key: cord-355755-fd40zy7z
authors: Alsadhan, Ibrahim; Alruwashid, Shahad; Alhamad, Maram; Alajmi, Sarah; Alshehri, Sara; Alfadhli, Eman; Ekhzaimy, Aishah
title: Diabetic Ketoacidosis Precipitated by COVID-19 infection: Case Series
date: 2020-10-27
journal: Curr Ther Res Clin Exp
DOI: 10.1016/j.curtheres.2020.100609
sha: 
doc_id: 355755
cord_uid: fd40zy7z

BACKGROUND: Coronavirus has evolved into a devastating pandemic since December 2019. Saudi Arabia's first case was reported in March 2020. Subsequently, some 220,000 cases and 2,000 deaths were recorded through July 2020. COVID-19 infection aggravates glycemic control and provokes acute hyperglycemic crises, according to some reports. We made the same observations in some of our patients diagnosed with COVID-19. However, we are unaware of any reported cases of DKA among COVID-19 patients in Saudi Arabia. OBJECTIVE: Highlighting the significance of hyperglycemia on COVID-19 patient outcomes. METHODS: Five patients with DKA were admitted and diagnosed with COVID-19 based on real-time reverse transcription-polymerase chain reaction (RT-PCR) assays. Electronic medical records were reviewed and informed consent was obtained prior to reporting the index cases. RESULTS: Five patients presenting with DKA complicating a concurrent COVID-19 infection were reported. Three were known to have preexisting diabetes and two had newly diagnosed diabetes based on significantly elevated glycated hemoglobin levels at admission. Four recovered and were discharged to their homes and one had a complicated course and died. CONCLUSION: Our cases demonstrate that COVID-19 infection can trigger DKA. DKA can occur among patients who are known to have diabetes mellitus or appears as a first presentation. Clinicians should be extremely careful in checking for admission hyperglycemia and closely monitor respiratory status during fluid resuscitation of COVID-19-related DKA.

A novel coronavirus, later named COVID-19 by the World Health Organization, was isolated from patients presenting with pneumonia in Wuhan, China late last year. This viral infection spread, triggering a global health crisis. Clinical presentations of COVID-19 infection may vary. The symptoms mostly manifest as fever and upper respiratory disease. However they can include gastrointestinal disease, severe pneumonia, organ failure, and death. (1) Diabetes mellitus has been shown to be a comorbidity that is associated with severe disease, acute respiratory distress syndrome (ARDS) and increased mortality in COVID-19. (2, 3, 4) The coexistence of diabetes mellitus and COVID-19 is an unfortunate situation in which one disease can complicate the other.

Decompensated diabetes, such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), are causes of morbidity and mortality among diabetic patients, despite advances in diagnostic criteria and treatment protocols. (5) This study describes five cases of COVID-19 who presented with DKA upon presentation, during Saudi Arabia's outbreak.

This case series is a descriptive study that follows a group of patients who had a diagnosis of acute hyperglycemic crisis upon presentation and positive RT-PCR for COVID-19 infection.

A literature review using the terms -diabetes mellitus,‖ -acute hyperglycemia‖ and -diabetic ketoacidosis,‖ in association with the term -COVID-19 infection‖ was conducted using PubMed as a primary search engine.

All studies covered in the literature review were published in English from 1998 to 2020.

Detailed history, laboratory investigations, clinical course and management outcomes were obtained from the electronic medical records of index cases and reviewed by two physicians. Informed consent was obtained from the patient or a family member.

A 44-year-old female on oral antidiabetic agents (metformin and gliclazide) was known to have had type 2 diabetes mellitus (T2DM) for the past nine years, along with hypertension, rheumatoid arthritis (RA) overlapping with systemic lupus erythematosus (SLE) and lupus nephritis (treated with prednisolone, etanercept, hydroxychloroquine and methotrexate). Her home medications did not include SGLT2 inhibitors or ACEI.

