PERSEVERE OR PERIL: DIABETES CARE IN TIMES OF COVID-19.

The peril of coronavirus infection started in November, 2019, in Wuhan, China (1) and advanced to become a global pandemic (2). Everybody, everywhere, has been equally at risk without discrimination for the novel coronavirus of zoonotic origin called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV), causing coronavirus disease (COVID-19). The number of COVID-19 patients exponentially increased due to a high propensity for person-to-person transmission in asymptomatic and symptomatic individuals. Although the estimated overall mortality is not high (~2%) (1), the total number of fatalities increasing daily has been terrifying the world (2). The total number of confirmed COVID-19 cases reported up to April 18, 2020, in the United States (U.S.) was about 700,000 with about 35,000 deaths (3), whereas on a worldwide scale more than 2 million cases have been confirmed, with almost 150,000 deaths (2). Patients with diabetes mellitus (DM) appeared to be particularly vulnerable to morbidity and mortality from COVID-19 (4,5). The U.S. Centers for Disease Control and Prevention (CDC) places diabetes in a category of high risk for COVID-19: “Older adults and people who have severe underlying medical conditions like heart or lung disease or diabetes seem to be at higher risk for developing more serious complications from COVID-19 illness (3).”

A study by Wang et al (5) provided a retrospective analysis of the clinical course for 28 consecutive patients with diabetes, admitted for confirmed COVID-19 to the hospital in Wuhan, China. All patients were hospitalized in early February, 2020, and followed for about 3 to 4 weeks. The average age was 70 years (the range was 53 to 82 years) and the majority were men (~70%) and had multiple medical problems. The patients presented with typical COVID-19 symptoms of fever, cough, fatigue, dyspnea, anorexia, and diarrhea, seen in 40 to 90% of cases. All patients were evaluated with a chest computed tomography and the majority had bilateral pneumonia. Treatment included antiviral (oseltamivir, or arbidol, or both, [100%] of patients), antibacterial (96%), and glucocorticoid (75%) therapy. Of 28 patients, 14 (50%) required intensive care unit (ICU) admission and 12 (about 40%) died. Of 14 ICU patients, 7 (50%) required invasive mechanical ventilation, and 12 of them (86%) died, whereas none of the non-ICU patients died. Reasons for fatalities were respiratory and multiorgan failure (10 of 12 patients) and sudden death (2 of 12 patients) of unknown cause. On admission, ICU compared to non-ICU patients were slightly older (71 years versus 66 years), had a significantly higher respiratory rate (29 breaths per minute versus 21 breaths per minute), and nonsignificantly higher systolic blood pressure (150 mm Hg versus 130 mm Hg), whereas other presenting symptoms, signs and comorbidities were similar. Predictably, at the time of admission, many but not all laboratory values were worse in ICU versus non-ICU patients, hemoglobin A1c (HbA1c) was similar (~7.5%), random glucose was 40% higher, and strikingly, 10-fold higher levels were observed for C-reactive protein, pro-brain natriuretic peptide, troponin I, procalcitonin, and interleukin 6 (IL-6). The authors explained a high mortality due to the hospital designation for severe cases (5).

This study, albeit small and not without limitations, emphasized that diabetes could be associated with a severe course of COVID-19, corresponding to other studies of COVID-19 (1,4). The reported mortality of 40% was strikingly different from the reported ~2% overall mortality in COVID-19 and about 7% mortality in patients with diabetes (1), but in agreement with ~50% mortality in critical cases (1,4). Published studies reported a higher DM prevalence among more severe than less severe cases of COVID-19; in ~200 hospitalized patients, DM was present in 25% of non-survivors and in 5% of survivors (4). Diabetes was present more frequently in patients with COVID-19 who developed acute respiratory distress syndrome (ARDS) compared with those who did not (19% versus 5%), respectively; however, DM per se was not a predictor of ARDS or progression to death (4). In a small series of cases (5), HbA1c was similar in ICU and non-ICU patients, suggesting that diabetes control prior to infection did not influence the severity of the COVID-19 course. Previously, diabetes and the level of its control prior to infection was an important risk for infection complications and mortality (6). A comparison of more than 85,000 patients with both type 1 diabetes (T1D) and type 2 diabetes (T2D), and more than 150,000 patients without DM, determined morbidity and mortality across 18 infection categories (6). The patients with optimal (HbA1c at 6 to 7% [42 to 53 mmol/mol]) and poor control (HbA1c ≥11% [≥97 mmol/mol]) of T2D, as well as poorly controlled T1D, had hospitalization risks for infection increased by about 40%, 4-fold, and 8-fold, respectively, compared to patients without diabetes. Comparisons within patients with DM confirmed that poor control was associated with an increased risk of infection-related hospitalization (17%) and mortality (16%) (6).

