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Review| Volume 162, 108142, April 2020

COVID-19 and diabetes: Knowledge in progress

  • Akhtar Hussain
    Correspondence
    Corresponding author at: Post Box: 1490, 8049 Bodø, Norway.
    Affiliations
    Faculty of Health Sciences, Nord University, Bodø 8049, Norway

    Faculty of Medicine, Federal University of Ceará (FAMED-UFC), Brazil

    International Diabetes Federation (IDF), 166 Chaussee de La Hulpe, B - 1170 Brussels, Belgium

    Diabetes Asian Study Group (DASG), Ambwadi, Ahmedabad 380015, Gujarat, India

    Centre for Global Health Research, Diabetic Association of Bangladesh, Dhaka 1000, Bangladesh
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  • Bishwajit Bhowmik
    Affiliations
    Centre for Global Health Research, Diabetic Association of Bangladesh, Dhaka 1000, Bangladesh

    Institute of Health and Society, Department of Community Medicine and Global Health, University of Oslo (UiO), Oslo 0318, Norway
    Search for articles by this author
  • Nayla Cristina do Vale Moreira
    Affiliations
    Faculty of Medicine, Federal University of Ceará (FAMED-UFC), Brazil

    Institute of Health and Society, Department of Community Medicine and Global Health, University of Oslo (UiO), Oslo 0318, Norway
    Search for articles by this author
Open AccessPublished:April 09, 2020DOI:https://doi.org/10.1016/j.diabres.2020.108142
COVID-19 and diabetes: Knowledge in progress
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      Highlights

      • •
        Diabetesis associated with severity and death in patients with COVID-19.
      • •
        Inflammation, hypercoagulation, impaired immunity may increase morbidity and mortality.
      • •
        Evidence does not support the discontinuation of ACEIs, ARBs or thiazolidinediones.
      • •
        Hypoglycemic events may occur with chloroquine use in people with diabetes and COVID-19.
      • •
        Rigorous glucose monitoring and dose adjustments of anti-diabetic drugs are important.
      • •
        Patient tailored therapy and lower thresholds for hospitalization may increase survival.

      Abstract

      Aims

      We aimed to briefly review the general characteristics of the novel coronavirus (SARS-CoV-2) and provide a better understanding of the coronavirus disease (COVID-19) in people with diabetes, and its management.

      Methods

      We searched for articles in PubMed and Google Scholar databases till 02 April 2020, with the following keywords: “SARS-CoV-2”, “COVID-19”, “infection”, “pathogenesis”, “incubation period”, “transmission”, “clinical features”, “diagnosis”, “treatment”, “diabetes”, with interposition of the Boolean operator “AND”.

      Results

      The clinical spectrum of COVID-19 is heterogeneous, ranging from mild flu-like symptoms to acute respiratory distress syndrome, multiple organ failure and death. Older age, diabetes and other comorbidities are reported as significant predictors of morbidity and mortality. Chronic inflammation, increased coagulation activity, immune response impairment, and potential direct pancreatic damage by SARS-CoV-2 might be among the underlying mechanisms of the association between diabetes and COVID-19. No conclusive evidence exists to support the discontinuation of angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers or thiazolidinediones because of COVID-19 in people with diabetes. Caution should be taken to potential hypoglycemic events with the use of chloroquine in these subjects. Patient tailored therapeutic strategies, rigorous glucose monitoring and careful consideration of drug interactions might reduce adverse outcomes.

      Conclusions

      Suggestions are made on the possible pathophysiological mechanisms of the relationship between diabetes and COVID-19, and its management. No definite conclusions can be made based on current limited evidence. Further research regarding this relationship and its clinical management is warranted.

      Keywords

      1. Introduction

      Coronaviruses are enveloped, positive single-stranded RNA viruses widely distributed in humans and animals worldwide [
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395 (Epub 2020/01/28. PubMed PMID: 31986264): 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      ]. Although most human coronavirus infections are mild, major outbreaks of two betacoronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002–2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, have caused deadly pneumonia, with mortality rates of 10% for SARS-CoV and 36% for MERS-CoV [
      • Song Z.
      • Xu Y.
      • Bao L.
      • Zhang L.
      • Yu P.
      • Qu Y.
      • et al.
      From SARS to MERS, thrusting coronaviruses into the spotlight.
      Viruses. 2019; 11 (Epub 2019/01/17. Epub 2019/01/17PubMed PMID: 30646565; PubMed Central PMCID: PMCPMC6357155)https://doi.org/10.3390/v11010059
      ].
      In December 2019, clusters of pneumonia cases of unknown etiology emerged in Wuhan, Hubei Province, China. Deep sequencing analysis from lower respiratory tract samples indicated a novel coronavirus as the causative agent, which was named Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), and the disease it causes called COVID-19 [
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395 (Epub 2020/01/28. PubMed PMID: 31986264): 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      ,

      World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it 2020 [31/03/2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it.

      ]. Although SARS-CoV-2 has shown phylogenetic and clinical similarities with SARS-CoV, the novel coronavirus appears to have a higher transmissibility and lower case fatality rates [
      • Ceccarelli M.
      • Berretta M.
      • Venanzi Rullo E.
      • Nunnari G.
      • Cacopardo B.
      Differences and similarities between Severe Acute Respiratory Syndrome (SARS)-CoronaVirus (CoV) and SARS-CoV-2. Would a rose by another name smell as sweet?.
      Eur Rev Med Pharmacol Sci. 2020; 24 (Epub 2020/03/21. PubMed PMID: 32196628): 2781-2783https://doi.org/10.26355/eurrev_202003_20551
      ]. On 30 January 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a Public Health Emergency of International Concern, and on March 11, the epidemic was upgraded to pandemic [

      World Health Organization. Rolling updates on coronavirus disease (COVID-19) 2020 [31/03/2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen.

      ]. As of today (02.04.2020), 827,419 confirmed cases are officially reported in more than 200 countries or territories with 40,777 deaths [

      World Health Organization. Coronavirus disease (COVID-19) Pandemic 2020 [02/04/2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019.

      ].
      We conducted a scoping review to provide a brief summary of the general characteristics of COVID-19, as well as a more detailed description and critical assessment of the association between this new infectious disease and diabetes. We hope this review can provide meaningful information for future research and ultimately contribute to better clinical management of patients with COVID-19 and diabetes.

      2. Methods

      A literature review was carried out to search for articles in PubMed and Google Scholar databases till 02 April 2020. The following keywords were used: “SARS-CoV-2”, “COVID-19”, “infection”, “pathogenesis”, “incubation period”, “transmission”, “clinical features”, “diagnosis”, “treatment”, “diabetes”, with interposition of the Boolean operator “AND”. We also retrieved the full text of the relevant cross references from the search results. Furthermore, we accessed the currently available scientific literature and recommendations in the WHO and United States Centers for Disease Control and Prevention (CDC) websites.

