10]Misure urgenti in materia di contenimento e gestione dell'emergenza epidemiologica da COVID-19. Regione Lombardia. (20A01273) (GU Serie Generale n.47 del 25-02-2020) https://www.gazzettaufficiale.it/eli/id/2020/02/25/20A01273/sgGoogle Scholar)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 3Admission trends to ICUs (left panel; the arrow shows the peak level reached on April 3) and ordinary wards (right panel; the March 29 arrow shows the 29,010 individual peak level) (Source: Sky TG 24 on data from the Ministry of Health processed by the ISS, modified) [[11]Ministero della salute, Report 19 aprile 2020. https://www.iss.it/coronavirusGoogle Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) When referring to the initial cases recorded in Lazio and in Lombardy, the epidemic has consistently followed parallel trends in the North (quite turbulent) and in the Center-South of Italy (much slower) and now, when freezing the official picture derived from data of the Ministry of Health processed by the Istituto Superiore di Sanità (ISS) as of April 18, 2020 (Table 1), we detect a huge difference between the two regions. Demographic data is quite different and strongly in favor of Lombardy in terms of number of provinces, municipalities, inhabitants, geographical surface and population density (people/km2) [[12]Sky TG 24 https://tg24.sky.it/cronaca/approfondimenti/foto/numero-contagi-coronavirus-italia.html#4 su dati forniti dal Ministero della salute, elaborati dell’Istituto Superiore di Sanità, https://www.iss.it/coronavirusGoogle Scholar]. In greater detail, when looking at results from the two regional capitals, accounting per se for the highest population density and consequently most relevant contagion spread risk, a paradox becomes immediately apparent: despite having fewer inhabitants than Rome (1,352,000 versus 2,873,000), Milan has suffered from a five-fold infection rate so far (see Table 2).Table 1Absolute number of SARS-CoV-2 infected individuals as of April 18, 2020 in Lombardy compared to Lazio. (Source: Data from the Ministry of Health processed by the ISS, modified). [10]Misure urgenti in materia di contenimento e gestione dell'emergenza epidemiologica da COVID-19. Regione Lombardia. (20A01273) (GU Serie Generale n.47 del 25-02-2020) https://www.gazzettaufficiale.it/eli/id/2020/02/25/20A01273/sgGoogle ScholarLOMBARDYTOWNCASESBergamo10,629Brescia11,758Como2,439Cremona5,407Lecco2,03Lodi2,714Monza Brianza4,042Milan15,546Mantova2,863Pavia3,536Sondrio937Varese2,106other / to be verified1,374TOTAL65,381LAZIOTOWNCASESRome4,018Frosinone505Rieti280Viterbo349Latina436other / to be verified80TOTAL5,668 Open table in a new tab Table 2Demographics from Lombardy and Lazio. (Source: Statistics from ISTAT - Istituto Nazionale di Statistica). [13]Statistiche ISTAT (Istituto Nazionale di Statistica). http://dati.istat.it/Google Scholar.Regionpopulationsurfacedensitynumber ofnumber ofinhabitantskm2inhabitants/km2municipalitiesprovincesLombardy10,060.57423,863.654221,50612Lazio5,879.08217,232.293413785 Open table in a new tab Which reason might underly such a clear difference? Despite discrepancies in timing, modality and rule severity, China and Italy adopted similar containment procedures, yet the spread of contagion was much faster in Northern than in Southern Italy (almost invariably comparable to Lazio). It is quite evident from Wuhan experience that the stricter the isolation rules for assessed or potentially infected people, the easier it is to prevent SARS-CoV-2 spreading. This was the case in Rome where, immediately after being diagnosed, the two Chinese infected persons were admitted into the Spallanzani Hospital, a 40-year-renowned research and care center for infectious diseases and all their travel-mates and contacts were identified and isolated into the Cecchignola military citadel on the outskirts of Rome. All over Lombardy, instead, due to the lack of symptoms of infected people for several days or even weeks, virus spread was much wider, thus reaching out to Veneto and Emilia-Romagna regions, and presumably required longer to develop earlier symptoms after being infected. This might be explained by the fact that the two Chinese cases in Rome were older than Case 1 in Codogno (i.e. 68 vs 38 years of age). The former followed an easily traceable tourist itinerary while the latter moved around quite easily and extensively among regions making it impossible to track down all contacts. Moreover, the evidence so far seems to indicate