key: cord-0750002-1kf48x26
authors: Modarelli, Rachel; Balikcioglu, Pinar Gumus; Hendrix, Grace; DeRusso, Michelle; Ozment, Caroline
title: The Perfect Storm: Rapid Progression of Diabetic Ketoacidosis in Pediatric Diabetes in the Setting of COVID-19
date: 2021-06-04
journal: AACE Clin Case Rep
DOI: 10.1016/j.aace.2021.05.007
sha: fc3036b05b65a38fce9b359f65fd599c8f548069
doc_id: 750002
cord_uid: 1kf48x26

OBJECTIVE: The coronavirus disease-2019 (COVID-19) pandemic has introduced countless challenges to the medical field. While pediatric patients are reported to have lower rates of COVID-19 mortality, the presence of pre-existing conditions can heighten the severity of their clinical presentation. CASE REPORT: Our patient, a six year old female with known type 1 diabetes, presented with acute onset of abnormal breathing and altered mental status. The day prior, she had one episode of emesis, diarrhea, and abdominal pain, but no fever. She presented to an outside hospital and was reported to have agonal breathing with a GCS of 8 (eyes open to pain, no verbal response to stimuli, and localizes pain). She was promptly intubated and initial labs revealed severe diabetic ketoacidosis (DKA). With a family member with COVID-19, she tested COVID-19 positive. RESULTS: Our patient’s rapid progression and severity of illness requires discussion of how COVID-19 might affect diabetes and indicates opportunities for improving clinical practice in children with preexisting diabetes. We discuss how COVID-19 might change the underlying pathophysiology of DKA and cause metabolic complications. Possible mechanisms include binding to angiotensin-converting enzyme 2 (ACE2) receptors, and enabling a proinflammatory “cytokine storm”. Additionally, ketoacidosis and altered mental status have been present in patients with COVID-19 without diabetes, which might potentiate the symptoms in developing DKA. CONCLUSION: Prompt recognition of DKA is warranted as caregivers may attribute the symptoms to COVID-19 rather than DKA, resulting in increased severity of illness on presentation with acute symptom onset, as described in this report.

verbal response to stimuli, and localizes pain). She was promptly intubated and initial labs 27 revealed severe diabetic ketoacidosis (DKA). With a family member with COVID-19, she tested 28 COVID-19 positive. 29

Results Our patient's rapid progression and severity of illness requires discussion of how 30 COVID-19 might affect diabetes and indicates opportunities for improving clinical practice in 31 children with preexisting diabetes. We discuss how COVID-19 might change the underlying 32 pathophysiology of DKA and cause metabolic complications. Possible mechanisms include 33 binding to angiotensin-converting enzyme 2 (ACE2) receptors, and enabling a proinflammatory 34 "cytokine storm". Additionally, ketoacidosis and altered mental status have been present in 35 patients with COVID-19 without diabetes, which might potentiate the symptoms in developing 36

Conclusion Prompt recognition of DKA is warranted as caregivers may attribute the symptoms 38 to COVID-19 rather than DKA, resulting in increased severity of illness on presentation with 39 acute symptom onset, as described in this report. open to pain, no verbal response to stimuli, and localizes pain) and she was reported to be 67 agonal breathing. Almost immediately, the patient was intubated. Remarkable labs included a 68 glucose of 486 mg/dL, venous blood gas with pH of 6.88, bicarbonate 4 mEq/L, lactate 5.8 69 mmol/L (0-1.0 mmol/L), beta hydroxybutyrate 11.9 mmol/L, anion gap 29 mEq/L which were 70 significantly worse than her initial diagnosis of Type 1 diabetes 6 months earlier. She was 71 diagnosed with severe diabetic ketoacidosis (DKA), and isotonic fluids and insulin were initiated. 72