      3. General characteristics of COVID-19

      3.1 Incubation period

      The incubation period is described as the time from infection to illness onset. In a study of 1099 patients from China with laboratory-confirmed symptomatic COVID-19, the median incubation period was four days (interquartile range, 2–7) [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ]. Another study including 181 confirmed cases reported a median incubation period of approximately 5 days, and that symptoms would develop in 97.5% of infected individuals within 12 days [
      • Lauer S.A.
      • Grantz K.H.
      • Bi Q.
      • Jones F.K.
      • Zheng Q.
      • Meredith H.R.
      • et al.
      The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application.
      Ann Intern Med. 2020; (Epub 2020/03/10. PubMed PMID: 32150748; PubMed Central PMCID: PMCPMC7081172)https://doi.org/10.7326/M20-0504
      ]. Based on the incubation period of SARS-CoV and MERS-CoV, as well as observational data, the United States CDC has estimated that symptoms of COVID-19 will usually develop within 2–14 days after exposure. Therefore, fourteen days has been the time applied internationally for monitoring and restricting the movement of healthy individuals (quarantine period) [

      Centers for Diasease Control and Prevention. Symptoms of Coronavirus 2020 [cited 31/03/2020]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html.

      ].

      3.2 Modes of transmission

      Most initial COVID-19 patients had a direct contact history with a local Chinese seafood and wildlife market, suggesting a common-source zoonotic exposure as the main mode of transmission [
      • Jalava K.
      First respiratory transmitted food borne outbreak?.
      Int J Hyg Environ Health. 2020; 226 (Epub 2020/02/24 PubMed PMID: 32088598)https://doi.org/10.1016/j.ijheh.2020.113490
      ]. Findings from virus genome sequencing analysis have pointed out that SARS-CoV-2 and bat coronavirus (bat CoV) might share the same ancestor, although bats are not for sale in this seafood market [
      • Guo Y.R.
      • Cao Q.D.
      • Hong Z.S.
      • Tan Y.Y.
      • Chen S.D.
      • Jin H.J.
      • et al.
      The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.
      Mil Med Res. 2020; 7 (Epub 2020/03/15. PubMed PMID: 32169119; PubMed Central PMCID: PMCPMC7068984): 11https://doi.org/10.1186/s40779-020-00240-0
      ]. Later cases were reported among health care workers and others without exposure history of wildlife or visiting Wuhan, which indicated human-to-human transmission [
      • Jalava K.
      First respiratory transmitted food borne outbreak?.
      Int J Hyg Environ Health. 2020; 226 (Epub 2020/02/24 PubMed PMID: 32088598)https://doi.org/10.1016/j.ijheh.2020.113490
      ]. Currently, it is considered that the virus can be mainly transmitted through droplets, direct contact and aerosols. Droplets transmission may occur when respiratory droplets, produced when an infected person coughs or sneezes, are ingested or inhaled by individuals nearby (within about 6 feet). A subject can also get infected by touching a surface or object contaminated with the virus and subsequently touching his/her mouth, nose, or eyes [
      • Adhikari S.P.
      • Meng S.
      • Wu Y.J.
      • Mao Y.P.
      • Ye R.X.
      • Wang Q.Z.
      • et al.
      Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review.
      Infect Dis Poverty. 2020; 9 (Epub 2020/03/19. PubMed PMID: 32183901; PubMed Central PMCID: PMCPMC7079521): 29https://doi.org/10.1186/s40249-020-00646-x
      ]. Additionally, it has been shown experimentally that the virus can remain viable in aerosols for at least 3 h [
      • van Doremalen N.
      • Bushmaker T.
      • Morris D.H.
      • Holbrook M.G.
      • Gamble A.
      • Williamson B.N.
      • et al.
      Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1.
      N Engl J Med. 2020; (Epub 2020/03/18 PubMed PMID: 32182409)https://doi.org/10.1056/NEJMc2004973
      ], and can be transmitted in closed environments if inhaled into the lungs [
      • Adhikari S.P.
      • Meng S.
      • Wu Y.J.
      • Mao Y.P.
      • Ye R.X.
      • Wang Q.Z.
      • et al.
      Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review.
      Infect Dis Poverty. 2020; 9 (Epub 2020/03/19. PubMed PMID: 32183901; PubMed Central PMCID: PMCPMC7079521): 29https://doi.org/10.1186/s40249-020-00646-x
      ]. Therefore, airborne transmission is a possibility during aerosol generating procedures, e.g., endotracheal intubation, bronchoscopy, non-invasive positive-pressure ventilation, tracheostomy, cardiopulmonary resuscitation, etc [

      World Health Organization. Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations 2020 [30/03/2020]. Available from: https://www.who.int/news-room/commentaries/detail/modes-of-transmission-of-virus-causing-covid-19-implications-for-ipc-precaution-recommendations.

      ]. Although viable virus has been identified in fecal swabs, the fecal-oral route does not appear to be a driver of COVID-19 transmission [
      • Guo Y.R.
      • Cao Q.D.
      • Hong Z.S.
      • Tan Y.Y.
      • Chen S.D.
      • Jin H.J.
      • et al.
      The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.
      Mil Med Res. 2020; 7 (Epub 2020/03/15. PubMed PMID: 32169119; PubMed Central PMCID: PMCPMC7068984): 11https://doi.org/10.1186/s40779-020-00240-0
      ].

      3.3 Period of infectivity

      It is uncertain how long an individual with COVID-19 remains infectious. The period of infectivity is often assessed indirectly by detection of viral RNA from respiratory specimens. However, viral RNA does not necessarily confirm the presence of infectious virus. Higher viral loads have been detected soon after symptom onset, suggesting that transmission may be more likely to occur in the earlier stages of infection [
      • Zou L.
      • Ruan F.
      • Huang M.
      • Liang L.
      • Huang H.
      • Hong Z.
      • et al.
      SARS-CoV-2 viral load in upper respiratory specimens of infected patients.
      N Engl J Med. 2020; 382 (Epub 2020/02/20. PubMed PMID: 32074444): 1177-1179https://doi.org/10.1056/NEJMc2001737
      ]. The viral shedding duration seems to vary according to the disease severity. It has been found that around 90% of patients with milder symptoms had a negative viral RNA test on nasopharyngeal swabs by day 10 post-onset, while the test remained positive for a longer time in all severe cases [
      • Liu Y.
      • Yan L.M.
      • Wan L.
      • Xiang T.X.
      • Le A.
      • Liu J.M.
      • et al.
      Viral dynamics in mild and severe cases of COVID-19.
      Lancet Infect Dis. 2020; (Epub 2020/03/23 PubMed PMID: 32199493)https://doi.org/10.1016/S1473-3099(20)30232-2
      ]. On the other hand, it has been reported that the viral load detected in asymptomatic patients was similar to that in symptomatic subjects [
      • Zou L.
      • Ruan F.
      • Huang M.
      • Liang L.
      • Huang H.
      • Hong Z.
      • et al.
      SARS-CoV-2 viral load in upper respiratory specimens of infected patients.
      N Engl J Med. 2020; 382 (Epub 2020/02/20. PubMed PMID: 32074444): 1177-1179https://doi.org/10.1056/NEJMc2001737
      ]. Indeed, transmission from asymptomatic carriers or individuals within the incubation period has been described [
      • Rothe C.
      • Schunk M.
      • Sothmann P.
      • Bretzel G.
      • Froeschl G.
      • Wallrauch C.
      • et al.
      Transmission of 2019-nCoV infection from an asymptomatic contact in Germany.
      N Engl J Med. 2020; 382 (Epub 2020/02/01. PubMed PMID: 32003551): 970-971https://doi.org/10.1056/NEJMc2001468
      ]. Nevertheless, the extent to which this occurs remains to be determined.