Presented to the Emergency Department (ED) on May 14, 2020 complaining of shortness of breath, productive cough with white sputum, central chest pain and fever documented at 39℃ for 6 days. Three days after the onset of her symptoms, she visited a medical center where she was given oral antibiotics. She became afebrile for two days, then her fever spiked again, accompanied by epigastric pain, nausea, vomiting and watery diarrhea. She presented to our hospital for further care. During her illness she was not able to take her oral antidiabetic medication as she was not tolerating oral medications.

Initial vital signs were: blood pressure of 135/73 mmhg (MAP 94 mmhg), heart rate of 121 beats/min, respiratory rate 22 breaths/min, body temperature 39.4℃, oxygen saturation of 89% by pulse oximetry on room air (requiring 2 l/min via nasal cannula to keep saturation above 92%) and a BMI of 32. She was diagnosed as COVID-19 positive, based on a realtime reverse transcriptase-polymerase chain reaction (RT-PCR) assay.

Upon admission, the patient's plasma glucose was 8 mmol/l (144 mg/dl), which increased within a few hours to 46 mmol/l (828 mg/dl), and her HbA1c was 11%. Blood chemistry revealed blood urea nitrogen 1.2 mmol/l (reference range 2.5-6.4 mmol/l), creatinine 96 µmol/l (reference range 53-115 µmol/l), sodium 125 mmol/l (reference range 136-154 mmol/l), potassium 4.1 mmol/l (reference range 3.5-5.1 mmol/l). Urine analysis was positive for ketone. Arterial blood gas analysis (ABGA) on room air demonstrated a high anion gap metabolic acidosis (HAGMA), with an anion gap of 19. A chest radiograph showed airspace disease.

Based on clinical, laboratory and radiologic findings, the patient was diagnosed with COVID-19 pneumonia and mild diabetic ketoacidosis (DKA). She was started on empiric antibiotics and symptomatic treatment for her COVID-19 infection. She was also started on a DKA protocol with intravenous fluids and insulin, plus a stress dose steroid therapy (hydrocortisone 100 mg IV every 8 hours, since was on prednisolone at home for her SLE and RA).

The patient's DKA resolved after eight hours on the DKA protocol (average insulin rate 9 units/hr). She then was started on insulin aspart and insulin glargine. However, her respiratory symptoms were worsening, with oxygen requirements increasing. She was determined to be clinically overloaded. Diuretics were initiated and antibiotics upgraded. In this deteriorating condition, the patient developed hypoxemic respiratory failure. A chest radiograph showed bilateral patchy opacities distributed throughout the lungs. The patient was moved to the intensive care unit (ICU), put on high flow nasal canula, in the awake prone position. A CT pulmonary embolism (PE) protocol was performed. No major PE was found, but multiple bilateral scattered patchy ground glass opacity was observed throughout the lungs, with some basal consolidation. The infectious diseases team assessed the patient and started her on tocilizumab on the fifth day following admission. She received total of two doses.

After 9 days of ICU care, the patient was moved to the ward while on 2 l/min nasal canula. Two days later, her oxygen saturation was 96% on room air. During her hospital stay she received hydrocortisone as stress dose for four days, then resumed her home dose of prednisolone. On May 29, 2020, after a hospital stay of 16 days, the patient was discharged to a quarantine facility in stable condition on insulin therapy.

55-year-old previously medically healthy female.

Presented to the ED on 16 th of May 2020 with four days' history of shortness of breath, cough and confusion that worsened progressively. She was diagnosed COVID-19 positive based on a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay. The family denied any history of fever, sore throat, or chest discomfort. She was not on any home medications.

