Abstract
Educational Objectives
Type 1 diabetes mellitus (T1DM) is a predominantly autoimmune process that can be incited by viral illness, and the incidence of which has increased since the start of the COVID-19 pandemic.
T1DM typically presents in childhood and early adolescence, although those with early-onset T1DM (before age 5 years old) are at higher risk for diabetic ketoacidosis (DKA) and developmental delays (due to both DKA and glycemic variability on the developing brain), so early recognition by pediatricians is imperative.
Introduction
Type 1 diabetes mellitus (T1DM) incidence increases with age during childhood, peaking during school age and early adolescence. 1 There has been a 3% increase in rate of new diagnosis of Type 1 Diabetes over the past few years, however since the start of the COVID-19 pandemic there have been reports of up to 33% to 166% increase in incidence.2-4 Type 1 diabetes mellitus is considered an autoimmune disease, presenting with autoantibodies believed to be triggered by a viral infection in those with a genetic predisposition. 3 It is uncommon for diabetes to present in infancy and is more likely to be due to neonatal (monogenic) diabetes mellitus (NDM) than T1DM prior to 6 months of life. 5
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, ie, COVID-19) is a novel coronavirus primarily causing respiratory symptoms, which have been generally milder in pediatric populations.6,7 COVID-19 is a single-stranded RNA-enveloped virus which infects cells through glycosylated proteins that cover the surface and bind to angiotensin-converting enzyme-2 (ACE2) receptors. 8 High levels of ACE2 expression have been found in the pancreas, which may lead to acute pancreatic injury and subsequent beta-cell damage, causing hyperglycemia. 9 There has been an increase in both the diagnosis of T1DM and the severity and incidence of diabetic ketoacidosis (DKA) since the start of the COVID-19 pandemic.2,10
Here, we present a case of new onset of T1DM in a very young infant with concurrent COVID-19 infection. There are a limited number of antibody-positive cases of T1DM reported in patients this young. Management of an infant with new onset diabetes also presents unique challenges. Not only do they have glycemic variability, but due to this, they are also at risk of developmental delays. 11 To our knowledge, this is the youngest reported case of antibody-positive T1DM with COVID-19 infection.
Case Report
A 5-month-old term, breast-fed, Caucasian female with no significant past medical history presented to the emergency department (ED) with Kussmaul respirations and altered mental status. Family reported about 5% weight loss and increase in appetite for 1 month, followed by increase in work of breathing and decreased oral intake for 1 day. Her family history was significant for a father with T1DM (diagnosed in his late teens, with DKA, but unknown diabetes antibody status). There was no report of polyuria or polydipsia. Her initial presentation to the ED was significant for tachycardia (190 beats per minute), tachypnea (68 breaths per minute), capillary refill >5 seconds, and altered mental status. Her initial lab values showed hyperglycemia (glucose >600 mg/dL), severe acidosis (pH 6.901, bicarbonate of 3.8 mmol/L), and beta-hydroxybutyrate level of 6.03 mmol/L, consistent with DKA. The serum glucose on a Complete Metabolic Profile (CMP) was 689 mg/dL. Sodium on the CMP was 151 mEq/L and blood urea nitrogen (BUN) was 30 mg/dL (calculated osmolality 351 mOsm/kg), consistent with a mixed DKA and hyperglycemic hyperosmolar state (HHS). A respiratory film array resulted positive for SARS-CoV-2 infection. Blood and urine cultures were negative. Chest X-ray demonstrated “bilateral hyperinflation with increased perihilar opacities,” consistent with a viral illness.