      3.4 Demography and clinical characteristics

      Even though all age groups have been affected by COVID-19, the median age appears to be around 47–59 years, and usually higher among severe cases and non-survivors. No specific gender bias seems to exist for the contamination with the virus, but men tend to have a higher propensity of the cases [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      JAMA. 2020; (Epub 2020/02/08. PubMed PMID: 32031570; PubMed Central PMCID: PMCPMC7042881)https://doi.org/10.1001/jama.2020.1585
      ,
      • Zhang J.J.
      • Dong X.
      • Cao Y.Y.
      • Yuan Y.D.
      • Yang Y.B.
      • Yan Y.Q.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      Allergy. 2020; (Epub 2020/02/23 PubMed PMID: 32077115)https://doi.org/10.1111/all.14238
      ]. Fewer cases have been identified among children and infants. In a large Chinese report including 72,314 patients, only 2% of those infected were younger than 20 years old [
      • Wu Zunyou
      • McGoogan Jennifer M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
      JAMA. 2020; 323: 1239https://doi.org/10.1001/jama.2020.2648
      ].
      The clinical spectrum of COVID-19 can be very heterogeneous. Most adults and children present mild flu-like symptoms, but some may rapidly develop acute respiratory distress syndrome (ARDS), respiratory failure, arrhythmias, acute cardiac injury, shock, multiple organ failure and death [
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395 (Epub 2020/01/28. PubMed PMID: 31986264): 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      JAMA. 2020; (Epub 2020/02/08. PubMed PMID: 32031570; PubMed Central PMCID: PMCPMC7042881)https://doi.org/10.1001/jama.2020.1585
      ]. The most commonly reported symptoms are fever, cough, fatigue, sputum production and shortness of breath. However, headache, upper respiratory symptoms (e.g., sore throat and rhinorrhea) and gastrointestinal symptoms (e.g., nausea and diarrhea) occur less often [
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395 (Epub 2020/01/28. PubMed PMID: 31986264): 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      ,
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      JAMA. 2020; (Epub 2020/02/08. PubMed PMID: 32031570; PubMed Central PMCID: PMCPMC7042881)https://doi.org/10.1001/jama.2020.1585
      ]. Although not described in the initial Chinese studies, smell and taste disorders (e.g., anosmia and dysgeusia) have also been found frequently in patients with COVID-19 in Italy [
      • Giacomelli A.
      • Pezzati L.
      • Conti F.
      • Bernacchia D.
      • Siano M.
      • Oreni L.
      • et al.
      Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study.
      Clin Infect Dis. 2020; (Epub 2020/03/28 PubMed PMID: 32215618)https://doi.org/10.1093/cid/ciaa330
      ].
      In laboratory examination results, most patients have normal or decreased white blood cell counts, particularly lymphocytopenia [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ]. However, in severe patients, the neutrophil count, inflammatory markers, D-dimer, blood urea, and creatinine levels are generally higher, with further decreased lymphocyte counts [
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395 (Epub 2020/01/28. PubMed PMID: 31986264): 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      ]. Chest computed tomography (CT) most commonly shows ground-glass opacifications with or without consolidative abnormalities. They are also more likely to be bilateral, have a peripheral distribution and involve the lower lobes [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ,
      • Shi H.
      • Han X.
      • Jiang N.
      • Cao Y.
      • Alwalid O.
      • Gu J.
      • et al.
      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): 425-434https://doi.org/10.1016/S1473-3099(20)30086-4
      ]. While some confirmed cases may present normal CT images [
      • Guo Y.R.
      • Cao Q.D.
      • Hong Z.S.
      • Tan Y.Y.
      • Chen S.D.
      • Jin H.J.
      • et al.
      The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.
      Mil Med Res. 2020; 7 (Epub 2020/03/15. PubMed PMID: 32169119; PubMed Central PMCID: PMCPMC7068984): 11https://doi.org/10.1186/s40779-020-00240-0
      ], abnormalities have also been identified prior to the development of symptoms in some patients [
      • Shi H.
      • Han X.
      • Jiang N.
      • Cao Y.
      • Alwalid O.
      • Gu J.
      • et al.
      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): 425-434https://doi.org/10.1016/S1473-3099(20)30086-4
      ].

      3.5 Diagnosis

      The diagnosis of COVID-19 cannot be made without microbiologic analysis. Patients who meet the criteria discussed below should undergo testing for SARS-CoV-2, in addition to testing for other respiratory pathogens (e.g., influenza, respiratory syncytial virus, etc). Since testing for COVID-19 in suspected cases is limited owing to inadequate capacity, local health authorities may introduce specific criteria for priority cases [

      World Health Organization. Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans 2020 [30/03/2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/laboratory-guidance.

      ]. Although many laboratory tests have been developed, real-time fluorescence (RT-PCR) has been the current standard diagnostic method for diagnosis of COVID-19, by detecting the positive nucleic acid of SARS-CoV-2 in sputum, throat swabs, and secretions of the lower respiratory tract samples [

      World Health Organization. Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans 2020 [30/03/2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/laboratory-guidance.

      ,
      • Li Z.
      • Yi Y.
      • Luo X.
      • Xiong N.
      • Liu Y.
      • Li S.
      • et al.
      Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis.
      J Med Virol. 2020; (Epub 2020/02/28 PubMed PMID: 32104917)https://doi.org/10.1002/jmv.25727
      ].

      3.5.1 Criteria for suspicion and testing

      Community surveillance should be introduced in all countries in order to register the new cases of COVID-19 and map the transmission route. According to the WHO and other literature, the following is recommended [

      World Health Organization. Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans 2020 [30/03/2020]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/laboratory-guidance.

      ,

      Centers for Disease Control and Prevention. Updated Guidance on Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19). 2020 [30/03/2020]. Available from: https://emergency.cdc.gov/han/2020/han00429.asp.

      ]:

      3.5.1.1 Preliminary symptoms for observations

      Individuals with new onset fever and/or respiratory tract symptoms (e.g., cough, dyspnea) or patients with severe lower respiratory tract illness, without any clear cause and without any history of close contact with a confirmed COVID-19 patient or have travelled to an area of community transmission.

      3.5.1.2 Tests should be performed depending on resources

      Subjects with new onset fever and/or respiratory tract symptoms (e.g., cough, dyspnea) or patients with severe lower respiratory tract illness, who have been in contact with COVID-19 patients or travelled within 14 days to a location where community transmission of SARS-CoV-2 is present. Furthermore, patients older than 60 years of age, as well as those with underlying conditions like diabetes, hypertension, cardiovascular diseases (CVDs), chronic renal disease, cancer and immunocompromising conditions, who develop symptoms of fever, cough and/or dyspnea should be prioritized for testing.

      3.5.1.3 Must be tested

      Persons in close contact (within 2 m) with a SARS-CoV-2 infected individual for a prolonged period or in direct contact with infectious secretions while not wearing personal protective equipment.

