Coronavirus Disease-2019, Diabetes and Dialysis in Southern Italy: The Second Wave Follow-up

Teresa Della Corte, BSc

Nutritionist, , Nefrocenter Research Network and Nyx Start-up, Naples, Italy; E-mail: tere.dellacorte@gmail.com

PREMISE

World Health Organization (WHO) declared the COVID-19 outbreak a pandemic on March 11, 2020¹ due to a rapidly spreading worldwide of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).² In March 2020, Italy got the second-largest number of confirmed cases, after China. The Italian government introduced progressive infection-mitigation measurements on March 9 and March 11, 2020, to dramatically reduce social interactions and prevent virus spread.^3,4 Contagion cases dramatically decreased during the following months. This led to progressively looser infection containment measures allowing free tourism and commerce-related exchanges among regions and mask-based socialization within coffee-bars, restaurants, pubs, and other gathering places while still adopting strict hand hygiene and proper inter-personal distancing. Unfortunately, as people interpreted that as fully regained freedom and, after a while, school reopening caused unrestricted use of public transportation, contagion rate progressively increased from August up to the present situation, which represents a severe challenge for our National Health Service (NHS) (Figure 1). However, the two periods of COVID-19 pandemic markedly differed from each other: between February and April, most cases occurred in Northern Italy, being the Central and Southern parts largely preserved while all regions appeared to be interchangeably under attack during the second infection wave (Figure 2).^5,6

Figure 1. Cases of Confirmed SARS-CoV-2 Infection Reported in Italy, by Date of Sample/Diagnosis (green) and Symptom Onset (blue)

Note: More recent data (grey squares) should be interpreted with caution due to the possible reporting delay of more recently diagnosed cases and the possibility that cases with a date of onset within the reporting period may not have been diagnosed yet. (source: COVID-19 integrated surveillance data in Italy as of November 15, 2020, modified. (reference 10) https://www.epicentro.iss.it/en/coronavirus/sars-cov-2- dashboard. (source: COVID-19 integrated surveillance data in Italy as of November 15, 2020, modified.¹⁰

Figure 2. Cases of COVID-19: per 100.000 Population by Region/Autonomous Province of Diagnosis (blue); by the Province of Residence (orange); in the last 30-days, by Region/Autonomous Province of Diagnosis (red)

Source: COVID-19 integrated surveillance data in Italy as of15 November, 2020, modified.¹⁰

In April, the difference between the two national areas seemed to depend on unevenly distributed weather and pollution conditions.^6,7 The latter were mostly due to pressing industrial activities involving the extensive use of public transportation by many workers undergoing long-term confinement within closed environments to provide our country with scheduled production rates.⁸ As reported by some authors, including ourselves, a few other factors might add to different contagion rates initially, including uneven tracking ability and implemented strategies against the viral spread.^7,9

Frail Population: Patients on Dialysis with and without Diabetes

During the first period of the SARS-CoV-2 pandemic, we analyzed contagion rate in both a large cohort of patients and health care professionals, including auxiliary workers (HCWs) from 18 Southern Italy Nefrocenter Consortium dialysis centers (DCs). Our results^10,11 were in agreement with those reported by the Italian National Institute of Health (NIH).¹² Our interest in people on dialysis relied on the high prevalence of comorbidities expected to shorten life expectancy per se observed in such population, including type 2 diabetes mellitus (T2DM),^13,14 arterial hypertension (AH) and cardiovascular disease (CVD) and on the high contagion risk entailed by repeated attendance of health care facilities.

There is some discrepancy between contagion prevalence (13.9%) and mortality rate (16.2%) in Chinese series¹⁵ and those reported in Italy (2.5%, except for Lombardy, where an average 7% death prevalence was reported, with a top 14% rate in Cremona).¹⁶ On adopting a prevention protocol in agreement with the Italian Nephrology Society (INS) recommendations^17,18 and with Chinese experience,¹⁹ Nefrocenter Consortium DCs reported as low as 0.24% a prevalence and 0.12% a mortality rate (2 and 1 out of 825 patients, respectively).¹¹ None got infected among the 351 health care personnel (HCP) members from the ¹⁸ DCs until April 23, 2020. The above observations support the high effectiveness of chosen contagion containment measures, especially considering repeated, long-standing exposure to promiscuity conditions of frail, immune-compromised individuals.^20-25 However, the lower inflammatory cytokine levels reported in dialyzed patients might have also contributed to the relatively mild clinical course of COVID-19 observed in that period.²⁶

Unfortunately, the second wave of COVID-19 pandemic is now quite different from the first one, by hitting all Italian regions almost equally with a high contagion rate both at home and in varying health care settings.^27,28 Due to the consequent large number of apparently healthy carriers, the above protocol might prove less efficient than before.