She was given two 10 mL/kg normal saline boluses and then started on isotonic IV fluids at a rate of twice maintenance until her glucose levels came down to 218 mg/dL after several hours. She was then started on an insulin drip at a rate of 0.05 units/kg/hour (a slower rate due to mixed DKA and HHS), and transferred to the pediatric intensive care unit where her blood gas, electrolytes, and beta-hydroxybutyrate were monitored until resolution of DKA. Her initial evaluation included a glycosylated hemoglobin (HbA1c) level of 8.6% and a positive insulin antibody, among other labs, consistent with a diagnosis of T1DM (shown in Table 1). Owing to young age at diagnosis, an Invitae Monogenic Diabetes Panel (Invitae Corporation, San Francisco, CA, USA; 28-gene panel, genes included listed at https://www.invitae.com/en/providers/test-catalog/test-55001) was sent to determine whether there was a monogenic mutation as the cause to her clinical presentation. However, this resulted as negative. An insulin pump (Insulet Omnipod DASH, Insulet Corporation, Acton, MA, USA) and continuous glucose monitor (CGM, Dexcom G6, Dexcom Company, San Diego, CA, USA) were started prior to discharge from the hospital due to patient’s young age and increased insulin sensitivity.
New Onset Diabetes Labs.
After discharge, she was also following with physical therapy (PT) due to gross motor delays. She was discharged from PT after 1 year of therapy due to meeting appropriate milestones at that time. She also was seen by Genetics as a consult during her admission and in 1-year follow-up. Owing to young age and developmental delays, further genetic testing was initially discussed, but her delays resolved with therapy, so testing was held for the time being. Initially, our patient had negative antithyroidperoxidase (TPO) antibodies, but 1 year after her T1DM diagnosis, she developed Hashimoto’s thyroiditis with positive anti-TPO antibodies and was started on thyroid hormone replacement when her thyroid stimulating hormone (TSH) level became elevated.
Discussion
There are a limited number of antibody-positive cases of T1DM reported in patients this young. To our knowledge, this is the youngest reported case of antibody-positive T1DM with COVID-19 infection. Although this patient was less than 6 months old, her monogenic diabetes panel (which includes 28 genes for NDM, including duplications and deletions) was negative. She has a family history of T1DM and positive insulin antibody, consistent with the diagnosis of T1DM. Having a parent with T1DM increases risk of development of diabetes; maternal diabetes can increase T1DM risk by 2% to 3% and paternal diabetes can increase risk up to 7%. 1 Classically, at least two autoantibodies are present in T1DM, but there are reports of heterogenous presentations with single autoantibody status (usually at an older age). 12 She was also eventually diagnosed with another autoimmune disease (Hashimoto’s), which is a common association with T1DM. 1
While NDM is rare overall (about 1 in 90 000-160 000 births), it is much more common than autoimmune-mediated T1DM when diabetes presents before 6 months old. It was reported that up to 80% of diabetes presenting before age 6 months is due to NDM (vs. T1DM). 5 Neonatal diabetes mellitus is monogenic form of diabetes due mutations in the beta-cell. It is important to recognize NDM early, as some forms can be treated with sulfonylureas instead of insulin. Neonatal diabetes mellitus can still present up until 12 months old, but after 6 months T1DM becomes the more predominant diagnosis. 5
The incidence of cases of new onset T1DM has been increasing annually around the world for the past several years. 3 Type 1 diabetes mellitus is considered an autoimmune disorder, and autoimmunity is very rare in infants under age 1 year. Viruses are often proposed as a common trigger for autoimmunity, promoting an inflammatory response against beta-cells in the case of T1DM. 13 This has previously been associated with viruses such as enteroviruses, rubella, mumps, parainfluenza, cytomegalovirus, and human herpesvirus-6.3,10,14 Yet, enteroviral RNA has been detected in those with newly diagnosed T1DM, signifying there may also be an acute phase of beta cell destruction in addition to the autoantibody-mediated long-term lymphocytic insulitis. 14 One protective factor seen in our patient in development of T1DM is that our patient was noted to be exclusively breast fed prior to her presentation. Breastmilk is reported to be protective against the development of T1DM. 10
Since the start of the COVID-19 pandemic, there have been several reports of an increase in cases of T1DM in those with COVID-19 infection, and a higher rate of DKA in those patients.2,3,15 COVID-19 is a novel virus, and not only does COVID-19 seem to induce autoimmunity in those with a predisposition, but it may also have direct effects on the beta cells. Angiotensin-converting enzyme-2 is the binding receptor for SARS-CoV-2 and is expressed in many tissues, including the lungs, kidney, heart, alveolar epithelial cells, and pancreatic endocrine cells. 8 This suggests COVID-19 may directly injure beta cells; pancreatic beta-cells are more prone to apoptosis than α cells, which are able to mount a more effective antiviral response. 9 Our patient in this case was acutely infected with COVID-19 and presented with both insulin autoantibodies and DKA (suggesting more severe insulin deficiency). Infants have a higher concentration of hemoglobin F, so it is also possible that the HbA1c could be higher than what resulted on testing. 16 There have been several other case reports of coincident new-onset T1DM and COVID-19, with positive diabetes autoantibodies, but DKA and elevated HbA1c at diagnosis.13,17 Therefore, these patients may have had pre-existing autoimmunity with decline of beta cell function due to direct destruction by COVID-19, or the COVID-19 could have caused both (autoimmunity and destruction). However, with multiple cases being reported, therefore this can be an area of further study.