      3.6 COVID-19 and comorbidities

      Although the pathophysiological mechanisms are still not understood, it has been observed that most severe and fatal cases with COVID-19 have occurred in the elderly or in patients with underlying comorbidities, particularly CVDs, diabetes mellitus, chronic lung and renal disease, hypertension, and cancer [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ,
      • Wu Zunyou
      • McGoogan Jennifer M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
      JAMA. 2020; 323: 1239https://doi.org/10.1001/jama.2020.2648
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Lancet. 2020; (Epub 2020/03/15. PubMed PMID: 32171076)https://doi.org/10.1016/S0140-6736(20)30566-3
      ,
      • Yang J.
      • Zheng Y.
      • Gou X.
      • Pu K.
      • Chen Z.
      • Guo Q.
      • et al.
      Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis.
      Int J Infect Dis. 2020; (Epub 2020/03/17 PubMed PMID: 32173574)https://doi.org/10.1016/j.ijid.2020.03.017
      ].
      One Chinese meta-analysis including 1527 patients showed that the most prevalent cardiovascular metabolic comorbidities with COVID-19 were hypertension (17.1%, 95% CI 9.9–24.4%) and cardio-cerebrovascular disease (16.4%, 95% CI 6.6–26.1%), followed by diabetes (9.7%, 95% CI 6.9–12.5%). In this report, patients with diabetes or hypertension had a 2-fold increase in risk of severe disease or requiring intensive care unit (ICU) admission, while those with cardio-cerebrovascular disease had a 3-fold increase [
      • Li B.
      • Yang J.
      • Zhao F.
      • Zhi L.
      • Wang X.
      • Liu L.
      • et al.
      Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.
      Clin Res Cardiol. 2020; (Epub 2020/03/13 PubMed PMID: 32161990)https://doi.org/10.1007/s00392-020-01626-9
      ]. In a sub-set of 355 patients with COVID-19 in Italy who died, the mean number of pre-existing underlying conditions was 2.7, and only 3 subjects did not have any comorbidity [
      • 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)https://doi.org/10.1001/jama.2020.4683
      ].
      It has been consistently reported that, in addition to pneumonia, SARS-CoV-2 may cause damage to other organs including the heart, liver and kidneys [
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395 (Epub 2020/01/28. PubMed PMID: 31986264): 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      JAMA. 2020; (Epub 2020/02/08. PubMed PMID: 32031570; PubMed Central PMCID: PMCPMC7042881)https://doi.org/10.1001/jama.2020.1585
      ]. Therefore, full attention should be paid to the treatment of the original comorbidities, especially in older patients with already severe underlying conditions.