The treatment of patients in this study (5) integrated several known medications. Glucocorticoids did not appear to influence the course of disease in ICU patients, whereas in a larger cohort, glucocorticoids were associated with a lower mortality in patients with ARDS (4), suggesting that a role of glucocorticoids in COVID-19 ARDS remains to be determined. The other medications included known antiviral and antibacterial therapy and appeared not to be efficacious in severely ill patients in the ICU, which was similar to other reports (4). There are no clinically established or approved drugs for COVID-19. To date, multiple medications tried for COVID-19 severely ill patients were not found to be helpful. The presently growing number of interventional clinical trials for novel and currently available therapies for treatment and prevention of COVID-19 have been registered (7). Antiviral medications include those previously used for influenza, hepatitis B, hepatitis C, filoviruses, and the human immunodeficiency virus. The antiviral combination of lopinavir/ritonavir (both protease inhibitors) previously shown to be effective for severe acute respiratory syndrome coronavirus (SARS-CoV) and not for COVID-19 is evaluated in multiple studies (7). Remdesivir, a novel nucleotide analogue antiviral, initially developed for the management of the Ebola virus and shown to be efficacious for middle East respiratory syndrome coronavirus (MERS-CoV) infection in the rhesus macaque model of MERS-CoV infection (8), is being assessed in several trials. The antimalarials chloroquine and hydroxychloroquine have shown apparent efficacy for COVID-19 (7). Immunomodulators include (among many others) anti-IL-6 (tocilizumab), anti-tumor necrosis factor (adalimumab), and fingolimod (sphingo-sine-1-phosphate receptor modulator, used against multiple sclerosis) (7). Meplazumab (anti-CD147) that inhibits not only T-cell chemotaxis, but also virus cell entry, has improved recovery in critical and severe COVID-19 cases in a trial comparing 17 meplazumab-treated and 11 controls in an open-label, concurrent control study (9). Mesenchymal stem cells (MSC) that possess immunomodulatory and tissue repair functions could be beneficial. Previously, in influenza H7N9-induced ARDS fatalities were lower in MSC-treated (18% of n = 17) patients compared to controls (55% of n = 44) in an open-label trial (10). In COVID-19, MSC appeared efficacious in a 2-week open trial: none of the 7 MSC-treated patients died and 3 were discharged, whereas of the 3 controls, 1 died and 1 progressed to ARDS (7). The other therapies in trials include convalescent plasma (from COVID-19 recovered patients), anti-angiogenic (bevacizumab), thalidomide, and modifiers of the gut microbiome (7). The majority of studies, however, do not have appropriate protocols for double blind placebo-controlled trials.

Vaccines are probably the best road for the future. Previous vaccine investigations for both MERS-CoV and SARS-CoV have been stopped due to successful disease containment. Allegedly more than 50 SARS-COV-2 vaccines are in development for the prevention of COVID-19 and several are in trials (7). If we assume the best-case scenario for the availability of a vaccine, do we expect that the public and particularly patients with diabetes will all get vaccinated? The evidence from previous experience is not encouraging. Several vaccines are recommended for adults with diabetes, including the annual vaccination for influenza and at least a one-time dose of the pneumococcal vaccine, regardless of age; a shingles vaccine starting at age 60; and a hepatitis B vaccine following a diabetes diagnosis among those aged 19 to 59 years. Vaccinations for influenza and pneumococcal pneumonia have proven efficacy for the reduction of morbidity and mortality in patients with diabetes (11). However, in a retrospective cohort analysis of more than 500,000 adults, only ~30% and ~20% among DM patients had flu and pneumococcal vaccines, respectively, far below the recommendations (11). It remains to be seen whether the scare induced by the current pandemic will be sufficient to make the general public and patients with DM more receptive for vaccination once a vaccine is available for the prevention of COVID-19.

Practicing endocrinologist can provide support and some recommendations in addition to a “shelter in place” and strict hygiene, while definitive treatment and prevention for COVID-19 is lacking. The CDC provides recommendations for the general public (3). Better control of DM is important as previously shown for other infections and potentially for decreasing the risk of COVID-19. A healthy diet and physical activity sound trivial, yet are recommended by the CDC for influenza (12), and have been shown to boost the immune system and potentially decrease the risk of viral infections in diabetics (13,14). Possible food scarcity (at home or at stores) provides “food for thought” and a “dietary spice” of controversy, namely, that fasting at least sometimes can be beneficial. In a clinical trial, 100 participants have been randomized to eat general or a fasting-mimicking diet (FMD, about 1,000 calories/day) for 5 days per month (15). After 3 FMD cycles, participants with a FMD compared to a control diet had decreased risk factors and biomarkers for diabetes, cardiovascular disease, cancer, and aging without major adverse effects (15). In conclusion, physicians can help patients prevent peril and preserve perseverance for staying safe and sanguine in this time of solitude.