Initial vital signs were blood pressure 82/61 mm Hg, heart rate 110 beats/min, respiratory rate 28 breaths/min, body temperature 36.1℃, and oxygen saturation 100% by pulse oximetry on 5 l via face mask. Upon admission, plasma glucose was 23.3 mmol/l (491 mg/dl) and HbA1c was 14.6%. Blood chemistry revealed blood urea nitrogen 9.5 mmol/l (reference range 2.5-6.4 mmol/l), creatinine 105µmol/l (reference range 53-115 µmol/l), sodium 153 mEq/l (reference range 136-154 mmol/l), potassium 2.7 mEq/l (reference range 3.5-5.1 mmol/l), and positive urine ketone. Arterial blood gas analysis (ABGA) on room air demonstrated a high anion gap metabolic acidosis (HAGMA) with pH 6.93, HCO3 7.7 mmol/l, anion gap 27. Severe diabetic ketoacidosis (DKA) was accordingly diagnosed.

The admission chest radiograph showed no major areas of consolidation. However, empiric antibiotics, and symptomatic respiratory treatment for COVID-19 infection as well as DKA protocol were initiated. No steroids were administered during the patient's stay. Her DKA resolved after 10 hours (average insulin infusion rate 11 units/hr). On the other hand, her dyspnea and radiological findings worsened. Mechanical ventilation with proning was initiated on day two following admission. After five days, the patient was extubated and moved to a ward. Subsequent COVID-19 tests were all negative. On day 10 (May 26, 2020), the patient was discharged on insulin therapy, along with metformin, and followed up by a diabetologist.

A 47-year-old previously medically healthy male.

Presented to the ED on May 25, 2020 complaining of fatigue, decreased activity, and generalized body pain for four days. No history of rhinorrhea, sore throat, shortness of breath, cough, chest pain, fever, headache, nausea, vomiting, abdominal pain, or diarrhea.

Prior to the patient's presentation, he was suffering from polydipsia, polyuria and nocturia, associated with unintentional weight loss of 35 kg (Was 125 kg, now 90 kg) over the prior two months.

He was not on any home medications.

Initial vital signs were blood pressure of 122/83 mmhg (MAP 96 mmhg), heart rate 113 beats/min, respiratory rate 33 breaths/min, body temperature 36.8℃, oxygen saturation of 89% by pulse oximetry on room air (requiring 2 l/min via nasal cannula for saturation over 92%) and a BMI of 26.8. He was diagnosed as COVID-19 positive, based on an RT-PCR assay.

Upon admission, plasma glucose was 24 mmol/l (432mg/dl) and HbA1c was 15.1%. Blood chemistry revealed blood urea nitrogen 4.7 mmol/l (reference range 2.5-6.4 mmol/l), creatinine 106 µmol/l (reference range 53-115 µmol/l), sodium 134 mmol/l (reference range 136-154 mmol/l) and potassium 4.5 mmol/l (reference range 3.5-5.1 mmol/l). Urine analysis was positive for ketone, ABGA on room air demonstrated HAGMA with pH of 7.1, HCO3 of 11 mmol/l, and an anion gap of 25. A chest radiograph revealed air space opacities within the bilateral lower lung zones.

The patient was diagnosed with COVID-19 pneumonia based on real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay, as well as newly diagnosed DM with first presentation as moderate DKA. He was started on empirical antibiotics, symptomatic treatment for his pneumonia, as well as DKA protocol with intravenous fluids and insulin.

The DKA resolved after 11 hours on DKA protocol (average insulin rate 7 units/hr). He was then started on insulin aspart and insulin glargine. The next day, the patient's oxygenation worsened, saturating 88% on 10 l/min simple face mask (required 15 L /min non-rebreather mask to saturate 95%), chest radiograph showed no significant interval change, ICU team were involved and no steroids were administered during his stay.

On day 5, the patient's oxygen requirements improved, titrated down to 6 l/min via simple face mask saturating > 92%. During his stay, he did not receive steroids and his oxygen concentration improved to 95% on room air. He was discharged to his home on June 5, 2020 in stable condition on oral antidiabetic agents and a follow up with a diabetologist.

Prior history A 40-year-old male who was known to have hypertension and type 1 diabetes mellitus (T1DM) on insulin lantus, insulin mixtard and enalapril. He was not on an SGLT2 inhibitor.

Presented to the ED on June 14, 2020 with a history of epigastric pain, fever, and shortness of breath for two days.