      4. Association between COVID-19 and diabetes

      4.1 Diabetes and Infection: General considerations and potential mechanisms

      Diabetes is one of the leading causes of morbidity and mortality throughout the world. The condition is associated with several macrovascular and microvascular complications, that ultimately impact the overall patient’s survival [
      • Williams R.
      • Karuranga S.
      • Malanda B.
      • Saeedi P.
      • Basit A.
      • Besançon S.
      • et al.
      Global and regional estimates and projections of diabetes-related health expenditure: results from the International Diabetes Federation Diabetes Atlas.
      Diabetes Res Clin Pract. 2020; 162108072https://doi.org/10.1016/j.diabres.2020.108072
      ]. A relationship between diabetes and infection has long been clinically recognized [
      • Pearson-Stuttard Jonathan
      • Blundell Samkeliso
      • Harris Tess
      • Cook Derek G
      • Critchley Julia
      Diabetes and infection: assessing the association with glycaemic control in population-based studies.
      Lancet Diabetes Endocrinol. 2016; 4: 148-158https://doi.org/10.1016/S2213-8587(15)00379-4
      ]. Infections, particularly influenza and pneumonia, are often common and more serious in older people with type 2 diabetes mellitus (T2DM) [
      • McDonald H.I.
      • Nitsch D.
      • Millett E.R.C.
      • Sinclair A.
      • Thomas S.L.
      New estimates of the burden of acute community-acquired infections among older people with diabetes mellitus: a retrospective cohort study using linked electronic health records.
      Diabet Med. 2014; 31: 606-614https://doi.org/10.1111/dme.2014.31.issue-510.1111/dme.12384
      ,
      • Li Sen
      • Wang Jiaxin
      • Zhang Biao
      • Li Xinyi
      • Liu Yuan
      Diabetes mellitus and cause-specific mortality: a population-based study.
      Diabetes Metab J. 2019; 43: 319https://doi.org/10.4093/dmj.2018.0060
      ]. Nevertheless, the evidence remains controversial regarding whether diabetes itself indeed increases susceptibility and impacts outcomes from infections, or the cardiovascular and renal comorbidities that are frequently associated with diabetes are the main factors involved [
      • Knapp Sylvia
      Diabetes and infection: is there a link? - A mini-review.
      Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107
      ].
      Diabetes and uncontrolled glycaemia were reported as significant predictors of severity and deaths in patients infected with different viruses, including the 2009 pandemic influenza A (H1N1) [
      • 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; 19https://doi.org/10.1186/s12879-019-4592-0
      ], SARS-CoV [
      • Yang J.K.
      • Feng Y.
      • Yuan M.Y.
      • Yuan S.Y.
      • Fu H.J.
      • Wu B.Y.
      • et al.
      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): 623-628https://doi.org/10.1111/j.1464-5491.2006.01861.x
      ] and MERS-CoV [
      • 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-z
      ]. In the current SARS-CoV-2 pandemic, some studies did not find a clear association between diabetes and severe disease [
      • Zhang J.J.
      • Dong X.
      • Cao Y.Y.
      • Yuan Y.D.
      • Yang Y.B.
      • Yan Y.Q.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      Allergy. 2020; (Epub 2020/02/23 PubMed PMID: 32077115)https://doi.org/10.1111/all.14238
      ,
      • Lippi G.
      • Plebani M.
      Laboratory abnormalities in patients with COVID-2019 infection.
      Clin Chem Lab Med. 2020; (Epub 2020/03/03 PubMed PMID: 32119647)https://doi.org/10.1515/cclm-2020-0198
      ]. However, other reports from China [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ,
      • Wu Zunyou
      • McGoogan Jennifer M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
      JAMA. 2020; 323: 1239https://doi.org/10.1001/jama.2020.2648
      ] and Italy [
      • 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)https://doi.org/10.1001/jama.2020.4683
      ] showed that older patients with chronic diseases, including diabetes, were at higher risk for severe COVID-19 and mortality.
      Scarce data exist regarding glucose metabolism and development of acute complications of diabetes (e.g., ketoacidosis) in patients with COVID-19. Infection of SARS-CoV-2 in those with diabetes possibly triggers higher stress conditions, with greater release of hyperglycemic hormones, e.g., glucocorticoids and catecholamines, leading to increased blood glucose levels and abnormal glucose variability [
      • Wang Aihong
      • Zhao Weibo
      • Xu Zhangrong
      • Gu Jianwen
      Timely blood glucose management for the outbreak of 2019 novel coronavirus disease (COVID-19) is urgently needed.
      Diabetes Res Clin Pract. 2020; 162: 108118https://doi.org/10.1016/j.diabres.2020.108118
      ]. On the other hand, a retrospective study from Wuhan reported that around 10% of the patients with T2DM and COVID-19 suffered at least one episode of hypoglycemia (<3.9 mmol/L) [
      • Zhou J.
      • Tan J.
      Diabetes patients with COVID-19 need better care.
      Metabolism. 2020; (Epub 2020/03/30. PubMed PMID: 32220612; PubMed Central PMCID: PMCPMC7102634)https://doi.org/10.1016/j.metabol.2020.154216
      ]. Hypoglycemia has been shown to mobilize pro-inflammatory monocytes and increase platelet reactivity, contributing to a higher cardiovascular mortality in patients with diabetes [
      • Iqbal A.
      • Prince L.R.
      • Novodvorsky P.
      • Bernjak A.
      • Thomas M.R.
      • 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 (Epub 2018/09/27. PubMed PMID: 30252067; PubMed Central PMCID: PMCPMC6391720): 1187-1199https://doi.org/10.1210/jc.2018-01168
      ]. Yet it remains largely unknown how exactly the inflammatory and immune response occurs in these patients, as well as whether hyper- or hypoglycemia may alter the SARS-CoV-2 virulence, or the virus itself interferes with insulin secretion or glycemic control. Furthermore, the impact of usual diabetes drug treatment on COVID-19 outcomes, as well as therapeutic approaches for COVID-19 on glucose regulation remains unspecified.
      Diabetes is a chronic inflammatory condition characterized by multiple metabolic and vascular abnormalities that can affect our response to pathogens [
      • Knapp Sylvia
      Diabetes and infection: is there a link? - A mini-review.
      Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107
      ]. Hyperglycemia and insulin resistance promote increased synthesis of glycosylation end products (AGEs) and pro-inflammatory cytokines, oxidative stress, in addition to stimulating the production of adhesion molecules that mediate tissue inflammation [
      • Knapp Sylvia
      Diabetes and infection: is there a link? - A mini-review.
      Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107
      ,
      • Petrie John R.
      • Guzik Tomasz J.
      • Touyz Rhian M.
      Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms.
      Canadian J Cardiol. 2018; 34: 575-584https://doi.org/10.1016/j.cjca.2017.12.005
      ]. This inflammatory process may compose the underlying mechanism that leads to a higher propensity to infections, with worse outcomes thereof in patients with diabetes [
      • Knapp Sylvia
      Diabetes and infection: is there a link? - A mini-review.
      Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107
      ].
      Several defects in immunity have been associated with hyperglycemia, even though the clinical relevance of some in vitro disturbances are still not fully understood [
      • Geerlings S.E.
      • Hoepelman A.I.
      Immune dysfunction in patients with diabetes mellitus (DM).
      FEMS Immunol Med Microbiol. 1999; 26 (Epub 1999/11/27 PubMed PMID: 10575137): 259-265https://doi.org/10.1111/j.1574-695X.1999.tb01397.x
      ]. Poorly controlled diabetes has been linked to inhibited lymphocyte proliferative response to different kinds of stimuli [
      • Moutschen M.P.
      • Scheen A.J.
      • Lefebvre P.J.
      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 (Epub 1992/05/01. PubMed PMID: 1397473): 187-201
      ], as well as impaired monocyte/macrophage and neutrophil functions [
      • Knapp Sylvia
      Diabetes and infection: is there a link? - A mini-review.
      Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107
      ]. Abnormal delayed type hypersensitivity reaction [
      • Geerlings S.E.
      • Hoepelman A.I.
      Immune dysfunction in patients with diabetes mellitus (DM).
      FEMS Immunol Med Microbiol. 1999; 26 (Epub 1999/11/27 PubMed PMID: 10575137): 259-265https://doi.org/10.1111/j.1574-695X.1999.tb01397.x
      ] and complement activation dysfunction [
      • Ilyas R.
      • Wallis R.
      • Soilleux E.J.
      • Townsend P.
      • Zehnder D.
      • Tan B.K.
      • et al.
      High glucose disrupts oligosaccharide recognition function via competitive inhibition: a potential mechanism for immune dysregulation in diabetes mellitus.
      Immunobiology. 2011; 216 (Epub 2010/08/03. PubMed PMID: 20674073; PubMed Central PMCID: PMCPMC3088832): 126-131https://doi.org/10.1016/j.imbio.2010.06.002
      ] have also been described in patients with diabetes. In vitro studies have shown that pulmonary epithelial cells exposure to high glucose concentrations significantly increases influenza virus infection and replication, indicating that hyperglycemia may enhance viral replication in vivo [
      • 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.2013.06.026
      ]. In animal models, structural lung changes have been related to diabetes, such as augmented vasculature permeability and collapsed alveolar epithelium [
      • Popov D.
      • Simionescu M.
      Alterations of lung structure in experimental diabetes, and diabetes associated with hyperlipidaemia in hamsters.
      Eur Respir J. 1997; 10 (Epub 1997/08/01 PubMed PMID: 9272930): 1850-1858https://doi.org/10.1183/09031936.97.10081850
      ]. On the other hand, patients with diabetes generally present a significant reduction in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), which is associated with raised plasma glucose levels [
      • 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): 14-19
      ].

      4.2 Aspects of SARS-CoV-2 pathogenesis and potential implications for clinical management of patients with COVID-19 and diabetes

