COVID-19 and Combined Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Nonketotic Coma: Report of 11 Cases

Abstract

We report 11 cases of combined diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic coma (HHNK) in coronavirus 2019 patients who presented to our institution in New Jersey, USA. The median age was 47 years (range 12-88 years). Out of the 11 patients, 7 were male and 4 were female. Out of 11 patients, 8 had type 2 diabetes mellitus (DM), 2 had undiagnosed DM, and 1 had type 1 DM. Presenting complaints included altered mental status, weakness, shortness of breath, cough, fever, vomiting, abdominal pain, chest pain, and foot pain. Out of 11 patients, pneumonia was diagnosed at presentation in 8 patients, while in 3 patients, chest X-ray was clear. Median value of initial glucose on presentation was 974 mg/dL (range 549-1556 mg/dL), and hemoglobin A1c on presentation was 13.8%. The median value of anion gap was 34 mEq/L. Out of the 11 patients, ketonemia was moderate in 6 patients, large in 3, and small in 2 patients. Acute kidney injury (AKI) occurred in 9 patients and 2 patients required renal replacement therapy. Out of the 11 patients, 6 required mechanical ventilation and 7 patients died. All the 6 patients requiring mechanical ventilation died. Our case series shows COVID-19 infection can precipitate acute metabolic complications in known DM patients or as first manifestation in undiagnosed DM patients. Patients can present with DKA/HHNK symptoms and/or respiratory symptoms. Mechanical ventilation is a poor prognostic factor. Further studies are needed to characterize prognostic factors associated with mortality in this vulnerable patient population.

Introduction

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS COV-2) and was declared a pandemic by the World Health Organization on March 11, 2020. COVID-19 most commonly affects the respiratory system, although it can also result in several extrapulmonary manifestations. These include thromboembolic, cardiovascular, and neurological complications.

Methods

We report 11 cases of combined diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic coma (HHNK) in COVID-19 patients who presented to our institution in New Jersey, USA. COVID-19 was diagnosed by real-time reverse-transcription polymerase chain reaction (PCR) assay. Diabetes mellitus (DM) was defined as glycated hemoglobin (HbA1c) ≥6.5% (48 mmol/mol) or already established diagnosis prior to the current admission. Criteria for combined DKA and HHNK on admission was pH <7.3, bicarbonate <18 mEq/L, glucose >250 mg/dL, anion gap >10 mEq/L, and ketonemia with effective serum osmolality >299 mOsm/kg. The electronic medical records of the 11 patients were reviewed and data on patients’ age, sex, ethnicity, medical history, body mass index, various laboratory values, HbA1c, oral antidiabetic agents, insulin, mechanical ventilation, treatment drugs for COVID-19, and clinical outcome were collected.

Results

Pertinent salient features are summarized in Table 1.

Table 1.

Showing pertinent clinical characterstics and laboratory values.