that, besides being burdened by higher mortality due to the frequent coexistence of other diseases, older subjects are more easily infected and severely ill and this might have caused weakness symptoms quite soon preventing the Chinese patients in Rome from moving around [13Statistiche ISTAT (Istituto Nazionale di Statistica). http://dati.istat.it/Google Scholar, 14La Repubblica, 4 aprile 2020. Troppa gente in giro a Milano. https://milano.repubblica.it/cronaca/2020/04/04/news/coronavirus_milano_sala_troppa_gente_in_giro_controlli-253101858/Google Scholar]. There are also anecdotical reports concerning a shorter incubation period in the elderly which might add to the above, yet further studies are still needed to validate such hypothesis. Are there any other possible explanations for accelerated coronavirus spread in Lombardy? Indeed, the most affected area in the region, including Milan and its hinterland, is quite rich in farms and industries asking for intensive daily commuting and in the early phases of the epidemic most activities were still in place and partially stopped only about two weeks later. In fact, beginning of March, after the outbreak had already shown its threatening potential, only “crucial” activities were allowed to go on including food and drug chains, logistic support providers, general practitioner (GP) offices, which anyway involved some 40% of the working population [[14]La Repubblica, 4 aprile 2020. Troppa gente in giro a Milano. https://milano.repubblica.it/cronaca/2020/04/04/news/coronavirus_milano_sala_troppa_gente_in_giro_controlli-253101858/Google Scholar]. So considerable train, metro and bus commuting, relatively late recognition and multiple outbreak sites might have favored such a large infection spreading pattern in Northern Italy. Two more observations might also be taken into account, albeit requiring further validation by controlled studies: (i) a large number of treatment-resistant pneumonia events occurring already in January were reported by GPs a posteriori, i.e. after SARS-CoV-2 outbreak, and might reflect the presence in the area of potentially unrecognized carriers responsible for the exponential spreading of coronavirus infection [[15]Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar] and (ii) more severe fine dust pollution and less favorable hygrometric and barometric environmental conditions characterize the whole Po Valley as compared to the rest of Italy, as also apparent from European Space Agency reports [17ESA. Coronavirus: nitrogen dioxide emissions fall in Italy http://www.esa.int/Space_in_Member_States/Italy/Coronavirus_calano_in_Italia_le_emissioni_di_diossido_di_azotoGoogle Scholar, 18Position paper. Relazione circa l’effetto dell’inquinamento da particolato atmosferico e la diffusione di virus nella popolazione. https://www.actu- environnement.com/media/pdf/news-35178-covid-19.pdfGoogle Scholar]. Finally, as far as type 2 diabetes mellitus (T2DM) is concerned, we now have to underline that, as recently pointed out by two Italian groups [15Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 19Onder G. Rezza G. Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.JAMA. 2020; (Epub 2020/03/24 PubMed PMID: 32203977)Crossref PubMed Scopus (2607) Google Scholar] and reported by Chinese scientists directly involved in the management of COVID-19 infection [20Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020:1–13. Epub 2020/02/29. PubMed PMID: 32109013.Google Scholar, 21Shi H. Han X. Jiang N. Cao Y. Alwalid O. Gu J Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.Lancet Infect Dis. 2020; 20 (Epub 2020/02/28 PubMed PMID: 32105637): 425-434Abstract Full Text Full Text PDF PubMed Scopus (2239) Google Scholar], the disease is extremely frequent and associates with a higher mortality rate in hospitalized patients (Table 3) [[22]Istituto Superiore di Sanità. Characteristics of SARS-CoV-2 patients dying in Italy Report based on available data on April 20th, 2020. https://www.epicentro.iss.it/en/coronavirus/bollettino/Report-COVID-2019_20_april_2020.pdfGoogle Scholar]. Such phenomenon, which was further confirmed in Italian patients by the most recent bulletin from the ISS, had become apparent, despite different prevalence estimates, since the very beginning of the epidemic in China [[15]Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar].Table 3Absolute and relative prevalence of most common pre-existing cardiovascular and metabolic comorbidities as retrieved from available charts