key: cord-0984575-hf9cyr16 authors: Smith, S.; Boppana, A.; Traupman, J. A.; Unson, E.; Maddock, D. A.; Chao, K. Y.; Dobesh, D. P.; Connor, R. I. title: Impaired glucose metabolism in patients with diabetes, prediabetes and obesity is associated with severe Covid-19 date: 2020-06-05 journal: nan DOI: 10.1101/2020.06.04.20122507 sha: df6f1f57d7e78cbd59536ad088e85de8c45a072c doc_id: 984575 cord_uid: hf9cyr16 Background: Identification of risk factors of severe Covid-19 is critical for improving therapies and understanding SARS-CoV-2 pathogenesis. Methods: We analyzed 184 patients hospitalized for Covid-19 in Livingston, New Jersey for clinical characteristics associated with severe disease. Results: The majority of Covid-19 patients had diabetes mellitus (DM) (62.0%), Pre-DM (23.9%) with elevated FBG, or a BMI > 30 with normal HbA1C (4.3%). SARS-CoV-2 infection was associated with new and persistent hyperglycemia in 29 patients, including several with normal HbA1C levels. Forty-four patients required intubation, which occurred significantly more often in patients with DM as compared to non-diabetics. Conclusions: Severe Covid-19 occurs in the presence of impaired glucose metabolism in patients with SARS-CoV-2 infection. The association of dysregulated glucose metabolism and severe Covid-19 suggests a previously unrecognized manifestation of primary SARS-CoV-2 infection. Exploration of pathways by which SARS-CoV-2 impacts glucose metabolism is critical for understanding disease pathogenesis and developing therapies. Early reports from China and later Italy examined risk factors for severe Covid-19 and identified advanced age as a major indicator for increased mortality. (4, 5) A recent study of over 4,000 patients with confirmed Covid-19 in the United States found older age (>65 years), obesity (BMI >40), chronic kidney disease and a history of heart failure were most associated with hospitalization, while critical illness was linked to low oxygen saturation (<88%) at admission, severe Covid-19 found 13% of patients had DM, reinforcing early observations that diabetes is a risk factor for more severe disease. (7) This is supported by data from a study of 24 patients hospitalized for Covid-19 in nine Seattle-area hospitals in which 58% of critically ill patients had DM and an average BMI of 33. (8) Interestingly, in the 2003 SARS-CoV outbreak in China, hyperglycemia and DM were also noted as risk factors for mortality and morbidity.(9) These . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.04.20122507 doi: medRxiv preprint observations and several in-depth reviews (10) (11) (12) have raised concerns that diabetics with elevated fasting blood glucose are at increased risk of developing severe Covid-19. We report here our experience of 184 patients admitted for Covid-19 to a teaching hospital in Livingston, New Jersey within the epicenter of the SARS-Cov-2 pandemic in the United States. Extending early observations, we find the vast majority of our Covid-19 patients are diabetic, prediabetic or obese. Moreover, we identify Covid-19 patients with PreDM and others with normal HbA1C levels who developed new onset DM, similar in presentation to Type 1 DM, coincident with recent acquisition of SARS-CoV-2 infection. Our data establish that impaired glucose metabolism, due to either DM or obesity, is significantly associated with severe Covid-19 in this high-risk population. A high percentage of patients testing positive for SARS-CoV-2 and referred to our . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.04.20122507 doi: medRxiv preprint practice were already known diabetics and receiving treatment for DM at the time of admission. We used the ADA definitions to diagnose DM, New Onset DM and PreDM.(13) A new diagnosis of DM was made in patients previously unaware of their condition based on an HbA1C >6.4%. New onset DM was defined by persistently elevated fasting blood glucose (FBG) > 125 mg/dL and requiring insulin therapy. Prediabetes (PreDM) was defined by an HbA1C of 5.7 -6.4%. Non-diabetic patients were defined as having an HbA1C < 5.7% and FBG ≤ 125 mg/dL. Fever was defined as Tmax ≥100°F during the first 6 hrs after admission. Hypoxia was defined as room oxygen saturation <94%. The primary indicator of severe Covid-19 was intubation. The need for intubation was determined on the basis of clinical presentation in patients receiving full care throughout their hospitalization. Death during hospitalization included patients put on comfort care at any time during or after admission. Comfort care measures were determined by the primary attending physician and included but were not limited to morphine drips or intensive care without further escalation of care. A one-sample proportion Z-test was used to determine the prevalence of DM, PreDM, and NonDM in Covid-19 patients as compared to the US population. The sample size used for this analysis was 184 with at least 10 patients in each DM status. One-sided hypothesis tests were used to determine if the proportions of Covid-19 patients with DM and PreDM were larger than the U.S. population proportions, and if the proportion of NonDM patients was smaller than the U.S. population proportion. A chi-squared test was used to determine significance between intubation and diabetes status within each patient group. 