Variable a	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8	Case 9	Case 10	Case 11
Age/sex	47/Male	79/Female	45/Male	51/Male	52/Male	35/Female	88/Female	43/Male	19/Male	12/Male	79/Female
Ethnicity	African American	Hispanic	Hispanic	White	Hispanic	Hispanic	White	Hispanic	Hispanic	African American	Middle Eastern
Medical history	DM	DM, HTN	DM	DM, HTN	None	HTN, DM, asthma, depression, anxiety	CAD, DM, HTN, DLD	DM, HTN, DLD, gout	DM	None	DM, HTN, DLD
Type 1 DM or type 2 DM or undiagnosed	Type 2 DM	Type 2 DM	Type 2 DM	Type 2 DM	Undiagnosed	Type 2 DM	Type 2 DM	Type 2 DM	Type 1 DM	Undiagnosed	Type 2 DM
Duration of DM	NR	NR	NR	Diagnosed within 3 months	Newly diagnosed DM	>15 years	NR	NR	NR	Newly diagnosed DM	NR
Hx of prior DKA/HHNK	NR	NR	NR	NR	NR	Multiple episodes	NR	NR	NR	NR	NR
Presenting sign and symptoms	Altered mental status	SOB, altered mental status	Altered mental status	Altered mental status, SOB, weakness	SOB, cough, weight loss	SOB, vomiting	Altered mental status	SOB, right foot pain, chest pain	Altered mental status	Vomiting, abdominal pain, altered mental status	SOB
Pneumonia present on admission	Positive	Positive	Positive	Positive	Positive	Positive	Negative	Positive	Negative	Negative	Positive
Home DM medications	Insulin sulfonylurea,	Insulin meds NR	Insulin, meds NR	NR	NA	Insulin, Metformin	Metformin, sitagliptin	Metformin, sulfonylurea, SGLT2 inhibitors	Insulin	None	Sulfonylurea metformin sitagliptin
BMI	36.54	25.28	22.04	25.71	24.38	27.5	34.38	29.3	17.7	23.43	26.5
HbA1c (%)	14.6	ND	ND	ND	ND	13.3	18.3	ND	14.4	13	8.4
pH	6.97	7.13	6.8	7.16	6.9	7.1	7.22	6.96	7.01	6.81	7.22
Bicarbonate (mEq/L)	5	14	3	10	4	5	14	10	4	2	6
Glucose on presentation (mg/dL)	1095	974	881	1092	552	610	1284	948	1556	1385	549
Serum ketones	Moderate	Moderate	Moderate	Moderate	Large	Large	Small	Small	Moderate	Large	Moderate
Anion gap (mEq/L)	42	31	34	37	36	35	29	27	42	34	30
Effective osmolarity (mOsm/kg)	322.83	352.11	306.94	362.67	348	308	351.33	303	340.44	357	302.5
White cell count (K/mm3)	12.2	20.5	27.0	23.5	18.3	11.1	11.8	16.4	22.5	21.0	10
Hemoglobin (g/dL)	15.2	13.4	15.8	16.3	15.6	12.9	15.8	17.7	9.1	15.8	14.7
Platelets (K/mm3)	182	341	416	476	378	304	421	484	248	404	291
Troponin (ng/mL)	1.251	0.223	0.427	3.535	0.1	0.01	0.5	7.2	0.01	1.403	0.022
Sodium (mEq/L)	131	149	129	151	159	137	140	125	127	140	136
Potassium (mEq/L)	5.1	6.0	6.7	6.1	4.6	4.8	6.3	5.8	7.5	2.3	4.0
Chloride (mEq/L)	84	104	92	104	119	97	97	88	81	104	100
Phosphorous (mg/dL)	11.6	2.1	7.4	11.1	3.8	5.6	5.9	5.3	13.9	4.9	3.3
BUN (mg/dL)	92	70	31	69	62	17	114	88	59	37	32
Creatinine (mg/dL)	4.29	2.65	2.27	2.05	2.98	1.01	2.88	2.74	2.95	1.78	1.09
AST (U/L)	31	141	31	26	463	23	16	42	15	9	14
ALT (U/L)	21	101	6	27	85	32	15	39	12	8	14
ESR (mm/h)	103	108	21	64	83	41	107	19	7	36	54
CRP (mg/L)	128.1	110.1	316.3	140.8	403	126	70.5	341.1	9.8	90.4	306.7
Ferritin (ng/mL)	7500	2231	ND	2266	7345	259	342	7500	338	551	1198
LDH (U/L)	1676	730	591	736	640	461	277	718	187	434	1286
D-dimer (µg/mL)	13.59	10.22	2.36	20	20	2.35	1.8	20	1.55	6.37	20
Fibrinogen (mg/dL)	572	ND	ND	ND	ND	ND	ND	853	276	335	715
Insulin IV or SC	IV	IV	IV	IV	IV	IV	IV	IV	IV	IV	IV
Acute renal replacement therapy	HD	None	None	None	None	None	None	HD	None	None	None
Intubated	Yes	No	Yes	Yes	Yes	No	No	Yes	No	No	Yes
Treatment of COVID-19	HCQ, azithromycin, cefepime	HCQ, azithromycin, ceftriaxone	HCQ, azithromycin	Ceftriaxone, doxycycline	HCQ, azithromycin	HCQ, ceftriaxone	HCQ, cefepime	HCQ, azithromycin, ceftriaxone	HCQ	HCQ, ceftriaxone	HCQ, azithromycin, ceftriaxone
Outcome	Died	Died	Died	Died	Died	Discharged	Discharged	Died	Discharged	Discharged	Died

Abbreviations: DM, diabetes mellitus; undiagnosed, first time diagnosed with diabetes; HTN, hypertension; CAD, coronary artery disease; DLD, dyslipidemia; NR, not reported; DKA, diabetic ketoacidosis; HHNK, hyperosmolar nonketotic coma; SOB, shortness of breath; NA, not applicable; SGLT2, sodium glucose cotransporter 2 inhibitor; BMI, body mass index; HbA1c, hemoglobin A1c; ND, not done; BUN, blood urea nitrogen; AST, aspartate transaminase; ALT, alanine transaminase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; LDH, lactate dehydrogenase; IV, intravenous; SC, subcutaneous; HD, hemodialysis; HCQ, hydroxychloroquine.

^aReference ranges: hemoglobin A1c 4% to 6 %, pH 7.36 to 7.44, bicarbonate 21 to 31 mEq/L, glucose 70 to 110 mg/dL, anion gap 3 to 10 mEq/L, effective osmolarity 283 to 299 mOsm/kg, leucocytes 4.5 to 11 K/mm³, hemoglobin 12 to 16 g/dL, platelets 140 to 440 K/mm³, troponin less than 0.03 ng/mL, sodium 135 to 145 mEq/L, potassium 3.5 to 5 mEq/L, chloride 98 to 107 mEq/L, phosphorus 2.5 to 5 mg/dL, BUN 7 to 23 mg/dL, creatinine 0.6 to 1.30 mg/dL, AST 13 to 39 U/L, ALT 7 to 52 U/L, ESR 0 to 10 mm/h, CRP <10 mg/L, ferritin 12 to 300 ng/mL, LDH 140 to 271 U/L, D-dimer <0.5 (µg/mL), fibrinogen 183 to 503 mg/dL.