concerning 1,890 COVID-19-positive people dying in Italian hospitals. [21]Shi H. Han X. Jiang N. Cao Y. Alwalid O. Gu J Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.Lancet Infect Dis. 2020; 20 (Epub 2020/02/28 PubMed PMID: 32105637): 425-434Abstract Full Text Full Text PDF PubMed Scopus (2239) Google Scholar.DiseaseN%Ischemic heart disease51827.4Atrial Fibrillation41121.7Heart failure29815.8Stroke20610.9Hypertension1,31769.7Type 2-Diabetes60331.9Obesity23012.2 Open table in a new tab Diabetes and uncontrolled glycaemia had already been reported as significant predictors of severity and deaths in patients infected with different viruses as well, including the 2009 pandemic influenza A (H1N1) [[23]Schoen Karla, Horvat Natally, Guerreiro Nicolau F.C., de Castro Isac, de Giassi Karina S. Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity. BMC Infect Dis. 2019;19(1).Google Scholar], SARS-CoV [[24]Yang J.K. Feng Y. Yuan M.Y. Yuan S.Y. Fu H.J. Wu B.Y. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS.Diabet Med. 2006; 23 (Epub 2006/06/09 PubMed PMID: 16759303): 623-628Crossref PubMed Scopus (444) Google Scholar] and MERS-CoV [[25]Banik Gouri Rani Alqahtani Amani Salem Booy Robert Rashid Harunor Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia.Virol. Sin. 2016; 31: 81-84https://doi.org/10.1007/s12250-015-3679-zCrossref PubMed Scopus (79) Google Scholar]. SARS-CoV-2 Infection in individuals with DM is expected to trigger higher stress conditions, with greater release of hyperglycemic hormones, e.g., glucocorticoids and catecholamines, leading to increased blood glucose levels and abnormal glucose variability [[26]Aihong Wang Zhao Weibo Xu. Jianwen Zhangrong, Gu Timely blood glucose management for the outbreak of 2019 novel coronavirus disease (COVID-19) is urgently needed.Diabetes Res Clin Pract. 2020; 162108118Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]. On the other hand, according to a retrospective study from Wuhan some 10% COVID-19-positive patients with T2DM suffered at least one hypoglycemic event (<3.9 mmol/L) [[27]Zhou J. Tan J. Diabetes patients with COVID-19 need better care.Metabolism. 2020 Mar; 24154216https://doi.org/10.1016/j.metabol.2020.154216Abstract Full Text Full Text PDF Scopus (83) Google Scholar]. Notoriously, hypoglycemia mobilizes pro-inflammatory monocytes and increases platelet reactivity, thus contributing to a higher cardiovascular mortality in patients with DM [[28]Hussain A. Bhowmik B. do Vale Moreira N.C. COVID-19 and Diabetes: Knowledge in Progress.Diabetes Res Clin Pract. 2020; 162108142https://doi.org/10.1016/j.diabres.2020.108142Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar]. In addition, hyperglycemia and insulin resistance enhance the build-up of glycosylation end products (AGEs) and pro-inflammatory cytokines causing severe oxidative stress and increased inflammation-related adhesion molecule release [29Iqbal A, Prince LR, Novodvorsky P, Bernjak A, Thomas MR, Birch L, et al. Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans. J Clin Endocrinol Metab. 2019;104(4):1187-99. Epub 2018/09/27. doi: 10.1210/jc.2018-01168. PubMed PMID: 30252067; PubMed Central PMCID: PMCPMC6391720.Google Scholar, 30Knapp Sylvia Diabetes and Infection: Is There a Link? - A Mini-Review.Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107Crossref PubMed Scopus (199) Google Scholar, 31Petrie John R. Guzik Tomasz J. Touyz Rhian M. Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms.Can J Cardiol. 2018; 34: 575-584https://doi.org/10.1016/j.cjca.2017.12.005Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. All this may in fact contribute to the mechanisms underlying the greater susceptibility to infections and the worse outcomes thereof observed in patients with DM [[30]Knapp Sylvia Diabetes and Infection: Is There a Link? - A Mini-Review.Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107Crossref PubMed Scopus (199) Google Scholar]. Mostly based on in vitro studies, hyperglycemia associates with several immune system defects, including inhibited lymphocyte proliferative response to different kinds of stimuli [32Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol. 1999;26(3-4):259-65. Epub 1999/11/27. doi: 10.1111/j.1574-695X.1999.tb01397.x. PubMed PMID: 10575137.)Google Scholar, 33Moutschen MP, Scheen AJ, Lefebvre PJ. Impaired immune responses in diabetes mellitus: analysis of the factors and mechanisms involved. Relevance to the increased susceptibility of diabetic patients to specific infections. Diabete Metab. 