Aim of Prevention Protocol and Infected Patient Management

Our study aimed to evaluate the efficiency of our previously described protocol¹¹ under the new ubiquitous contagion conditions. The secondary outcomes were (i) SARS-CoV-2-infection mortality rate and risk factors; (ii) identifying further actions to be taken to provide SARS-CoV-2 positive dialyzed patients and HCP with undeferrable treatment in the 18 Campania region-located private Nefrocenter Consortium DCs contracted to the Italian NHS.

PROTOCOL

As defined according to INS recommendations^28,29,30 and Chinese experience,^19,31 the protocol has been running since the epidemic outbreak in Lombardy, i.e., February 20, 2020, to limit the spread of contagion among both patients and HCP directly or indirectly involved in dialysis-related activities. We already described protocol details,¹¹ to which we added recommendations on the management of COVID-19 patients under the latest documents released by the Italian Ministry of Health (MoH), the ISS, and the WHO.^32-34 Figure 3 provides a detailed protocol flowchart. As for the HCP, the latter was superimposable to the previous one oriented to people on dialysis,¹¹except for eventually occurring COVID-19 dedicated DCs.

Figure 3. Identification and Management Flowchart of SARS-CoV-2 Positive Dialysis Patients

*Asymptomatic, pre-symptomatic or mild symptomatic infection (fever, cough, dysgeusia, dysosmia, headache, myalgia, in the absence of dyspnea and X-ray abnormalities (stage 1 and 2 according to NIH classification [64]); ^° moderate, severe or critical illness according to the same classification.

METHODS

On April 23 and November 13, 2020, 381 HCP members underwent regular monitoring (Table 1), while dialysis patients ranged 825 to 873 according to the expected shifting prevalence over time (mean±SD: 853±30 per month throughout the 6.5-months). Overall Italian all-cause mortality rate was 11.8% in April and 14.8% in November vs. a.

Following Italian MoH recommendations, suspect cases underwent oro-pharyngeal swabs for virus detection using ribonucleic acid (RNA) polymerase chain reaction (PCR).^3-5 Those found positive were then carefully followed-up with quantitative IgM- and IgG-based serologic tests.^34-36

To define COVID-19 disease severity, we chose the NIH classification³⁷ as the most suitable one in our clinical setting, heavily clogged with hectic health care activities.

T2DM diagnosis and comorbidities/complications related to DM relied on criteria defined by the ADA Standards of Medical Care in Diabetes 2019³⁸ and on the International Classification of Diseases, Clinical Modification (ICD-9-CM, V82.9 2014),³⁹ respectively.

The study was conducted following the Helsinki Declaration 1975 and subsequent amendments. The protocol was approved by the Ethics Committee of the University of Campania “Luigi Vanvitelli” on June 3, 2020 (Protocol Registration N. 1394- b) as follow-up of previous paper, already approved on April 30, 2020 (protocol registration n. 1394), and published on the same Journal.¹¹

It was formally approved by the Ethics Committee of the University of Campania “Luigi Vanvitelli” on April 30, and again for the present analysis as an extension of the previous approval on November 3, 2020. According to good clinical practice guidelines, the data was processed anonymously, and no patient started the study before signing informed consent. All the subjects enrolled signed the informed consent.

Results, expressed as mean±SD or %, relied on the utilization of the Statistical Analysis System (SAS) Program (Release 9.4, SAS Institute, Cary, NC, USA), which also allowed to perform the chi-square test with Yates correction or Fisher Exact test for categorical variables, as well as the analysis of variance for repeated measures (rANOVA) supplemented by the two-tailed Student’s ttest or Mann-Whitney U-test with 95% confidence intervals (CI) for parametric variables or nonparametric variables, respectively. The least acceptable significance level was set at a p<0.05.