The median age was 47 years (range 12-88 years). Out of the 11 patients, 7 were males and 4 were females. Ethnicity distribution in our patients was as follows: 6 were Hispanic, 2 African American, 2 White, and 1 Middle Eastern descent. Comorbidities of the patients were hypertension, dyslipidemia, asthma, anxiety, depression, coronary artery disease, and gout. Out of the 11 patients, 8 had type 2 DM, 2 had undiagnosed DM, and 1 had type 1 DM. Presenting complaints included altered mental status, weakness, SOB, cough, fever, vomiting, abdominal pain, chest pain, and foot pain. Out of the 11 patients, pneumonia was diagnosed at presentation in 8 patients, while in 3 patients, chest X-ray was clear. Only 2 patients had BMI in the obesity range (more than 30). Bicarbonate 10 mEq/L in all the patients except one (14 mEq/L). One patient was taking SGLT 2 inhibitor, which is known to increase the risk of ketoacidosis. Median value of initial glucose on presentation was 974 mg/dL (range 549-1556 mg/dL) and for HbA1c on presentation was 13.8%. The median value of anion gap was 34 mEq/L. Out of 11 patients, ketonemia was moderate in 6 patients, large in 3, and small in 2 patients. All the patients received standard treatment protocol for combined DKA and HHNK with intravenous insulin infusion and intravenous fluids. Inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, and ferritin) elevated in all patients except one. D-dimer was elevated in all the 11 patients. Acute kidney injury occurred in 9 patients, and 2 patients required renal replacement therapy. Transaminases were elevated in 2 patients only. Out of the 11 patients, 6 required mechanical ventilation and 7 patients died. All the 6 patients requiring mechanical ventilation died.

Discussion

Analysis of 5700 patients hospitalized with COVID-19 in the New York City area, the most common comorbidities noted were hypertension, obesity, and diabetes. ¹ In a meta-analysis, DM has been associated with severe COVID-19, disease progression, acute respiratory distress syndrome development, and mortality in patients with COVID-19. ² Pal et al report a mortality rate approaching 50% in the setting of DKA with COVID-19. ³ COVID-19 can precipitate severe manifestations of DM, including DKA and HHNK. ⁴ Limited literature is available regarding COVID-19 and combined DKA/HHNK. A recent systematic review of literature reported only 19 patients and emphasized differentiating isolated DKA from combined DKA and HHNK as latter tends to have higher mortality than DKA alone. ³ Goldman et al report a prevalence of 1.8% of patients admitted for COVID-19 presented with DKA. ⁵

Higher levels of inflammation-related biomarkers in DM patients compared with non-DM patients has been noted. ⁶ In the Zhu et al study of 952 COVID-19 patients with preexisting type 2 diabetes, poor glycemic control was associated with increased need for medical interventions, multi-organ injuries, and higher mortality as compared with well-controlled glycemic control patients. ⁷ A significant increase in DKA at diabetes diagnosis has been noted during the COVID-19 period in 2020 as compared with the 2 previous years (44.7% in 2020 vs 24.5% in 2019 vs 24.1% in 2018). ⁸ A New York study reported mortality of 50% in COVID-19 patients with DKA on admission or developed during their hospital course. ⁹ Health care providers should target optimal glycemic control in patients with DM especially during the COVID-19 pandemic; however, Palermo et al note the unique concerns and complications of DKA with COVID-19 given the need to prevent transmission, reducing health care worker exposure, and preserving protective personal equipment and offer suggestions on using subcutaneous insulin for management. ¹⁰

The pathological mechanisms precipitating acute metabolic complications (DKA/HHNK) in DM patients with COVID-19 is not fully understood at present. Angiotensin-converting enzyme 2 (ACE2) serves as a functional receptor for SARS-CoV-2 and is expressed in multiple tissues (alveolar cells, myocardial cells, endocrine tissues of the pancreas, proximal tubule cells of the kidney, esophagus, ileum epithelial cells, and bladder urothelial cells).^11,12 SARS-CoV-2 could cause direct damage to the pancreatic tissue leading to acute hyperglycemia. Suwanwongse et al reported 3 cases of newly diagnosed diabetes and DKA in patient with COVID-19 and propose that COVID-19 unmasked existing diabetes by aggravating its metabolic complications. ¹³

Conclusion

Our case series shows that COVID-19 infection can precipitate acute metabolic complications in known DM patients or as first manifestation in undiagnosed DM patients and is associated with substantial mortality. Patients can present with DKS/HHNK symptoms and/or respiratory symptoms. Effective communication with a health care provider and proper patient and family members education during the illness can prevent the acute metabolic complications of DM. Further studies are needed to characterize prognostic factors associated with mortality in this vulnerable patient population. Health care providers should be aware of this life-threatening complication of COVID-19 so that appropriate interventions can be done.