95% confidence intervals were . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.04.20122507 doi: medRxiv preprint calculated using standard errors. Statistical significance was defined as a P-value < 0.05. All statistical analyses were performed using R version 3.4.4. During a seven-week period, 184 patients were admitted to the hospital for Covid-19 and referred to our practice. The average age of study patients was 64.4 years (range: 21-100 yrs.) with 86 (46.7%) females and 98 (53.3%) males (Table 1 ). The racial and ethnic composition of the study population was black (53.8%), white (25.5%), Latino (6.5%) and Asian (6.0%). Clinical presentation at the time of admission included hypoxia (83.7%) and fever (62.5%) ( Table 1) . Hypoxia and fever occurred together often (48.9%); only a small percentage (7.6%) of patients presented without fever or hypoxia. The most common preexisting conditions included hypertension (60.3%), hyperlipidemia (33.7%), dementia (13.0%),chronic kidney disease (13.0%) coronary artery disease (12.0%), and congestive heart failure (10.9%) ( Table 1) . The majority of Covid-19 patients had DM (62.0%), PreDM (23.9%) or BMI > 30 with normal HbA1C (4.3%). The prevalence of DM was 4.7-fold higher in this patient group as compared to the general US population, while the prevalence of PreDM was 1.3-fold higher. (14) A significant number of patients were clinically obese. The mean BMI of the study patients was 29.8 (17.5-61.4), including 20 patients with BMIs > 40. HbA1C levels measured at admission in 171 patients also showed significant elevation with 64 patients (37.4%) having values between 5.7-6.4% and 82 (48.0%) having values ≥ 6.5%. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.04.20122507 doi: medRxiv preprint To determine whether patient age was associated with differences in clinical presentation, data on BMI, HbA1C and initial FBG were stratified by age at admission. The rates of DM and PreDM were similar in patients ≤60 yrs as compared to those > 60 yrs (Table 2 ) as were mean initial FBG levels (200.5 vs 165.4 mg/dL). However, patients ≤60 years of age were significantly more likely to be clinically obese. As compared to patients >60 yrs, the frequency of obesity and the mean BMI in those ≤60 yrs were significantly higher (26.6% vs 65.3% and 27.2 vs 33.4, respectively; p < 0.0001) ( Table 3) . Patients ≤ 60 yrs were also significantly more likely to be severely obsese with a BMI>40 (20.0% vs 3.7%, p = 0.0013). Similarly, patients ≤ 60 yrs had a significantly higher mean HbA1C level than older patients (8.0 vs 6.9%; p = 0.003) suggesting more pronounced metabolic dysregulation in younger patients. Taken together, these data indicate that younger patients may be more likely to present with abnormalities in glucose metabolism due to obesity, which may put them at increased risk of developing severe Covid-19. These findings are consistent with a recent report of 265 Covid-19 patients demonstrating a significant inverse correlation of age and BMI in which younger patients hospitalized for Covid-19 were more often obese. (15) Intubation was evaluated as an indicator of Covid-19 progression and severity in hospitalized patients. To determine whether higher rates of intubation were associated with uncontrolled glycemia, data on BMI, HbA1C and FBS were evaluated for intubated patients and . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.04.20122507 doi: medRxiv preprint HbA1C levels were available for 41 intubated patients and revealed only four (9.8%) had normal values. Of these, three were known to be diabetic and receiving treatment for DM. In total, 40 of 41 (97.6%) intubated patients had either elevated HbA1C or were receiving therapy for DM. As compared to patients not requiring intubation, the mean HbA1C of intubated patients was significantly higher (8.0 vs 7.2%; p = 0.034; C.I. = 0.07-1.67). Accordingly, the rate of intubation among patients with poorly-controlled DM (HbA1C ≥7.5%) was significantly higher than that of patients with HbA1C < 7.5% (31.5 vs 17.8%; p = 0.045). The mean FBG at admission for intubated patients was also significantly increased when compared to that of patients not requiring intubation (238.0 vs 163.7 mg/dL; p = 0.013; C.I. = 9.02-135.9) suggesting that uncontrolled glycemia, due to obesity or DM, is a significant risk factor for severe Covid-19. To determine whether Covid-19 severity was associated with diabetes status, patients is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.04.20122507 doi: medRxiv preprint the onset and progression of diabetes are associated with a corresponding increase in the likelihood of severe Covid-19 requiring intubation. Twenty-four patients died without intubation. The average age of these patients was 80.5 yrs (range 45-100 yrs) and the majority were put on comfort care with DNR orders in place. Among these patients 17 (70.8%) had DM, four (16.7%) were PreDM and three (12.5%) were nonDM. Obesity, PreDM and DM are typically associated with elevated blood glucose levels. We . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. Our data in patients with severe Covid-19 and DM are consistent with a recent report by Bhatraju and colleagues.(8) In both studies, 58-62% of patients severely ill with Covid-19 were diabetic with mean BMIs >30 and the majority had elevated blood glucose. Additionally, we found 24% of patients with moderate-severe Covid-19 in our study were prediabetic. Taken together these data suggest that insulin resistance and uncontrolled glycemia play a significant role in worsening Covid-19. In all critically ill Covid-19 patients, blood glucose levels were elevated and tight glycemic control may therefore be an important consideration for improving clinical outcomes. Several studies on Covid-19 patients have reported on diabetes as a pre-existing diagnosis. In two recent observational studies, ~36% of Covid-19 patients were diabetic. (16, 17) These studies relied on passive surveillance at the time of admission. Similarly, 42.9% of our patients were known diabetics at the time of admission. However, we specifically reviewed prior medical . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. It is unlikely the development of severe Covid-19 in these patients can be explained by the direct effect of changes in glucose metabolism on host immunity. To date, we have not seen Covid-19 patients with underlying diseases of immune dysregulation including AIDS or lupus. Nor have we seen Covid-19 patients with active lymphoma. Rather, these data suggest that SARS-CoV-2 infection is associated with physiologic changes in glucose metabolism that may permit the virus to replicate more efficiently. Replication of SARS-CoV-2 in host cells is mediated by the ACE2 cell surface enzyme, which serves as the primary receptor for the virus. (19) As part of the renin-angiotensin system, ACE2 is expressed in many tissues, including pancreatic beta and apocrine cells. As noted in early reports from China, mild elevations of lipase produced by pancreatic apocrine cells may occur, and we have seen this in many, but not all, of our Covid-19 patients. (19) Clinically, SARS-. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. CoV-2 appears to cause new or worsening hyperglycemia, which may lead to more severe pneumonia. In our experience, a tipping point is reached in Covid-19 patients who have symptoms lasting anywhere from two days to over three weeks and the disease then "takes off". Hospitalization before this acceleration can reduce the rate of critical illness. It is important to note that our study has several limitations. Patients were seen at a single clinical site and cared for by one group of clinicians. While it is possible our study population is disproportionately weighted towards patients with poor underlying health, the Covid-19 patients in this study were consecutive referrals to our service over the course of seven weeks in a suburban hospital. It is, therefore, unlikely that a selection bias exists, except for the criteria used by the admitting physicians. Diabetes itself was not considered a criterion for referral. Given the urgency of finding solutions to this present crisis, our findings may assist in prognostication and triage decisions. Our data shed light on the impact of DM, preDM and uncontrolled hyperglycemia in driving severe Covid-19 and will facilitate identification of novel pathogenesis pathways associated with SARS-CoV-2 infection. This, in turn, may lead to new approaches to therapeutic intervention. Our data currently support the use of tight glycemic control in patients with hyperglycemia. Our observations are also in line with the WHO recommendation that corticosteroids not be used for COVID-19 pneumonia. Finally, our findings caution that Covid-19 patients with DM, PreDM or obesity should be monitored closely. Those not infected should be particularly careful to avoid exposure to SARS-CoV-2. This information may be useful in healthcare and other settings to reduce the chances of infection in these high-risk individuals and, conversely, to help triage nonDM, normal glycemic Covid-19 patients safely and efficiently. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.04.20122507 doi: medRxiv preprint CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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