RESULTS

In Italy the two periods of the pandemic were characterized by a strong association between mortality rate and often intertwined comorbidities, mostly represented by AH, Type 2 DM (T2DM), ischemic heart disease (IHD), and chronic kidney disease (CKD).^5,10 As reported in Table 2, while showed no significant period-dependent differences, data from the ISS on mortality rate and factors associated with COVID-19 pointed to co-existing comorbidities, mostly represented by the AH, T2DM and CKD triplet, as an extremely unfavorable prognostic factor.

Table 1 shows our 873 patients’ general features as of November 2020 and differences among main comorbidities as referred to the presence/absence of T2DM. People with T2DM were older and had a higher BMI and comorbidity rate except for dementia, stroke, and respiratory failure (p<0.05); those on insulin were 77.9%. Results were almost superimposable to those we observed in April 2020.

Table 3, comparing SARS-CoV-2 contagion data from both periods, shows the strikingly different infection prevalence occurring within the HCP (n=75 vs. 0) despite strict compliance to the prevention protocol within all DCs over time. However, SARS CoV-2 positive HCP had only mild symptoms (NIH classification scores 1-2).³⁵ if so ever (thus requiring no hospitalization). Based on triage and tracking investigations, they had got mostly infected outside the DCs, mainly when spending August-September holidays in places characterized by a high virus circulation rate.

More patients showed to be infected in November than in April (2 out of 825 people; 0,24%) as well, summing up to 89 out of 873 people (10.19%). As many as 22 patients from the November cohort required hospitalization for moderate-severe symptoms (24.7% of the 89 SARS-CoV-2 positive subjects and 2.5% of the whole attending population), with death unavoidably coming in 19 (86.3% of hospitalized and 21.3% of infected patients) compared to the only one recorded in April (0.12%).

Table 4 shows differences among SARS-CoV-2 positive (n=89) and negative (n=784) patients as for type and number of comorbidities, compared to those from ISS reports issued before the pandemic (Table 2). No HIV infection, autoimmune disease, or obesity cases were present in our population. The prevalence of all comorbidities was significantly higher in SARS-CoV-2 positive patients except for cancer (we avoided statistics for the too few [only two] active cases reported during the past five years). Also, all SARS-CoV-2 positive patients, compared to only 61.8% of SARSCoV-2 negative ones, suffered at least three comorbidities.

DISCUSSION AND CONCLUSION

From the analysis of the two pandemic periods, quite different pictures arise. During the first wave, due to government directives and the ubiquitous fear of a virus, which was unknown even to the experts, the whole population strictly observed contagion prevention strategies. As a result, the virus spread kept at low-levels in Italy, despite significant differences between the Northern regions and the others,^40,41 despite reported long-term persistence of viral particles and a potentially high infection risk within health care facilities.^41-43

The lack of any contagion signs among the HCP while detecting only two infected patients in the DCs during the first period¹¹ seems to support both the favorable environmental condition outside DCs and the effectiveness of containment’s protocol adopted inside the DCs.¹¹ The explanation for that seemed to rely on the hypothesized large removal of the already reduced inflammatory storm-related cascade of cytokines by dialysis⁴⁴ produced by the defective immune system characterizing people with CKD19 during the acute phases of SARS-CoV-2 infection.³⁷ Of course, all the above could not nullify but only mitigate CKD patients’ comorbidity-related frailty and high mortality rate reported by the ISS.¹⁰

On the opposite, SARS-CoV-2 positive HCP members and patients found during the second wave of the pandemic were quite many, yet, being infection severity negligible among the HCP, a high prevalence of cases of moderate-severe symptoms leading to hospitalization was recorded among patients. Only 13.4% of the HCP (n=14) was over 50-years of age vs. 100% of patients. Only 36.0% of the infected HCP had one comorbidity (invariably AH), while 100% of infected patients suffered at least three comorbidities. Apropos of that, our data support the strong association found by the ISS in the Italian population between at least three combined comorbidities and the high morbidity and mortality rate of people on dialysis.^45,46,47