Initial vital signs were blood pressure 104/90mm Hg, heart rate 140 beats/min, respiratory rate 34 breaths/min, body temperature 38℃, and oxygen saturation 91% by pulse oximetry on 4 L via nasal cannula. Laboratory findings showed increased plasma glucose of 16 µmol/(288 mg/dL), and HbA1c was 11.3%. Blood chemistry revealed blood urea nitrogen 10 mmol/l (reference range 2.5-6.4 mmol/l), creatinine 88µmol/l (reference range 53-115 µmol/l), sodium 138 mEq/l (reference range 136-154 mmol/l), and potassium 4.8 mEq/l (reference range 3.5-5.1 mmol/l). Urine analysis confirmed presence of ketones and glucose. ABGA on 4 l of oxygen showed pH 7.30, HCO3 14.1 mmol/l, an anion gap of 25. His chest radiograph demonstrated bilateral prominent vascular markings. The patient was swabbed for COVID-19 which proved positive in the RT-PCR test.

The patient was accordingly diagnosed with mild diabetic ketoacidosis and COVID-19 pneumonia. He was initiated on DKA protocol, and empirical antibiotics. His DKA resolved after 10 hours (average insulin infusion rate 5 units/hr). However, his oxygen demand increased so he was started on a high flow nasal cannula and shifted to prone position. On the third day of hospitalization dexamethasone 6 mg IV daily and anti-viral agents (remdesivir) were initiated. His overall status and oxygen requirements improved, and he was discharged on July 4, 2020. The patient was followed up by his diabetologist.

A 70-year-old male known to have T2DM on insulin, dyslipidemia on atorvastatin, hypertension on bisoprolol, obesity, and ischemic heart disease on aspirin. At home, he was not on an ACE inhibitor or SGLT2 inhibitors.

He was brought to the emergency room on June 18, 2020 with confusion and a decreased level of consciousness for a few hours. Patient was unwell and complained of abdominal pain, decreased appetite and generalized weakness and fatigue for few days, but had no respiratory symptoms, fever, or shortness of breath.

The patient's initial vital signs were normal, apart from high blood pressure (160/85 mm Hg). Admission laboratory findings showed an increased plasma glucose level of 27.8 mmol/l (500 mg/dL), and HbA1c of 9.9%. Urine ketones was detected. ABG pH: 7.18, HCO3: 14 mmol/l, Pco2 40, Po2 95 with an anion gap of 20. His admission chest radiograph showed no major lung consolidation. He was consequently diagnosed with moderate DKA and treated with intravenous fluids, regular insulin infusion with an average rate of 6 units/hr, and empiric antibiotics. DKA resolved on day two following admission, but his level of consciousness did not improve. He had a CT scan of the brain, which did not demonstrate any acute insult. Two days after admission his fever spiked to 38.9°C and he developed a productive cough and shortness of breath. His COVID-19 swab taken on the day of admission proved positive with the RT-PCR test. He was not initiated on steroids during his stay.

On day four following admission, the patient's oxygen demand increased and he was moved to the intensive care unit (ICU), where invasive mechanical ventilation was initiated in a prone position. He received multiple antibiotics, convalescent plasma, and inotropes. However, the patient's condition did not improve. He developed bradycardia, followed by cardiac arrest. Cardiopulmonary resuscitation (CPR) was performed and the patient was revived after many cycles. However, his condition continued to deteriorate with sepsis and multiorgan failure. Eventually, patient died after 30 days of hospitalization on July 17, 2020.

We have described five cases of COVID-19 of patients who presented with DKA complicating a COVID-19 infection. Three were known to have preexisting diabetes and two with newly diagnosed diabetes based on the significantly elevated glycated hemoglobin levels during admission. Four patients recovered and were discharged home in a stable condition. One had a complicated course in which he suffered from sepsis and multiorgan failure. He died after 30 days of hospitalization.