      Patients with COVID-19 commonly show on admission lymphocytopenia, and to a lesser extent thrombocytopenia and leukopenia, which are more prominent among those with severe disease [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ]. Further, elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and C-reactive protein, as well as increased coagulation activity, marked by higher d-dimer concentrations, were also associated with severity [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Lancet. 2020; (Epub 2020/03/15. PubMed PMID: 32171076)https://doi.org/10.1016/S0140-6736(20)30566-3
      ]. In T2DM, besides the marked inflammatory process previously discussed, an imbalance between coagulation and fibrinolysis takes place, with increased levels of clotting factors and relative inhibition of the fibrinolytic system. Both insulin resistance and T2DM are associated with endothelial dysfunction, and enhanced platelet aggregation and activation. These abnormalities favor the development of a hypercoagulable pro-thrombotic state [
      • Dunn E.J.
      • Grant P.J.
      Type 2 diabetes: an atherothrombotic syndrome.
      Curr Mol Med. 2005; 5 (Epub 2005/05/17. PubMed PMID: 15892651): 323-332https://doi.org/10.2174/1566524053766059
      ]. Additionally, atherosclerosis, vascular inflammation and endothelial dysfunction are also part of the pathogenesis of other chronic conditions, e.g., hypertension and CVDs [
      • Petrie John R.
      • Guzik Tomasz J.
      • Touyz Rhian M.
      Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms.
      Canadian J Cardiol. 2018; 34: 575-584https://doi.org/10.1016/j.cjca.2017.12.005
      ]. Animal studies involving SARS-CoV reported that older age was related to defects in T-cell and B-cell function and excess inflammation markers. Thus, T2DM alone or in association with older age, hypertension and/or CVDs might contribute to a deficient control of SARS-CoV-2 replication and more prolonged proinflammatory response, potentially leading to poor outcomes [
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Lancet. 2020; (Epub 2020/03/15. PubMed PMID: 32171076)https://doi.org/10.1016/S0140-6736(20)30566-3
      ].
      Viral entry into the host cells is a fundamental component of cross-species transmission, particularly for the coronaviruses (CoVs). Upon exposure of the host to the virus, all CoVs, through a Spike protein, bind to cells that express specific receptors. After binding to the target cells, the host-cell protease cleaves the spike, which allows the virus to enter and replicate [
      • Letko Michael
      • Marzi Andrea
      • Munster Vincent
      Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.
      Nat Microbiol. 2020; 5: 562-569https://doi.org/10.1038/s41564-020-0688-y
      ]. The angiotensin-converting enzyme 2 (ACE2) has been identified as one of the main receptors for both SARS-CoV [
      • Li W.
      • Moore M.J.
      • Vasilieva N.
      • Sui J.
      • Wong S.K.
      • Berne M.A.
      • et al.
      Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
      Nature. 2003; 426 (Epub 2003/12/04. PubMed PMID: 14647384): 450-454https://doi.org/10.1038/nature02145
      ] and SARS-CoV-2 [
      • Letko Michael
      • Marzi Andrea
      • Munster Vincent
      Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.
      Nat Microbiol. 2020; 5: 562-569https://doi.org/10.1038/s41564-020-0688-y
      ]. ACE2 is widely expressed on the respiratory tract, heart, kidneys, intestines, cerebral neurons, endothelium of arteries and veins, immune cells and pancreas [
      • Song Z.
      • Xu Y.
      • Bao L.
      • Zhang L.
      • Yu P.
      • Qu Y.
      • et al.
      From SARS to MERS, thrusting coronaviruses into the spotlight.
      Viruses. 2019; 11 (Epub 2019/01/17. Epub 2019/01/17PubMed PMID: 30646565; PubMed Central PMCID: PMCPMC6357155)https://doi.org/10.3390/v11010059
      ]. A Chinese study compared 39 SARS-CoV patients without previous diabetes, who did not receive steroid treatment, with 39 matched healthy siblings and showed that 20 of the 39 SARS-CoV patients developed diabetes during hospitalization. Since immunostaining for ACE2 was strong in the pancreatic islets, it was suggested that SARS-CoV might have damaged islets and caused acute insulin dependent diabetes mellitus [
      • Yang Jin-Kui
      • Lin Shan-Shan
      • Ji Xiu-Juan
      • Guo Li-Min
      Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes.
      Acta Diabetol. 2010; 47: 193-199https://doi.org/10.1007/s00592-009-0109-4
      ]. Therefore, although further evidence is needed, pancreatic damage may also be present in COVID-19 patients, possibly contributing to worse outcomes in subjects with diabetes.
      Previous studies have reported decreased mortality and endotracheal intubation in patients with viral pneumonia who were in continued use of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) [
      • Henry Christopher
      • Zaizafoun Manaf
      • Stock Eileen
      • Ghamande Shekhar
      • Arroliga Alejandro C.
      • White Heath D.
      Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia.
      Bayl Univ Med Cent Proc. 2018; 31: 419-423https://doi.org/10.1080/08998280.2018.1499293
      ,
      • Mortensen E.M.
      • Pugh M.J.
      • Copeland L.A.
      • Restrepo M.I.
      • Cornell J.E.
      • Anzueto A.
      • et al.
      Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia.
      Eur Respir J. 2008; 31 (Epub 2007/10/26.PubMed PMID: 17959631): 611-617https://doi.org/10.1183/09031936.00162006
      ]. These medications are postulated to have significant immunomodulatory effects [
      • Gullestad L.
      • Aukrust P.
      • Ueland T.
      • Espevik T.
      • Yee G.
      • Vagelos R.
      • et al.
      Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure.
      J Am Coll Cardiol. 1999; 34 (Epub 1999/12/10 PubMed PMID: 10588224): 2061-2067https://doi.org/10.1016/s0735-1097(99)00495-7
      ] and reduce pulmonary and systemic inflammatory response by decreasing cytokines [
      • Henry Christopher
      • Zaizafoun Manaf
      • Stock Eileen
      • Ghamande Shekhar
      • Arroliga Alejandro C.
      • White Heath D.
      Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia.
      Bayl Univ Med Cent Proc. 2018; 31: 419-423https://doi.org/10.1080/08998280.2018.1499293
      ,
      • Mortensen E.M.
      • Pugh M.J.
      • Copeland L.A.
      • Restrepo M.I.
      • Cornell J.E.
      • Anzueto A.
      • et al.
      Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia.
      Eur Respir J. 2008; 31 (Epub 2007/10/26.PubMed PMID: 17959631): 611-617https://doi.org/10.1183/09031936.00162006
      ]. They are commonly used by those with diabetes and hypertension [
      • Chamberlain James J.
      • Rhinehart Andrew S.
      • Shaefer Jr., Charles F.
      • Neuman Annie
      Diagnosis and management of diabetes: synopsis of the 2016 American diabetes association standards of medical care in diabetes.
      Ann Intern Med. 2016; 164: 542https://doi.org/10.7326/M15-3016
      ], therefore, their impact on the clinical course of COVID-19 has been widely debated. Considering that ACE2 is a functional receptor for SARS-CoV-2 and its levels can be increased by ACEIs and ARBs, it has been argued that these drugs might affect negatively the outcome of COVID-19 patients [
      • Zheng Y.Y.
      • Ma Y.T.
      • Zhang J.Y.
      • Xie X.
      COVID-19 and the cardiovascular system.
      Nat Rev Cardiol. 2020; (Epub 2020/03/07. Epub 2020/03/07. PubMed PMID: 32139904)https://doi.org/10.1038/s41569-020-0360-5
      ]. On the contrary, some have advocated that ACEIs and ARBs might rather be beneficial [
      • Gurwitz D.
      Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.
      Drug Dev Res. 2020; (Epub 2020/03/05 PubMed PMID: 32129518)https://doi.org/10.1002/ddr.21656
      ]. SARS-CoV infection and the virus Spike protein reduce ACE2 expression. Mice injected with SARS-CoV Spike presented worsened acute lung failure, which could be attenuated by blocking the renin-angiotensin pathway [
      • Kuba K.
      • Imai Y.
      • Rao S.
      • Gao H.
      • Guo F.
      • Guan B.
      • et al.
      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.
      Nat Med. 2005; 11 (Epub 2005/07/12. PubMed PMID: 16007097): 875-879https://doi.org/10.1038/nm1267
      ]. Nevertheless, a retrospective analysis performed on 112 patients with COVID-19 and CVD did not show a significant difference in the proportion of ACEI/ARB medication between survivors and non-survivors [
      • Peng Y.D.
      • Meng K.
      • Guan H.Q.
      • Leng L.
      • Zhu R.R.
      • Wang B.Y.
      • et al.
      Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV.
      Zhonghua Xin Xue Guan Bing Za Zhi. 2020; 48 (Epub 2020/03/04. PubMed PMID: 32120458): E004https://doi.org/10.3760/cma.j.cn112148-20200220-00105
      ]. Similar to ACEIs and ARBs, ibuprofen [
      • Qiao W.
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      Ibuprofen attenuates cardiac fibrosis in streptozotocin-induced diabetic rats.
      Cardiology. 2015; 131 (Epub 2015/04/22 PubMed PMID: 25896805): 97-106https://doi.org/10.1159/000375362
      ] and thiazolidinediones [
      • Zhang W.
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      Pioglitazone upregulates hepatic angiotensin converting enzyme 2 expression in rats with steatohepatitis.
      Ann Hepatol. 2013; 12 (Epub 2013/10/12 PubMed PMID: 24114819): 892-900
      ] can also result in increased levels of ACE2, thus generating questions regarding the safety of these drugs in patients with COVID-19.
      Although diabetes has been associated with worse outcomes in COVID-19 patients, the susceptibility to SARS-CoV-2 infection may not be higher in people with diabetes. According to several studies, the prevalence of diabetes in people infected with the virus is about the same as in the general population, even slightly lower [
      • Li B.
      • Yang J.
      • Zhao F.
      • Zhi L.
      • Wang X.
      • Liu L.
      • et al.
      Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.
      Clin Res Cardiol. 2020; (Epub 2020/03/13 PubMed PMID: 32161990)https://doi.org/10.1007/s00392-020-01626-9
      ,
      • Fadini G.P.
      • Morieri M.L.
      • Longato E.
      • Avogaro A.
      Prevalence and impact of diabetes among people infected with SARS-CoV-2.
      J Endocrinol Invest. 2020; https://doi.org/10.1007/s40618-020-01236-2
      ]. A meta-analysis of 12 studies describing data from 2,108 Chinese patients with COVID-19 reported a diabetes prevalence of 10.3% [
      • Fadini G.P.
      • Morieri M.L.
      • Longato E.
      • Avogaro A.
      Prevalence and impact of diabetes among people infected with SARS-CoV-2.
      J Endocrinol Invest. 2020; https://doi.org/10.1007/s40618-020-01236-2
      ], which was similar to the national prevalence of 10.9% reported in 2013 [
      • Wang L.
      • Gao P.
      • Zhang M.
      • Huang Z.
      • Zhang D.
      • Deng Q.
      • et al.
      Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013.
      JAMA. 2017; 317 (Epub 2017/06/28. PubMed PMID: 28655017; PubMed Central PMCID: PMCPMC5815077): 2515-2523https://doi.org/10.1001/jama.2017.7596
      ]. An Italian study conducted among 146 patients with confirmed SARS-CoV-2 infection at the University Hospital of Padova found an equivalent pattern. The prevalence of diabetes in these patients was 8.9% (mean age 65.3 years), while it was 11.0% among people aged 55–75 years (mean age 65 years) from the same region in 2018 [
      • Longato Enrico
      • Di Camillo Barbara
      • Sparacino Giovanni
      • Saccavini Claudio
      • Avogaro Angelo
      • Fadini Gian Paolo
      Diabetes diagnosis from administrative claims and estimation of the true prevalence of diabetes among 4.2 million individuals of the Veneto region (North East Italy).
      Nutr Metab Cardiovasc Dis. 2020; 30: 84-91https://doi.org/10.1016/j.numecd.2019.08.017
      ]. Although underreporting may be an issue to consider, potential biological mechanisms should not be disregarded. It has been shown that dipeptidyl peptidase-4 (DPP-4) is the primary receptor of MERS-CoV [
      • Song Z.
      • Xu Y.
      • Bao L.
      • Zhang L.
      • Yu P.
      • Qu Y.
      • et al.
      From SARS to MERS, thrusting coronaviruses into the spotlight.
      Viruses. 2019; 11 (Epub 2019/01/17. Epub 2019/01/17PubMed PMID: 30646565; PubMed Central PMCID: PMCPMC6357155)https://doi.org/10.3390/v11010059
      ]. Since DPP-4 inhibitors are commonly applied in the treatment of diabetes worldwide, future research should explore whether DPP-4 may also act as receptor for SARS-CoV-2, thus contributing to a potential protective effect of these drugs against COVID-19 [
      • Fadini G.P.
      • Morieri M.L.
      • Longato E.
      • Avogaro A.
      Prevalence and impact of diabetes among people infected with SARS-CoV-2.
      J Endocrinol Invest. 2020; https://doi.org/10.1007/s40618-020-01236-2
      ,
      • Gentile S.
      • Strollo F.
      • Ceriello A.
      COVID-19 infection in Italian people with diabetes: lessons learned from our future (an experience to be used).
      Diabetes Res Clin Pract. 2020; 162108137
      ].
      So far, no anti-SARS-CoV-2 drug or vaccine has been officially approved for COVID-19 treatment [
      • Li H.
      • Zhou Y.
      • Zhang M.
      • Wang H.
      • Zhao Q.
      • Liu J.
      Updated approaches against SARS-CoV-2.
      Antimicrob Agents Chemother. 2020; (Epub 2020/03/25 PubMed PMID: 32205349)https://doi.org/10.1128/AAC.00483-20
      ]. Several clinical trials are in progress to assess the safety and efficacy of potential treatment alternatives, including remdesivir, tocilizumab, lopinavir/ritonavir, ribavirin, interferon, chloroquine phosphate, arbidol, among others [