How to explain the considerable difference observed between the two periods? On displaying pandemic trend in Italy since the very beginning, Figure 1 depicts the exponential rise observed in November, and Figure 2 provides evidence of the ubiquitous virus spread. In other words, the positive effect of lockdown performed in spring 2020 vanished after summertime containment measure loosening. Media repeatedly and uselessly stigmatized unstoppable dangerous behaviors, including thoughtless aggregation of many people, totally disregarded social distancing and failure to wear masks despite numerous infected people identified daily all over Europe. In greater detail, during the summer discos opened again everywhere in Europe and especially in Sardinia (an almost COVID-free region until mid-August), international travel exchanges started again. Simultaneously, more and more events, including festivals, funerals, mass religious celebrations/processions, and political gatherings, involved hundreds of people, and school reopening overcrowded public transportation – thus hindering social distancing during rush hours. All phenomena mentioned above made the virus spread much faster than before, especially in the presence of many, mostly young, asymptomatic infected people who largely hindered effective tracking despite ever-updated safety protocols issued at regular intervals.^48-51 To overcome this problem, the Italian government offered the IMMUNI App for smart phones associated with Bluetooth Low Energy technology for free in order to track suspected cases and identify contacts with SarsCoV-2 positive people.⁴² However, due to privacy concerns, only a few people felt confident enough to download and use the App, thus nullifying such a nation-wide strategy.⁵²

All this shows how contagion containment measures adopted by our DCs were not enough to fight the global infection risk pending on the whole Italian social community around. The most evident proof of this is the fact that, opposite to what we observed during the previous period, many HCP members “imported” the SARS-CoV-2 virus from highly infected touristic places before the second wave. Since early September 2020, the Nefrocenter Consortium adopted an add-on protocol meant to identify, track and monitor suspected cases, and thus stop contagion spread within its DCs by identifying and isolating suspected cases and their contacts. It also organized COVID-dedicated DCs to keep patients on dialysis, as suggested by other experiences,^53-57 while reinforcing safety procedures for the sake of health personnel, patients, and relatives.

In conclusion, we now summarize lessons learned from such stressing experience to help the scientific community take the weighty responsibility of assisting dialyzed people appropriately and safely in times of COVID-19 contagion:

1. CKD patients are frail and as susceptible to SASR-CoV-2 as anybody else;
2. The impaired immune responsivity, despite possible pro-inflammatory cytokine clearance provided by dialysis, might not prevent CKD patients from undergoing severe/lethal consequences;
3. The high comorbidity rate is an unfavorable factor increasing the risk of clinically severe infections eventually leading dialysis patients to hospitalization;
4. Patients chronically undergoing dialysis have a very high-risk of dying after hospitalization for moderate/severe infection symptoms;
5. Environmental circulation of SARS-CoV-2 virus also dramatically increases contagion rate in dialysis units independently of highly effective safety protocols complying with current recommendations from local and national health institutions;
6. However, adopting a suitable surveillance and monitoring protocol for suspected/infected subjects grants an effective contagion tracking activity, thus preventing local COVID-19 outbreaks within DCs.

LIMITATIONS

The present study suffers the main limitation of being based on a single Italian region endowed with a socio-economic reality somewhat differing from other ones characterized by equally relevant virus circulation rates, further exacerbated by highly concentrated industrial activities and massive use of means of transport.

However, its multicenter structure and the large size of its population allow for reliable, updated results. Also, it deserves credit for warning dialysis specialists about the fact that, despite proving effective for the HCP, prevention protocols could fail to protect the frailest patients with T2DM from the effects of an aggressive outer environment.

ACKNOWLEDGEMENTS

We acknowledge the logistic support of Nefrocenter Research Network & Nyx, research startup, Naples, Italy.

INFORMED CONSENT

Written informed consent was obtained from all participants before enrollment.

FUNDING

The study did not have a sponsor/funder. Nefrocener Research Network & Nyx Statrup paid only the printing costs in a nonconditioning way.

AUTHORSHIP

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

AUTHOR’S CONTRIBUTION

SG, ES, CR and FS created the paper and wrote it. CA, TDC, MP critically read the paper. All have complied with data collection, critically assessed the results, and approved the final text. All collaborators critically read and approved the final text.

STUDY INVESTIGATOR

For full investigator list see the Appendix.

COMPLIANCE WITH ETHICS GUIDELINES

This study was conducted in conformance with good clinical practice standards. The study was led in accordance with the Declaration of Helsinki 1975, as revised in 2013. Written informed consent was obtained from all participants before enrollment.