1992;18(3):187-201. Epub 1992/05/01. PubMed PMID: 1397473.Google Scholar], and impaired monocyte/macrophage and neutrophil functions [[30]Knapp Sylvia Diabetes and Infection: Is There a Link? - A Mini-Review.Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107Crossref PubMed Scopus (199) Google Scholar]. In vitro studies have shown that pulmonary epithelial cells exposure to high glucose concentrations significantly increases influenza virus infection and replication, pointing to hyperglycemia-enhanced viral replication in vivo [[34]Kohio Hinissan P. Adamson Amy L. Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection.Virology. 2013; 444: 301-309https://doi.org/10.1016/j.virol.2013.06.026Crossref PubMed Scopus (76) Google Scholar]. In animal models, structural lung changes have been related to diabetes, such as augmented vasculature permeability and collapsed alveolar epithelium [[35]Dunn E.J. Grant P.J. Type 2 diabetes: an atherothrombotic syndrome.Curr Mol Med. 2005; 5 (Epub 2005/05/17. 10.2174/1566524053766059 PubMed PMID: 15892651): 323-332Crossref PubMed Scopus (71) Google Scholar]. Finally, abnormal delayed-type hypersensitivity reaction and complement activation dysfunction [[36]Lange P. Groth S. Kastrup J. Mortensen J. Appleyard M. Nyboe J. et al.Diabetes mellitus, plasma glucose and lung function in a cross-sectional population study.Eur Respir J. 1989; 2 (Epub 1989/01/01 PubMed PMID: 2651148): 14-19Crossref PubMed Google Scholar] have been reported in patients with DM. All of the above suggests that the greatest possible attention should be paid to the high risk for more severe lung involvement pending on people with DM during COVID-19 infection, due to a significantly lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) in the presence of raised glucose levels [[37]Song Z., Xu Y., Bao L., Zhang L., Yu P., Qu Y. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019 Jan 14;11(1). pii: E59. doi: 10.3390/v11010059.Google Scholar]. So which pathogenetic elements underly higher susceptibility to COVID-19 disease and mortality rate in people with DM? The virus itself and its toxins precipitate a cytokine thunderstorm exacerbating hypercoagulation in patients with DM [20Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020:1–13. Epub 2020/02/29. PubMed PMID: 32109013.Google Scholar, 34Kohio Hinissan P. Adamson Amy L. Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection.Virology. 2013; 444: 301-309https://doi.org/10.1016/j.virol.2013.06.026Crossref PubMed Scopus (76) Google Scholar] who, by definition, face a clear-cut prothrombotic state [[35]Dunn E.J. Grant P.J. Type 2 diabetes: an atherothrombotic syndrome.Curr Mol Med. 2005; 5 (Epub 2005/05/17. 10.2174/1566524053766059 PubMed PMID: 15892651): 323-332Crossref PubMed Scopus (71) Google Scholar], further aggravated by chronic low-grade inflammation causing atherosclerosis-related endothelial dysfunction and insulin-resistance associated arterial hypertension [[36]Lange P. Groth S. Kastrup J. Mortensen J. Appleyard M. Nyboe J. et al.Diabetes mellitus, plasma glucose and lung function in a cross-sectional population study.Eur Respir J. 1989; 2 (Epub 1989/01/01 PubMed PMID: 2651148): 14-19Crossref PubMed Google Scholar]. All above-mentioned phenomena are known to become more and more severe as age increases and this is in line with the observation that octogenarian individuals are mostly affected by SARS-CoV-2 disease [[19]Onder G. Rezza G. Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.JAMA. 2020; (Epub 2020/03/24 PubMed PMID: 32203977)Crossref PubMed Scopus (2607) Google Scholar]. With respect to that, an issue deserving special attention is the quite similar SASR-CoV-2 infection rate in people without or with DM [[25]Banik Gouri Rani Alqahtani Amani Salem Booy Robert Rashid Harunor Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia.Virol. Sin. 2016; 31: 81-84https://doi.org/10.1007/s12250-015-3679-zCrossref PubMed Scopus (79) Google Scholar] in front of a much greater severity of the disease as reported by the Italian ISS in the latter. At this point we also feel like underlining that some hypoglycemic treatment strategies might turn out to be protective. Dipeptidyl-dipeptidase-4 (DPP-4) was shown, in fact, to be the primary receptor of MERS-CoV [[37]Song Z., Xu Y., Bao L., Zhang L., Yu P., Qu Y. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019 Jan 14;11(1). pii: E59. doi: 10.3390/v11010059.Google Scholar]: the possibility that DPP-4 also acts as a receptor for SARS-CoV-2 warrants investigation and, should this be the case, in agreement with the hypothesis put forward by Iacobellis [[38]Iacobellis G. COVID-19 and diabetes: Can DPP-4 inhibition play a role ?.Diabetes Res Clin Pract. 2020; 26108125https://doi.org/10.1016/j.diabres.2020.108125Abstract Full Text Full Text PDF Scopus (211) Google Scholar], DPP-4 inhibitors, well-renowned treatment tools in T2DM, should be explored for their anti-viral potential in the human [[15]Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. Opposite to that, it has been recently hypothesized that Sodium-Glucose-Transporter-2 inhibitors (SGLT-2i), Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1RAs), Pioglitazone and even Insulin might induce an over-expression of the ACE2 receptor which was also found to bind to coronaviruses in the alveoli [[39]Pal R. Bhadada S.K. Should anti-diabetic medications be reconsidered amid COVID-19 pandemic?.Diabetes Res Clin Pract. 2020; 163108146https://doi.org/10.1016/j.diabres.2020.108146Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar], and therefore increase the risk for a more severe expression of SARS-CoV-2 infection in people with diabetes [[40]Ceriello A. Stoian A.P. Rizzo M. COVID-19 and diabetes management: what should be considered?.Diabetes Res Clin Pract. 2020; 163108151https://doi.org/10.1016/j.diabres.2020.108151Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. Corticosteroid utilization also requires special attention with respect to COVID-19 disease severity in people with DM [[41]World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance, 13 March 2020 Geneva2020 [28/03/2020]. Available from: https://www.thelancet.com/action/showPdf?pii=S0140- 6736%2820%2930317-2.Google Scholar]. Acute lung damage and acute respiratory distress syndrome (ARDS) are partly due to the host immune response and corticosteroids were broadly used in SARS-CoV and MERS-CoV infections [42Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020; 395 (Epub 2020/02/12. 10.1016/S0140-6736(20)30317-2 PubMed PMID: 32043983): 473-475Abstract Full Text Full Text PDF PubMed Scopus (1382) Google Scholar, 43Arabi Yaseen M. Balkhy Hanan H. Hayden Frederick G. Bouchama Abderrezak Luke Thomas Baillie J. Kenneth Al-Omari Awad Hajeer Ali H. Senga Mikiko Denison Mark R. Nguyen-Van-Tam Jonathan S. Shindo Nahoko Bermingham Alison Chappell James D. Van Kerkhove Maria D. Fowler Robert A. Middle East Respiratory Syndrome.N Engl J Med. 2017; 376: 584-594https://doi.org/10.1056/NEJMsr1408795Crossref PubMed Scopus (277) Google Scholar] due to their ability to suppress histologically proven virus-dependent lung inflammation with diffuse alveolar damage [[44]Jaber Emami Pasutto Franco M. Mercer John R. Jamali Fakhreddin. Inhibition of insulin metabolism by hydroxychloroquine and its enantiomers in cytosolic fraction of liver homogenates from healthy and diabetic rats.Life Sci. 1998; 64: 325-335Crossref Scopus (39) Google Scholar]. However, they also inhibit immunity and pathogen clearance and, in the face of very little benefit if so ever, have been associated with delayed viral RNA clearance or increased mortality and rate of complications, including diabetes, psychosis, and avascular necrosis [[42]Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020; 395 (Epub 2020/02/12. 10.1016/S0140-6736(20)30317-2 PubMed PMID: 32043983): 473-475Abstract Full Text Full Text PDF PubMed Scopus (1382) Google Scholar]. Due to all the above, the interim guidance from the WHO on clinical management of severe acute respiratory infection advises against the use of corticosteroids upon suspicion of SARS-CoV-2 infection outside clinical trials [[45]Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-67. Epub 2017/11/22. doi: 10.1164/rccm.201706- 1172OC. PubMed PMID: 29161116.Google Scholar], yet corticosteroids were extensively utilized before that in at least 34% of the large number of Northern Italian hospitalized patients [[46]Gentile S, Strollo F, Ceriello A. The need for diabetes care customization in the ICU at the time of SARS-CoV-2 outbreak. Diab Therapy 2020, in pressGoogle Scholar]. At analysing the growth curve of coronavirus infection in Italy, the massive referral to the hospitals of so many people within a very a short period strikes the eye when compared to the small number of hospitalized patients in the South (Figura 4). In the stormy and overcrowded emergency conditions faced by health professionals at the start of