      World Health Organization. Overview of the types/classes of candidate therapeutics 2020 [28/03/2020]. Available from: https://www.who.int/blueprint/priority-diseases/key-action/Table_of_therapeutics_Appendix_17022020.pdf?ua=1.

      ]. One promising pharmacological option of relevance for patients with diabetes is chloroquine and its hydroxy-analogue hydroxychloroquine. Widely used for malaria and autoimmune diseases, chloroquine has also been reported as a potential broad-spectrum antiviral drug. Although the efficacy and safety of chloroquine for COVID-19 treatment remain unclear, a recent study showed that the drug was highly effective in controlling SARS-CoV-2 infection in vitro. In addition to its immunomodulant and anti-inflammatory effect, chloroquine increases endosomal pH and interferes with the glycosylation of cellular receptors of SARS-CoV, thereby blocking viral infection [
      • Wang M.
      • Cao R.
      • Zhang L.
      • Yang X.
      • Liu J.
      • Xu M.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      Cell Res. 2020; 30 (Epub 2020/02/06. PubMed PMID: 32020029; PubMed Central PMCID: PMCPMC7054408): 269-271https://doi.org/10.1038/s41422-020-0282-0
      ]. Preliminary results from more than 100 patients included in a Chinese clinical trial showed that chloroquine was superior to the control group in shortening the disease course, inhibiting pneumonia exacerbation, promoting a virus negative conversion and radiological improvement without severe side effects [
      • Gao J.
      • Tian Z.
      • Yang X.
      Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
      Biosci Trends. 2020; 14 (Epub 2020/02/20. PubMed PMID: 32074550): 72-73https://doi.org/10.5582/bst.2020.01047
      ]. On the other hand, several studies have reported that hydroxychloroquine improves glycemic control in decompensated, treatment-refractory patients with diabetes [
      • Rekedal L.R.
      • Massarotti E.
      • Garg R.
      • Bhatia R.
      • Gleeson T.
      • Lu B.
      • et al.
      Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases.
      Arthritis Rheum. 2010; 62 (Epub 2010/08/20. PubMed PMID: 20722019; PubMed Central PMCID: PMCPMC2992611): 3569-3573https://doi.org/10.1002/art.27703
      ,
      • Gerstein H.C.
      • Thorpe K.E.
      • Taylor D.W.
      • Haynes R.B.
      The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas–a randomized trial.
      Diabetes Res Clin Pract. 2002; 55 (Epub 2002/02/19. PubMed PMID: 11850097): 209-219https://doi.org/10.1016/s0168-8227(01)00325-4
      ]. It has even been approved to treat T2DM in India as an add-on therapy for patients who do not achieve glycemic targets with two other oral glucose-lowering drugs [
      • Kumar V.
      • Singh M.P.
      • Singh A.P.
      • Pandey M.S.
      • Kumar S.
      • Kumar S.
      Efficacy and safety of hydroxychloroquine when added to stable insulin therapy in combination with metformin and glimepiride in patients with type 2 diabetes compare to sitagliptin.
      Int J Basic Clin Pharmacol. 2018; 7: 1959-1964https://doi.org/10.18203/2319-2003.ijbcp20183930
      ]. Although inflammation is associated with impaired glucose control, the underlying mechanism of hydroxychloroquine’s hypoglycemic effect remains unclear [
      • Rekedal L.R.
      • Massarotti E.
      • Garg R.
      • Bhatia R.
      • Gleeson T.
      • Lu B.
      • et al.
      Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases.
      Arthritis Rheum. 2010; 62 (Epub 2010/08/20. PubMed PMID: 20722019; PubMed Central PMCID: PMCPMC2992611): 3569-3573https://doi.org/10.1002/art.27703
      ]. It has been described that chloroquine increases the C peptide response, potentially reflecting an improved pancreatic β-cell function [
      • Gerstein H.C.
      • Thorpe K.E.
      • Taylor D.W.
      • Haynes R.B.
      The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas–a randomized trial.
      Diabetes Res Clin Pract. 2002; 55 (Epub 2002/02/19. PubMed PMID: 11850097): 209-219https://doi.org/10.1016/s0168-8227(01)00325-4
      ]. Reduced intracellular insulin degradation and increased insulin accumulation have also been identified as possible effects of hydroxychloroquine in animals models [
      • Emami Jaber
      • 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: 325-335https://doi.org/10.1016/S0024-3205(98)00568-2
      ]. Given the previously reported impact of chloroquine/hydroxychloroquine on glucose metabolism, caution should be taken when the drug is administered to patients with diabetes and COVID-19. A dose adjustment of the oral antidiabetic drugs and/or insulin might be necessary in order to prevent potential hypoglycemic events.
      The effect of corticosteroids on COVID-19 is also under investigation [

