key: cord-0754484-gk19md1u
authors: Smith, Stephen M.; Boppana, Avinash; Traupman, Julie A.; Unson, Enrique; Maddock, Daniel A.; Chao, Kathy; Dobesh, David P.; Brufsky, Adam; Connor, Ruth I.
title: Impaired glucose metabolism in patients with diabetes, prediabetes and obesity is associated with severe Covid‐19
date: 2020-06-26
journal: J Med Virol
DOI: 10.1002/jmv.26227
sha: 4752ad751b916195e5a3bd0a6f2747e92e7676a3
doc_id: 754484
cord_uid: gk19md1u

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, including those with DM, PreDM and obesity. Covid‐19 is asociated with elevated FBG and several patients presented with new onset DM or in DKA. The association of dysregulated glucose metabolism and severe Covid‐19 suggests that SARS‐CoV‐2 pathogenesis involves a novel interplay with glucose metabolism. Exploration of pathways by which SARS‐CoV‐2 interacts glucose metabolism is critical for understanding disease pathogenesis and developing therapies. This article is protected by copyright. All rights reserved.

Early reports from China and later Italy examined risk factors for severe 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, first d-dimer (>2500), first ferritin (>2500) and first C-reactive This article is protected by copyright. All rights reserved.

protein (>200) indicating hypoxia and inflammation in patients with clinically progressive disease 6 .

A number of studies have identified an increased risk of severe disease in Covid- 19 patients with underlying health conditions. Data compiled by the COVID-19

Associated Hospitalization Surveillance Network (COVID-NET) identified hypertension (49.7%), obesity (48.3%), chronic lung disease (34.6%), diabetes mellitus (DM) (28.3%) and cardiovascular disease (27.8%) as the most commonly found co-morbidities among hospitalized Covid-19 patients in the United States 3 . A recent study of Lopinavir-Ritonavir in adults hospitalized with 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 Seattlearea 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 observations and several indepth 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. This article is protected by copyright. All rights reserved.

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.

Patients with Covid-19 were referred to our practice by the Emergency Medicine 

A high percentage of patients testing positive for SARS-CoV-2 and referred to our 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 This article is protected by copyright. All rights reserved.

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. We developed a simple, scoring system for outcomes, based up a patient's diabetes status, BMI, A1C, Age and initial blood glucose level. For details, please see Supplemental Information.

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 calculated using standard errors. Statistical This article is protected by copyright. All rights reserved.

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. In addition to DM, as described herein, 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 1.3fold 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

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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%.

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 This article is protected by copyright. All rights reserved.

with uncontrolled glycemia, data on BMI, HbA1C and FBS were evaluated for intubated patients and compared to their non-intubated counterparts. Among 184 hospitalized patients receiving full care for Covid-19, 44 (23.9%) required intubation. The mean BMI of patients requiring intubation was significantly higher than that of non-intubated patients (32.3 vs 29.3; p = 0.030; 95% C.I. = 0.3-5.8). More strikingly, patients with a BMI > 40 were intubated at a significantly higher rate than patients with BMIs < 25 (47.4 vs 15.6%;

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, 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.

We developed a simple scoring system, the Smith Center Covid-19 Severity Score, Accepted Article patients expired (with or without prior intubation). The minimum and maximum total scores are 0 and 25. The mean scores for the alive, never intubated, intubated and/or expired and expired groups were 10.2, 13.1, and 13.4 respectively. The differences between the alive/never intubated group and the other two groups were statisticially significant with p-values < 0.0001. More importantly, 31 patients had a SCCSS <=7, 30 had a good outcome; the other patient, who has end-stage renal disease, was intubated and lived; none died. A screening system, such as the SCCSS, might be useful in triaging patients, especially in resource limited areas.

Obesity, PreDM and DM are typically associated with elevated blood glucose levels. We found blood glucose was increased in the majority of Covid-19 patients at 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. This article is protected by copyright. All rights reserved.

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 records to ascertain each patient's diabetes status.

Further, we diagnosed an additional 17.1% during this admission. Most studies have not reported on prediabetes, a recognized syndrome with impaired glucose metabolism. By measuring HbA1C levels in every patient, we diagnosed 20.4% with prediabetes. Because of active surveillance, our data diabetes and prediabetes are replete and accurate. We have seen several non-diabetic Covid-19 patients with persistently high FBG levels.

Binding of ACE2 by SARS-CoV-2 in COVID 19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease 18 . A known history of diabetes (DM) and ambient hyperglycemia were found to be independent risk factors for morbidity and mortality in SARS 9 . In a follow-up analysis of 135 patients, high fasting plasma glucose was an independent predictor of SARS mortality 19 . Diabetes was found in 7.4% of a cohort of hospitalized COVID 19 patients and appeared to be a risk factor for severity of disease 20 . This article is protected by copyright. All rights reserved.

Mortality of COVID 19 in patients with diabetes was found to be 7.6% versus 0.9% in patients with no co-morbidities 4 . 

leading to hyperglycemia and upregulation of ACE2 in the lung, and further virus binding and inflammation. Poor glycemic control could therefore make the disease more severe. In a case series of 138 COVID 19 patients, glucocorticoid therapy was used in 44.9% of non-ICU patients and 72.2% of ICU patients 22 , and presumably this glucocorticoid use made hyperglycemia, and possibly clinical symptoms, more severe.

Aberrently glycosylated ACE2 in the lung, nasal airways, tongue, and oropharynx in uncontrolled hyperglycemia could increase SARS-CoV-2 viral binding sites, thus leading to a higher propensity to COVID 19 infection and a higher disease severity.

If true, this argues for better glycemic control in patients with pre-diabetes and diabetes as a potential mechanism to slow COVID 19 spread and reduce the severity of symptoms. Additionally, since 3.8% of the American population without a history of diabetes or pre-diabetes has a hemoglobin A1c over 6.1% in random sampling 23 , use of high A1c as a risk stratification for COVID 19 could have merit.

Clinically, SARS-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 This article is protected by copyright. All rights reserved.

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. Tight glycemic control was associated with a decrease in mortality (HR 0.14 CI 0.06-0.60, p=0.008) as well as a decrease in ARDS (HR 0.47, CI 0.27-0.83, p=0.009) in an observational study of 500 propensity score matched COVID-19 patients 24 . 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. 

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