The protocol was approved by the Ethics Committee of the University of Campania “Luigi Vanvitelli” on June 3, 2020 (protocol registration n. 1394-b) as follow-up of previous paper, already published on the same Jornal “COVID-19, DIABETES AND DIALYSIS: AN INTERNAL MEDICINE CONUNDRUM: Proposal for a suitable and easy-to-handle prevention protocol” (reference 11).

DATA AVAILABILITY

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

1. World Health Organization (WHO). Virtual press conference on COVID-19—11 March 2020. March 11, 2020. Website. https://www.who.int/docs/default-source/coronaviruse/transcripts/who-audioemergencies-coronavirus-press-conferencefulland-final-11mar2020.pdf?sfvrsn=cb432bb3_

2. Accessed November 15, 2020. 2. Bedford J, Enria D, Giesecke J, Heymann DL, Ihekweazu C, Kobinger G, et al. COVID-19: Towards controlling of a pandemic. Lancet. 2020; 395(10229): 1015-1018. doi: 10.1016/S0140- 6736(20)30673-5

3. Government of Italy. Decree of the president of the Council of Ministers 9 March 2020. March 9, 2020 [In: Italian]. Website. https://www.gazzettaufficiale.it/eli/id/2020/03/09/20A01558/ sg. Accessed November 15, 2020.

4. Government of Italy. Decree of the president of the Council of Ministers 11 March 2020. March 11, 2020. Website. https:// www.gazzettaufficiale.it/eli/id/2020/03/11/20A01605/sg [In: Italian]. Accessed November 15, 2020.

5. Gentile S, Strollo F, Ceriello A. COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used). Diabetes Res Clin Pract. 2020; 162: 108137. doi: 10.1016/j.diabres.2020.108137

6. Setti L, Passarini F, De Gennaro G, Barbieri P, Perrone MG, Borelli M, et al. Airborne transmission route of COVID-19: Why 2 Meters/6 Feet of inter-personal distance could not be enough. Int J Environ Res Public Health. 2020; 17(8): 2932. doi: 10.3390/ ijerph17082932

7. Fattorini D, Regoli F. Role of the chronic air pollution levels in the Covid-19 outbreak risk in Italy. Environ Pollut. 2020; 264: 114732. doi: 10.1016/j.envpol.2020.114732

8. Gentile S, Mambro A, Strollo F. Parallel epidemics, or nearly so: Certainties and uncertainties about SARS-CoV-2 in Italy. Diabetes Res Clin Pract. 2020; 164: 108195. doi: 10.1016/j.diabres.2020.108195

9. Romagnani P, Gnone G, Guzzi F, Negrini S, Guastalla A, Annunziato F, et al. The COVID-19 infection: lessons from the Italian experience. J Public Health Policy. 2020; 41(3): 238-244. doi: 10.1057/s41271-020-00229-y

10. IstitutoSuperiore di Sanità. Characteristics of SARS-CoV-2 patients dying in Italy: Report based on available data. Website. https://www.epicentro.iss.it/en/coronavirus/bollettino/ReportCOVID-2019_11_november_2020.pdf. Accessed November 11, 2020.

11. Strollo F, Satta E, Romano C, Alfarone C, Corte TD, Guarino G, et al. Coronavirus disease-2019, diabetes and dialysis: an internal medicine conundrum proposal for a suitable and easy-tohandle prevention protocol. Diabetes Res Open J. 2020; 6(2): 27-36. doi: 10.17140/DROJ-6-147

12. ISS Report, april 23, 2020. Characteristics of SARS-CoV-2 patients dying in Italy Report based on available data on April 23^th, 2020. IstitutoSuperiore di Sanità. Website. https://www.epicentro. iss.it/en/coronavirus/bollettino/Report-COVID-2019_23_ april_2020.pdf. Accessed October 22, 2020.

13. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011; 305(24): 2532-2539. doi: 10.1001/jama.2011.861

14. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, et al. US Renal data system 2013 annual data report. Am J Kidney Dis. 2014; 63(1 Suppl): A7. doi: 10.1053/j.ajkd.2013.11.001

15. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Ji Goldstein-Fuchs J, et al. Diabetic kidney disease: A report From an ADA consensus conference. Diabetes Care. 2014; 37(10): 2864- 2883. doi: 10.2337/dc14-1296

16. D’Aria I. Intervista a Fabio Malberti all’Ospedale di Cremona del 21 aprile 2020. Coronavirus, i pazienti in dialisi rischiano di più. La Repubblica [In: Italian]. Website. https://www. repubblica.it/salute/medicina-e-ricerca/2020/04/21/news/ coronavirus_i_pazienti_in_dialisi_rischiano_di_piu_ma_con_la_ cura_a_domicilio_meno_covid-positivi-254523027/. Accessed October 22, 2020.

17. Italian Society of Nephrology (SIN). Protocollo CORONAVIRUS & DIALISI. Website. https://sinitaly.org/wp-content/ uploads/2020/02/Coronavirus-Dialisi.pdf. Accessed October 22, 2020.

18. Ministero della Salute. Covid-19-Raccomandazioni per gli operatori sanitari. Website. http://www.salute.gov.it/portale/ nuovocoronavirus/dettaglioContenutiNuovoCoronavirus.jsp?lin gua=italiano&id=5373&area=nuovoCoronavirus&menu=vuoto. Accessed October 22, 2020.

19. Ma Y, Diao B, Lv X, Zhu J, Liang W, Liu L, et al. 2019 novel coronavirus disease in hemodialysis (HD) patients: Report from one HD center in Wuhan, China. Med Rxiv. 2020; doi: 10.1101/2020.02.24.20027201

20. Naicker S, Yang C-W, Hwang S-J, Liu B-C, Chen J-H, Jha V. The novel coronavirus 2019 epidemic and kidneys. Kidney Int. 2020; 97(5): 824-828. doi: 10.1016/j.kint.2020.03.001

21. Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (COVID-19) – China. 2020. Zhonghua Liu Xing Bing Xue Za Zhi. 2020; 41(2): 145-151. doi: 10.3760/cma.j.is sn.0254-6450.2020.02.003

22. Zhou J, Li C, Zhao G, Chu H, Wang D, Hoi-Ning Yan H, et al.Human intestinal tract serves as an alternative infection route forMiddle East respiratory syndrome coronavirus. Sci Adv. 2017; 3(11): eaao4966. doi: 10.1126/sciadv.aao4966

23. Daichou Y, Kurashige S, Hashimoto S, Suzuki S. Characteristic cytokine products of Th1 and Th2 cells in hemodialysis patients. Nephron. 1999; 83(3): 237-245. doi: 10.1159/000045516

24. Wang R, Liao C, He H, Hu C, Wei Z, Hong Z, et al. COVID-19 in hemodialysis patients: A report of 5 cases. Am J Kidney Dis. 2020; 76(1): 141-143. doi: 10.1053/j.ajkd.2020.03.009

25. Tang B, Li S, Xiong Y, Tian M, Yu J, Xu L, et al. Coronavirus disease 2019 (COVID-19) pneumonia in a hemodialysis patient. Kidney Med. 2020; 2(3): 354-358. doi: 10.1016/j.xkme.2020.03.001

26. Perico L, Benigni A, Remuzzi G. Should Covid-19 concern nephrologist? Why and to what extent? The emerging impasse of angiotensin blockade. Nephron. 2020; 144(5): 213-221. doi: 10.1159/000507305

27. Razzini K, Castrica M, Menchetti L, Maggid L, Negronia L, Orfeo NV, et al. SARS-CoV-2 RNA detection in the air and on surfaces in the COVID-19 ward of a hospital in Milan, Italy. Sci Total Environ. 2020; 742: 140540. doi: 10.1016/j.scitotenv.2020.140540

28. Felice C, Di Tanna GL, Zanus G, Grossi U. Impact of COVID-19 Outbreak on Healthcare Workers in Italy: Results from a National E-Survey. J Community Health. 2020; 45(4): 675-683. doi: 10.1007/s10900-020-00845-5

29. Italian Society of Nephrology (SIN). Protocol CORONAVIRUS & DIALISI. Website. https://sinitaly.org/wp-content/ uploads/2020/02/Coronavirus-Dialisi.pdf. Accessed October 22, 2020.