Due to concern for cerebral edema given the acute change in her mental status, she was given protein (CRP), erythrocyte sedimentation rate (ESR), troponin, hepatic function panel, and 78 coagulation studies. These labs were largely normal with the exception of an elevated D-dimer 79 1,112 ng/mL (<500 ng/mL). She was appropriate for extubation around twelve hours later with 80 return to her baseline mental status and with improved acidosis. She transitioned to 81 subcutaneous insulin on day two of her hospital stay. On day three of hospitalization she 82 developed sore throat, productive cough, fatigue, headache, and fever (max 39.5C) that 83 persisted for four more days until she was afebrile, had improved oral intake, and was then 84 discharged home in good condition. One suspected interaction of COVID-19 is with the renin angiotensin-aldosterone system. The 94 angiotensin-converting enzyme 2 (ACE2) is expressed in large quantities in the lung, intestine 95 and pancreas to name a few. Its role is to convert angiotensin II to angiotensin, which 96 contributes to a decrease in inflammation, an increase in insulin, and vasodilation (2). SARS-97

CoV-1, the virus responsible for SARS outbreak in 2003, has been proven to bind ACE2 via the 98 spike protein (12). It would be reasonable to propose that as the relative of SARS-CoV-1, 99 COVID-19 might cause downregulation of ACE2 upon binding and furthermore, destruction of 100 the islet cells (8, 10). This downregulation could then lead to increased angiotensin II, which 101 dysfunction, leading to oxidative stress and further triggering inflammatory factors (7). 103

Our patient was only receiving 0.5u/kg/day of insulin since her diabetes diagnosis six months 105 earlier, meaning she likely had some degree of functioning islet cells prior to her illness, also 106 referred to as the "honeymoon period". At post-discharge follow up, she was receiving closer to 107 1 u/kg/day of insulin. She was not reported to have elevated glucose levels at her visits prior to 108 this presentation, signifying that her increase in insulin needs are less likely due to non- Another connection between these two disease processes is the inflammatory markers present. 114

The cytokine interleukin-6 (IL-6) has been shown to be elevated in patients with COVID-19 due 115 to the hyper-inflammatory state, independent of DKA. IL-6 has also been elevated in patients 116 with DKA as a driver of ketogenesis (9). With both disease states occurring simultaneously, it is 117 possible that the patient's overall inflammatory response may create a worse clinical status 118 when compared to other precipitating agents. Unfortunately, the interleukin-6 level was not 119 collected for the patient described above. 120 121 Ketosis 122

Pathologic ketosis and ketoacidosis can be seen in various disease states such as DKA, 123 starvation, toxin ingestions, among others. In diabetes alone, the decreased insulin levels will 124 induce the ketogenesis pathway. When patients become ill, there is a higher level of counter-125 regulatory hormones such as epinephrine, which is shown to induce lipolysis, activating the cohort (5). Results were that 6.4% of patients had ketosis on admission, with only 35% of 129 those patients having diabetes. COVID-19 is thought to potentiate fat breakdown, leading to 130 ketosis and furthermore, to ketoacidosis (5). This suggests that COVID-19, independent of DKA, 131 could cause ketosis and potentially ketoacidosis in severe disease. Lastly, it is important to recognize that the initial symptoms reported by our patient were not 142 respiratory, but rather gastrointestinal and neurologic symptoms manifested as emesis/diarrhea 143 and altered mental status respectively. In patients with DKA, altered mental status is shown to 144 primarily be related independently with acidosis (6). A surveillance study completed in the UK 145 identified altered mental status as a symptom in 31% of patients with COVID-19, which was 146 disproportionately more common in younger patients (labeled as under 60 years old) (11 "sick day rules" at the first sign of illness. A confusing picture is painted when parents may 163 recognize symptoms of COVID-19 rather than DKA, resulting in late recognition when acute 164 symptoms occur, as described in this case. More data will need to be collected to fully 165 understand the pathophysiology of COVID-19 and how exactly it might worsen DKA. Research 166 so far suggests that it may cause an increase in inflammatory markers, decrease in insulin 167 secretion secondary to downregulation of ACE2 and destruction of islet cells, increase in insulin 168 resistance, increase in ketosis and ketoacidosis, and potentially lead to altered mental status (1, 169 5, 8, 9) . Further research into these proposed mechanisms could better guide the management 170 of patients as well as introduce targeted treatments. 171

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Hyperketonemia and ketosis increase the risk of 184 complications in type 1 diabetes

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