Few cases were reported identifying DKA in type 2 diabetes patients as a presentation of COVID-19. (6) (7) (8) In another study, 42 (6.4%) of 658 of hospitalized patients with confirmed COVID-19 presented with ketosis on admission. Of this group, 27 (64.3%) did not have diabetes, while 15 (35.7%) did. Three (20.0%) of those with diabetes and ketosis had ketoacidosis. Ketosis was found to increase the length of hospital stay and mortality. (9) Contrary to this finding, another study found that COVID-19 patients with diabetes who developed DKA were more likely to survive compared to patients without DKA. (10) The relationship between diabetes and COVID-19 is two-sided-one disease can complicate the other. On the one hand, diabetes is associated with an increased risk of severe COVID-19. The triglyceride and glucose index which is a reliable surrogate marker of insulin resistance were found to be predictive of severe COVID-19 illness and mortality. (11) On the other, COVID-19 may worsen glycemic control and cause acute hyperglycemia crises among hospitalized patients with preexisting diabetes or induced new onset diabetes. (12) The pathophysiology of COVID-19-induced DKA in patients with T2DM is not well understood. Several mechanisms have been proposed. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for severe acute respiratory syndrome coronavirus (SARS coronavirus). ACE2 receptors are present in many organs and tissues including pancreatic beta cells. Acute damage of β-cells of the pancreas may ensue after the coronavirus binds to ACE2 receptors in β-cells and leads to insulin deficiency and subsequent DKA in patients with type 2 diabetes, or triggers acute onset diabetes. (13) ACE2 lowers angiotensin II levels because of its conversion to angiotensin. (6) (7) (8) (9) (10) (11) (12) Angiotensin II-specific receptors are present on exocrine, endocrine, and vascular cells of the pancreas. Therefore, downregulation of ACE2 after binding with SARS coronavirus causes an elevation in angiotensin II level resulting in vasoconstriction and reduced blood flow to islet cells, accompanied by delayed insulin release and aggravated hyperglycemia. (14) In addition, insulin counterregulatory hormones that are secreted as a result of severe illness, or stress lead to increased hepatic and renal glucose production, impaired glucose utilization in peripheral tissues and aggravated hyperglycemia.

Chee et al. noted two important therapeutic implications that could complicate DKA management in patients with diabetes and concurrent COVID-19. As result of downregulation of ACE2 by SARS-CoV-2, the renin-angiotensin-aldosterone system (RAAS) is activated, with increased levels of angiotensin II and aldosterone. This enhanced hypokalemia risk during DKA management with intravenous insulin infusion. Careful monitoring of potassium levels and proper supplementation is accordingly required in patients presenting with DKA and COVID-19. Secondly, RAAS activation upsurges pulmonary vascular permeability which may damage lung parenchyma, and excessive fluid resuscitation during DKA management could worsen the acute respiratory distress syndrome. Hence, careful fluid monitoring and replacement is warranted in such patients. (8) 

In conclusion, we reported five patients presenting with DKA complicating a concurrent COVID-19 infection. Four recovered and were discharged to their homes and one had a complicated course and died. Our cases demonstrate that COVID-19 infection can trigger DKA. DKA can present in patients who are known to have diabetes mellitus or appear as a first presentation. Clinicians should be careful not to overlook admission hyperglycemia in managing COVID-19-related hyperglycemia. In addition, we observed that patient respiratory status declined after the resolution of their DKA, supporting the previously mentioned theory that activation of RAAS system due to downregulation of ACE2 following binding with SARS coronavirus leads to pulmonary vascular permeability and thus susceptibility to fluid overload. Therefore, we recommend careful fluid replacement and monitoring in those patients. During the COVID-19 pandemic, use of telemedicine via phone or video consultations for patients with diabetes is essential to ensure adequate glycemic control and prevent acute complications of diabetes. To the best of our knowledge, this is the first case series reporting DKA precipitated by COVID 19 infection in Saudi Arabia. Studies to identify the rate and the mechanism of COVID-19-induced DKA in diabetic patients are warranted.

No potential conflict of interest relevant to this article was reported.

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