30. Ministero della Salute. Covid-19-Raccomandazioni per gli operatori sanitari. Website. http://www.salute.gov.it/portale/ nuovocoronavirus/dettaglioContenutiNuovoCoronavirus.jsp?lig ua=italiano&id=5373&area=nuovoCoronavirus&menu=vuoto. Accessed October 22, 2020.

31. Kliger AS, Silberzweig J. Mitigating risk of COVID-19 in dialysis facilities. Clin J Am Soc Nephrol. 2020; 15(5): 707-709. doi: 10.2215/CJN.03340320

32. Ordinanza del Capo della Protezione Civile n. 640 del 27 febbraio 2020. Website. http://www.protezionecivile.gov.it/ amministrazione-trasparente/provvedimenti/dettaglio/-/asset_publisher/default/content/ocdpc-n-640-del-27-febbraio2020-ulteriori-interventi-urgenti-di-protezione-civile-in-relazione-all-emergenza-relativa-al-rischio-sanitario-connesso-a. Accessed October 22, 2020.

33. Le indicazioni dei CDC. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19 (aggiornamento al 5 maggio 2020). Website. https://www.epicentro.iss. it/coronavirus/sars-cov-2-sorveglianza. Accessed October 22, 2020.

34. World Health Organization (WHO). WHO Interim guidance Laboratory testing for coronavirus disease (COVID-19) in suspected human cases (Aggiornamento al 19 marzo 2020). https://www.who.int/emergencies/diseases/novel-coronavirus-2019?gclid=Cj0KCQiAh4j-BRCsARIsAGeV12CovORp8MKFxvNXn03kwYFFvHCDOLZvJEME39I7TKOSDQnoQax4eaQaAmI4EALw_wcB. Accessed October 22, 2020.

35. Ministero della Salute, ISS, WHO document 2020. Prevenzione e risposta a COVID-19: evoluzione della strategia e pianificazione nella fase di transizione per il periodo autunno-invernale Approfondimento complementare ai documenti generali già resi pubblici su preparedness, pianificazione e contesti specifici. Misure aggiuntive di contenimento del contagio e gestione dei casi SARS-CoV-2 positivi. [In: Italian]. Website. http://www.salute. gov.it/imgs/C_17_pagineAree_5373_16_file.pdf. Accessed October 22, 2020.

36. World Health Organization (WHO). Clinical management of COVID-19; Interim guidance 27 May 2020. Geneva: WHO; 2020. Website. https://apps.who.int/iris/bitstream/ handle/10665/332196/WHO-2019-nCoV-clinical-2020.5- eng. pdf?sequence=1&isAllowed=y. Accessed October 22, 2020.

37. National Institutes of Health. COVID-19 Treatment Guide lines. Management of persons with COVID-19. Bethesda, MD NIH; 2020. Website. https://files.covid19treatmentguidelines. nih.gov/guidelines/covid19treatmentguidelines.pdf. Accessed October 22, 2020.

38. ADA Classification and diagnosis of diabetes. Standards of medical care in diabetes-2019. Diabetes Care. 2019; 42(Suppl 1): S13-S28. doi: 10.2337/dc19-Sint01

39. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). National Center for Health Statistics. Website. https://www. cdc.gov/nchs/icd/icd9cm.htm. Accessed January 7, 2020.

40. Gentile S, Mambro A, Strollo F. Parallel epidemics, or nearly so: Certainties and uncertainties about SARS-CoV-2 in Italy. Diabetes Res Clin Pract. 2020; 164: 108195. doi: 10.1016/j.diabres.2020.108195

41. Yuan J, Li M, Lv G, Lu ZK. Monitoring transmissibility and mortality of COVID-19 in Europe. Int J Infect Dis. 2020; 95: 311- 315. doi: 10.1016/j.ijid.2020.03.050

42. Presidenza del Consiglio dei Ministri. App Immuni. Website. http://www.governo.it/it/approfondimento/immuni/15336. Accessed October 22, 2020.

43. Sky-Th-24. App Immuni, ecco perché il sistema di tracciamento non ha funzionato. Website. https://tg24.sky.it/tecnologia/2020/10/23/app-immuni-non-funziona. Accessed October 20, 2020.