the epidemic in the absence of any experience with treating COVID-19 disease, a broader recourse to high doses of corticosteroids most likely occurred than later on, when in fact better treatment strategies were identified and emergency departments were less congested. It can be assumed that the above mentioned logistic and environmental factors strongly affected clinical course and mortality rates of COVID-19-infected people and even more in those with DM. Indeed, Fig. 4 clearly shows that death rate was significantly higher in infected Northern Italy inhabitants than in their Southern counterpart (i.e. 17.2% vs 5.5%, respectively). According to current protocols, subject to the exceptions needed for treatment personalization, the use of corticosteroids is extremely limited if so ever. This might also help healthcare teams adopt an intensive, fully integrated therapeutic approach for their patients with DM, especially those in the ICUs, involving drugs expected to prevent at their best both hypoglycemic events and dramatic hyperglycemic spikes contributing to marked glycemic variability, i.e. a severe mortality risk driver [[47]Ceriello A. Monnier L. Owens D. Glycemic variability in diabetes: clinical and therapeutic implications.Lancet Diab Endocrinol. 2019; 7: 221-230Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar] (see Fig. 5).Fig. 5Territorial differences in SARS-CoV-2 infection within Italy as of April 16, 2020 (Source: Data from the Ministry of Health processed by the ISS, modified) [[16]ISS, Characteristics of SARS-CoV-2 patients dying in Italy Report based on available data on April 16, 2020, https://www.epicentro.iss.it/en/coronavirus/bollettino/Report-COVID-2019_16_april_2020.pdfGoogle Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) A final report coming from TOSCA, a recent nationwide study on people with T2DM, known to affect mostly older patients who, in turn, are at higher risk for severe COVID-19 disease, shows that a high adherence to the Mediterranean diet is significantly more frequent among people living in the southern regions of Italy [[48]Vitale M, Masulli M, Calabrese I, Rivellese AA, Bonora E, Signorini S, et al.; TOSCA.IT Study Group. Impact of a Mediterranean Dietary Pattern and Its Components on Cardiovascular Risk Factors, Glucose Control, and Body Weight in People with Type 2 Diabetes: A Real-Life Study. Nutrients. 2018 Aug 10;10(8). pii: E1067. doi: 10.3390/nu10081067Google Scholar]. The latter, however, display a slightly higher phenolic acid and lignan intake due to a higher consumption of cereals and legumes and a slightly lower total polyphenol intake as flavonoids and stilbenes due to lower wine consumption [[49]Vitale M, Masulli M, Rivellese AA, Bonora E, Cappellini F, Nicolucci A, et al.; TOSCA.IT Study Group. Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The TOSCA.IT Study. Eur J Nutr. 2018 Mar;57(2):679-688. doi: 10.1007/s00394-016-1355-1. Epub 2016 Dec 21.Google Scholar]. This takes on a particular significance when comparing the absolute and relative death rate of subjects with T2DM in Lombardy (11,384 deaths; 56.9% of infected individuals) to that observed in Lazio (259 deaths; 1.3% of infected individuals). Might this add to the picture? At the moment, ours can only be taken as speculation but we strongly believe that also lifestyle components deserve further investigation with respect to COVID-19 disease. In conclusion, based on official Ministry of Health and ISS statements we are fully aware that:•a strikingly different trend was observed for SARS-CoV-2 infection between Northern and Southern Italy;•strict containment rules are the best way to prevent SARS-CoV-2 epidemics from spreading;•territory-oriented medicine might play an effective guardian role and should therefore be listened to and strengthened;•people with T2DM are more susceptible to SARS-CoV-2 infection, with twice as high mortality risk as metabolically healthy people;•high amounts of polyphenol-derived antioxidants from cereals and legumes typical of the Mediterranean diet might help to stop SARS-CoV-2 infection from spreading. To borrow from Plutarch, the conditions described above are asymmetrically parallel. So, asymmetry proved to be detrimental to Italy, and especially its Northern part and to somewhat spare the Central and Southern areas so far, whose ancient Greek culture-derived lifestyle might have positively, albeit almost unexplainedly and inadvertently, influenced the susceptibility to coronavirus infection.