In addition to the increase in T1DM cases since the start of COVID, there has also been an increase in DKA, with some studies showing the rate of DKA in children with new onset T1DM more than doubled from 2019 to 2020.10,15,18 This may partially be due to a delay in seeking care early in the pandemic, but could also be due to the effect of COVID-19 on the beta cells causing more acute loss of beta cell function and resulting severe DKA.3,5,15 The odds of presenting in DKA is higher in infants as well due to the difficulty of recognizing early signs of diabetes at this age and some evidence of a more aggressive beta cell decline in infants. 5 It can be especially difficult to diagnose in infants with respiratory viruses (like our patient) since Kussmaul respirations can be mistaken for viral symptoms. 19 Diabetic ketoacidosis is classified by hyperglycemia >200, a venous pH <7.3, and a bicarbonate level of <15 mmol/L, and is the result of a severe insulin deficiency. It commonly presents with polyuria, polydipsia, and weight loss, progressing to nausea, vomiting, Kussmaul respirations (rapid, deep breathing), and altered mental status. 20 In our case, our patient also had hyperosmolality, complicating her management. It is important to slowly decrease her glucose with fluids alone, prior to adding insulin. Owing to her age and the DKA/HHS mixed picture, a slower insulin rate was also used. 21 With DKA and HHS, there is significant risk of cerebral edema (CE), so treatment is focused on slowly correcting hypovolemia and hyperglycemia, while continuously administering insulin and dextrose. Mortality rates for CE range from 21% to 24%; 22 therefore, it is necessary in infants to be conservative with fluids and use a slower insulin rate (like with our patient) to prevent CE.
Finally, there are data showing that patients with early-onset diabetes are more likely to have developmental delays and lower cognition than those with later onset. This is likely due to severe DKA episode (which can cause cerebral edema and reduced cerebral blood flow) and glycemic variability, for which the developing brain can be vulnerable to the extreme blood glucose values both high and low.11,20 One report noted an almost two-fold increase in prevalence of development, learning, and language disorders in those with diabetes. 23 Another study suggested a 3 to 7 point difference in IQ, with a larger difference in cognitive function in those diagnosed earlier, with greater glycemic extremes, and with DKA episodes. 11 Our patient did have some motor delays requiring PT, which may have been worsened by the young at diagnosis of diabetes.
In conclusion, this is to our knowledge one of the youngest reported infants with antibody-positive T1DM and the youngest with the combination of T1DM and COVID-19 infection reported in the literature. It highlights the increasing incidence of T1DM and DKA in the post-COVID-19 era, especially in younger children. Monitoring for developmental delays is also extremely important in this younger population as well and may become more important with the increasing incidence of T1DM in younger children.
Author Contributions
JP, AL, and RH all contributed to the drafting of the article, critical revisions, and approval of the final version of the article to be published.
Footnotes
Acknowledgements
The authors would like to thank the patient and her family for giving consent to publish this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Written informed consent was obtained from the patient’s parents prior to the submission of this publication. No internal review board approval was required by our institution.