44. Huang L, Wang Y, Wang L, Lv Y, Liu Q. Coronavirus disease 2019 (COVID-19) pneumonia in a hemodialysis patient: A case report. Medicine (Baltimore). 2020; 99(27): e20956. doi: 10.1097/MD.0000000000020956

45. Rombolà G, Hedemperger M, Pedrini L, Farina M, Aucella F, Messa P, et al. Practical indications for the prevention and management of SARS‑CoV‑2 in ambulatory dialysis patients: Lessons from the first phase of the epidemics in Lombardy. J Nephrol. 2020; 33(2): 193-196. doi: 10.1007/s40620-020-00727-y2020

46. Ikizler TA. COVID-19 and dialysis units: What do we know now and what should we do? Am J Kidney Dis. 2020; 76(1): 1-3. doi: 10.1053/j.ajkd.2020.03.008

47. Chen G, Zhou Y, Zhang L, Wang Y, Hu R-R, Zhao X, et al. Core principles for infection prevention in hemodialysis centers during the COVID-19 pandemic. Infect Control Hosp Epidemiol. 2020; 41(7): 865-866. doi: 10.1017/ice.2020.109

48. La Stampa newspaper. Covid, discoteche aperte in Sardegna: aperta un’inchiesta per epidemia colposa. [In: Italian]. Website. https://www.lastampa.it/cronaca/2020/11/10/news/coviddiscoteche-aperte-in-sardegna-aperta-un-inchiesta-per-epidemiacolposa-1.39523163. Accessed Novembre 10, 2020.

49. Comune di Budoni. Coronavirus: ORDINANZA N. 31 DEL 4 LUGLIO 2020 – Processioni religiose e manifestazioni tradizionali. Website. http://www.comunebudoni.gov.it/index. php?id=76&oggetto=112. Accessed Novembre 10, 2020.

50. Coronavirus, stop a matrimoni e funerali: le regole in chiesa dalla messa in tv alla confessione a distanza. 9 marzo 2020. Website. https://www.ilsole24ore.com/art/coronavirus-stop-matrimoni-e-funerali-regole-chiesa-messa-tv-confessione-distanzaADCPyxB?refresh_ce=. Accessed Novembre 10, 2020.

51. Unità di Crisi Regionale della Campania. ex Decreto P.G.R.C. n. 51 del 20/3/2020. PROTOCOLLO DI SICUREZZA ANTIDIFFUSIONE SARS-COV-2 WEDDING E CERIMONIE. Website. https://thewam.net/wp-content/uploads/2020/09/ all-3-ord-75-protocollo-wedding-cerimonie.pdf. Accessed Novembre 10, 2020.

52. Sky-Th-24. App Immuni, ecco perché il sistema di tracciamento non ha funzionato. Website. https://tg24.sky.it/tecnologia/2020/10/23/app-immuni-non-funziona. Accessed October 20, 2020.

53. Meijers B, Messa P, Ronco C. Safeguarding the maintenance hemodialysis patient population during the Coronavirus disease 19 pandemic. Blood Purif. 2020; 49(3): 1-6. doi: 10.1159/000507537

54. de Sequera Ortiz P, Quiroga Gili B, del a Fuente GA, Macía Heras M, Salgueira Lazo M, del Pino y Pino MD, et al. Protocolo de actuación ante la epidemia de enfermedad porc oronavirus enlos pacientes de diálisisy trasplantados renales. [In: Spanish]. Nefrologia. 2020; 40(3): 253-257. doi: 10.1016/j.nefro.2020.03.001

55. Wang H. Maintenance hemodialysis and coronavirus disease 2019 (COVID-19): Saving lives with caution, care, and courage. Kidney Med. 2020; 2: 365-366. doi: 10.1016/j.xkme.2020.03.003 33

56. Meijers B, Messa P, Ronco C. Safeguarding the maintenance hemodialysis patient population during the coronavirus disease 19 pandemic. Blood Purif. 2020; 49(3): 259-264. doi: 10.1159/000507537

57. BC Renal. HD Infection Control: COVID-19 (WORKING COPY Mar 17, 2020). Guideline: Novel coronavirus (COVID-19) for Hemodialysis Outpatients. Website. http://www.bcrenalagency. ca/resource-gallery/Documents/COVID-19_Guideline_ for_Hemodialysis_Programs.pdf. Accessed October 22, 2020.