Letter to the editor: Unexpected high mortality in COVID-19 and diabetic ketoacidosis
Authors: Natalia Chamorro-Pareja, Sahana Parthasarathy, Jayabhargav Annam, Julie Hoffman, Christine Coyle, Preeti Kishore
Journal: Metabolism (2020)

Patients with diabetes mellitus (DM) appear to be at a greater risk for severe symptoms and complications, including death from COVID-19 [1Muniyappa R. Gubbi S. COVID-19 pandemic, coronaviruses, and diabetes mellitus.Am J Physiol Endocrinol Metab. 2020; 318: E736-e741Crossref PubMed Scopus (551) Google Scholar,2Zhou J. Tan J. Letter to the Editor: diabetes patients with COVID-19 need better blood glucose management in Wuhan, China.Metab Clin Exper. 2020; 107Abstract Full Text Full Text PDF Scopus (101) Google Scholar]. DM is a common comorbidity in patients affected with COVID-19 and may cause ketosis, ketoacidosis, and diabetic ketoacidosis (DKA) [3Li J. Wang X. Chen J. Zuo X. Zhang H. Deng A. COVID‐19 infection may cause ketosis and ketoacidosis.Diabetes Obes Metab. 2020; : 1-7https://doi.org/10.1111/dom.14057Crossref Scopus (352) Google Scholar]. In patients with DM, acute hyperglycemic crises such as DKA and hyperosmolar hyperglycemic state can be precipitated by an acute illness such as COVID-19 and it can result in catastrophic outcomes. At Jacobi Medical Center, an epicenter of the COVID-19 pandemic crisis, we noted that a significant proportion of patients with COVID-19 also presented with DKA. We identified 50 such patients admitted with COVID-19 from March 10th to April 30th of 2020 who concomitantly had DKA upon admission or developed DKA during their hospital course. DKA was defined as blood glucose >250 mg/dL, an elevated anion gap, and positive ketones in blood or urine. COVID-19 was confirmed by real-time reverse-transcription polymerase chain reaction (PCR) assay (BioReference Laboratories, Elmwood Park, NJ). Among the evaluated patients, 32 (64%) were male, the median age was 59 years (IQR 42.3–70), 16 (31%) were Hispanic, 15 (30%) were African American, and the median body mass index (BMI) was 27.15 kg/m2 (see Table 1). Six of the 50 patients (12%) had a previous diagnosis of Type 1 DM with a median hemoglobin A1C (HbA1C) before the admission of 11%. Forty-four (88%) patients had previously diagnosed type 2 DM and their median HbA1c before the admission was 8.05%. Eight patients (16%) had previously undiagnosed DM. Twenty (40%) patients were on oral hypoglycemic agents with only 2 on SGLT2 inhibitors (which are known to increase the risk of ketoacidosis), 24 (48%) were on a home insulin regimen, and 4 (8%) patients were receiving treatment with GLP-1 agonists.Table 1Characteristics of the study population.DemographicsGender – no./total no. (%) Male 32/50 (64) Female 18/50 (36)Race – no./total no. (%) Asian 1/50 (2) Black 15/50 (30) Hispanic 16/50 (32) Other 8/50 (16) Unknown 7/50 (14) White 3/50 (6)Age (years) Median 59 Interquartile range (IQR) 42.3–70.0BMI (kg/m2) Median 27.15 Interquartile range (IQR) 23.2–33.0Diabetes history – no./total no. (%) Previously undiagnosed diabetes 8/50 (16) Type 1 DM 6/50 (12) Type 2 DM 44/50 (88)Home antidiabetic regimen – no./total no. (%) Insulin 24/50 (48) Oral hypoglycemic agents 20/50 (40) Metformin 17/50 (34) Sulfonyl urea 4/50 (8) DPPIV inhibitors 3/50 (6) SGLT2 inhibitors 2/50 (2) GLP-1 agonist 4/50 (8)Laboratory values Most recent HbA1c before admission (%) no./total no. (%) HbA1c ≥ 8 14/50 (28) HbA1c < 8 10/50 (20) HbA1c unknown 26/50 (52) HbA1c on admission (%)- no./total no. (%) HbA1c ≥ 8 30/50 (60) HbA1c < 8 4/50 (8) HbA1C unknown 16/50 (32)Initial glucose level upon presentation Median (range) – mg/L 506.5 (252.0–1485.0)Anion gap Median (range) – mEq/L 28.1 (14.3–41.2)Ketones Median (range) – mmol/L 2.22 (0.44–11.7)Ferritin Median (range) – ng/mL 1215.0 (50.0 to >100,000.0)C-reactive protein Median (range) – mg/L 246.7 (3.4–620.8)d-Dimer Median (range) – ng/mL 33,369.0 (164.0- >69,000.0)Therapy Insulin – no./total no. (%)Subcutaneous 7/50 (14)Intravenous Infusion 43/50 (86)Insulin needs/24 h Median (range) – units 115.5 (9.0–240.0)Fluids/24 h Median (range) – mL 3000.0 (1000.0–8000.0)Outcomes at a median of 9 days (range, 1–31) – no./total no. (%) Acute kidney injury 38/50 (76) Renal replacement therapy 11/50 (22) Intubation 21/50 (42) ICU care 26/50 (52) Death 25/50 (50) Remained hospitalized 1/50 (2) Discharged from hospital 24/50 (48) Open table in a new tab The median value of the initial glucose on presentation in our sample population was 506.5 mg/dL (252.0–1485.0 mg/dL). Forty-three (86%) patients were treated with intravenous insulin infusion protocol and 7 (14%) were treated with subcutaneous insulin protocol. The mean insulin and the intravenous fluids requirements in the first 24 h were 115. 5 units and 3000 mL respectively. Thirty-eight (76%) patients developed acute kidney injury (AKI) during admission, 11 (22%) patients required renal replacement therapy, 26 (52%) required intensive care unit (ICU) admission, 21 (42%) were intubated, and 25 (50%) patients died. The median length of stay was 9 days (range 1–31); one patient was still admitted at the time of data evaluation. In general, patients who died (50%) were older than those who survived (mean age 65.2 vs. 49 years), had higher ferritin (mean 8229.6 vs. 3373.4 ng/mL), and higher C-reactive protein levels (mean 355.3 vs. 167.2 mg/L). Mortality was higher in males than females (65.6% vs. 22.2%), and in patients who developed AKI (60.5%), who required dialysis (90.9%), and intubation (80.9%) (see Table 2).Table 2Comparison of variables between deceased vs non-deceased patients.CharacteristicsDeceasedNon-deceasedAge – years Mean (SD)65.2 (15.0)40.0 (17.5)Male No./total no. (%)21/50 (42)11/50 (22)Female No./total no. (%)4/50 (8)14/50 (28)BMI – kg/m2 Mean (SD)28.8 (7.0)28.7 (7.9)Initial glucose – mg/dL Mean (SD)544.3 (211.9)575.6 (304.8)Ferritin – ng/mL Mean (SD)8229.6 (21,416.0)3373.4 (7505.4)C-reactive protein – mg/L Mean (SD)355.3 (109.9)167.2 (120.2)d-Dimer – ng/mL Mean (SD)13,201.4 (20,578.2)13,698.3 (20,817.3)Anion gap – mEq/L Mean (SD)26.0 (7.4)28.3 (7.9)Insulin requirements/24 h – units Mean (SD)111.3 (64.1)96.8 (60.2)Fluids requirements/24 h – mL Mean (SD)2937.0 (1235.5)3776.5 (1842.1)Outcomes Acute kidney injury (AKI) – no./total no. (%)23/50 (46)15/50 (30) Renal replacement therapy – no./total no. (%)10/50 (20)1/50 (2) ICU care – no./total no. (%)15/50 (30)11/50 (22) Intubation – no./total no. (%)17 /50(34)4/50 (8) Open table in a new tab In conclusion, mortality in patients with COVID-19 and DKA at our institution was higher than expected when compared with patients admitted historically with DKA in the United States [4Benoit S.R. Zhang Y. Geiss L.S. Gregg E.W. Albright A. Trends in diabetic ketoacidosis hospitalizations and in-hospital mortality — United States, 2000–2014.MMWR Morb Mortal Wkly Rep. 2018; 67: 362-365Crossref PubMed Scopus (170) Google Scholar] and the mortality for hospitalized COVID-19 patients in our area [5Richardson S. Hirsch J.S. Narasimhan M. et al.Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.JAMA. 2020; 323: 2052-2059Crossref PubMed Scopus (6493) Google Scholar,6Wadhera R.K. Wadhera P. Gaba P. et al.Variation in COVID-19 hospitalizations and deaths across New York City boroughs.JAMA. 2020; 323: 2192-2195Crossref PubMed Scopus (496) Google Scholar]. Many of these patients developed AKI which likely contributed to the increased risk of adverse outcomes. As has been previously described, in our analysis, age and male sex were associated with higher mortality in patients with COVID-19 and DKA [7Weiss P. Murdoch D.R. Clinical course and mortality risk of severe COVID-19.Lancet. 2020; 395: 1014-1015Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar,8Li X. Xu S. Yu M. et al.Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.J. Allergy Clin. Immunol. 2020; S0091-6749 ([published online ahead of print, 2020 Apr 12]): 30495-4https://doi.org/10.1016/j.jaci.2020.04.006Abstract Full Text Full Text PDF Scopus (1524) Google Scholar]. Moreover, majority of our patients were Hispanic or African American, and it has been proposed that these patients have a higher risk of mortality from COVID-19 [9Laurencin C.T. McClinton A. The COVID-19 pandemic: a call to action to identify and address racial and ethnic disparities.J Racial Ethn Health Disparities. 2020; 7: 398-402Crossref PubMed Scopus (523) Google Scholar,10Palaiodimos L. Kokkinidis D.G. Li W. et al.Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.Metabolism. 2020; 108: 154262Abstract Full Text Full Text PDF PubMed Scopus (582) Google Scholar]. Interestingly, majority of these patients with DKA had type 2 diabetes and contrary to expectation many did not have poorly controlled diabetes mellitus before admission [11Pettus J.H. Zhou F.L. Shepherd L. et al.Incidences of severe hypoglycemia and diabetic ketoacidosis and prevalence of microvascular complications stratified by age and glycemic control in U.S. adult patients with type 1 diabetes: a real-world study.Diab Care. 2019; 42: 2220Crossref PubMed Scopus (96) Google Scholar,12Klonoff D.C. Umpierrez G.E. Letter to the editor: COVID-19 in patients with diabetes: risk factors that increase morbidity.Metab Clin Exper. 2020; 108: 154224Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. This suggests that COVID-19 can contribute to the development of hyperglycemic crisis in patients with diabetes irrespective of glycemic control. Previous studies with the related virus SARS CoV have suggested a role of pancreatic beta cell damage in worsening hyperglycemia [13Yang J.K. Lin S.S. Ji X.J. Guo L.M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes.Acta Diabetol. 2010; 47: 193-199Crossref PubMed Scopus (747) Google Scholar,14Yang J.K. Feng Y. Yuan M.Y. et al.Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS.Diabet Med. 2006; 23: 623-628Crossref PubMed Scopus (539) Google Scholar] [15Angelidi A.M. Belanger M.J. Mantzoros C.S. Commentary: COVID-19 and diabetes mellitus: what we know, how our patients should be treated now, and what should happen next.Metab Clin Exper. 2020; 107: 154245Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Future research is needed to explore mechanisms for why COVID-19 infection leads to the development of DKA and high mortality rates. NCP, SP, JA, and PK contributed to the design and implementation of the data collection, and to the analysis of the results. All author's discussed the results and contributed to the final manuscript. Authors' have no conflict of interest and this work was not supported by any external funding.