      World Health Organization. Overview of the types/classes of candidate therapeutics 2020 [28/03/2020]. Available from: https://www.who.int/blueprint/priority-diseases/key-action/Table_of_therapeutics_Appendix_17022020.pdf?ua=1.

      ]. Acute lung damage and ARDS are partly due to the host immune response. While corticosteroids suppress lung inflammation, they also inhibit immunity and pathogen clearance [
      • 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. PubMed PMID: 32043983): 473-475https://doi.org/10.1016/S0140-6736(20)30317-2
      ]. In SARS-CoV and MERS-CoV infections, pulmonary histology showed inflammation and diffuse alveolar damage [
      • Arabi Y.M.
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      ]. Therefore, corticosteroids were broadly applied [
      • Stockman Lauren J
      • Bellamy Richard
      • Garner Paul
      • Low Donald
      SARS: systematic review of treatment effects.
      PLoS Med. 2006; 3: e343https://doi.org/10.1371/journal.pmed.0030343
      ,
      • Arabi Y.M.
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      • Sindi A.A.
      • Almekhlafi G.A.
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      Am J Respir Crit Care Med. 2018; 197 (Epub 2017/11/22 PubMed PMID: 29161116): 757-767https://doi.org/10.1164/rccm.201706-1172OC
      ]. However, evidence did not show benefits, rather it was reported delayed viral RNA clearance or increased mortality and rate of complications, including diabetes, psychosis, and avascular necrosis [
      • 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. PubMed PMID: 32043983): 473-475https://doi.org/10.1016/S0140-6736(20)30317-2
      ]. The interim guidance from the WHO on clinical management of severe acute respiratory infection when SARS-CoV-2 infection is suspected advises against the use of corticosteroids outside clinical trials [

      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.

      ]. Considering the hyperglycemic effect [
      • Clore John
      • Thurby-Hay Linda
      Glucocorticoid-induced hyperglycemia.
      Endocr Pract. 2009; 15: 469-474https://doi.org/10.4158/EP08331.RAR
      ] and the impact of these drugs on the immune response [
      • 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. PubMed PMID: 32043983): 473-475https://doi.org/10.1016/S0140-6736(20)30317-2
      ], special caution should be taken in patients with diabetes included in trials assessing the safety and efficacy of corticosteroids for COVID-19 [
      • Clore John
      • Thurby-Hay Linda
      Glucocorticoid-induced hyperglycemia.
      Endocr Pract. 2009; 15: 469-474https://doi.org/10.4158/EP08331.RAR
      ].
      No data is available regarding the most appropriate management of patients with diabetes infected by SARS-CoV-2, as well as patients with COVID-19 who develop glycemic decompensation. Rigorous glucose monitoring and careful consideration of drug interactions might attenuate worsening of symptoms and adverse outcomes. Although hyperglycemia is usually the main concern in this context, one should not disregard the possibility of hypoglycemic episodes as a result of the interplay between drug treatment, viral pathogenesis and typical metabolic disturbances of diabetes. Patient tailored therapeutic strategies and optimal glucose control goals should be formulated based on disease severity, presence of comorbidities and diabetes-related complications, age and other factors. A multidisciplinary team approach, including infectologists, endocrinologists, pulmonologists, psychologists, nutritionists and exercise rehabilitation specialists may be necessary during the prolonged hospitalization periods and recovery. Special attention should be paid to those with diabetic nephropathy, or diabetes-related heart complications, since they are also at higher risk for severe COVID-19 and death [
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • Liang W.H.
      • Ou C.Q.
      • He J.X.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      N Engl J Med. 2020; (Epub 2020/02/29. PubMed PMID: 32109013): 1-13https://doi.org/10.1056/NEJMoa2002032. PubMed PMID: 32109013
      ,
      • Zhang J.J.
      • Dong X.
      • Cao Y.Y.
      • Yuan Y.D.
      • Yang Y.B.
      • Yan Y.Q.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.
      Allergy. 2020; (Epub 2020/02/23 PubMed PMID: 32077115)https://doi.org/10.1111/all.14238
      ]. Finally, increased vigilance and testing in outpatient diabetes clinics for COVID-19, as well as lower thresholds for hospitalization of these patients may have a positive impact on their outcomes.

      5. Conclusions

      COVID-19 has rapidly spread since its initial identification in Wuhan and has shown a broad spectrum of severity. Early isolation, early diagnosis, and early management might collectively contribute to a better control of the disease and outcome. Diabetes and other comorbidities are significant predictors of morbidity and mortality in patients with COVID-19. Future research is urgently needed to provide a better understanding regarding potential differences in genetic predispositions across populations, underlying pathophysiological mechanisms of the association between COVID-19 and diabetes, and its clinical management.

      Funding

      None.

      Author Contributions

      A.H., N.C.d.V.M. and B.B. conceptualized and wrote the paper; A.H. and N.C.d.V.M. revised the text; and all approved the final manuscript.

      Authorship

      All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship and take responsibility for the integrity of the work. They confirm that this paper will not be published elsewhere in the same form, in English or in any other language, including electronically.

      Declaration of Competing Interest

      None.

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      Published online: April 09, 2020
      Accepted: April 6, 2020

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