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Abstract
Objectives To describe the incidence of new onset paediatric diabetes mellitus, clinical characteristics and patterns of presentation to emergency departments (ED) during the COVID-19 pandemic, and to assess whether this increase was associated with SARS-CoV-2 infection.
Design Retrospective medical record review.
Setting Forty nine paediatric EDs across the UK and Ireland.
Patients All children aged 6 months to 16 years presenting to EDs with (1) new onset diabetes or (2) pre-existing diabetes with diabetic ketoacidosis (DKA), during the COVID-19 pandemic (1 March 2020–28 February 2021) and the preceding year (1 March 2019–28 February 2020).
Results There were increases in new onset diabetes (1015 to 1183, 17%), compared with background incidence of 3%–5% in the UK over the past 5 years. There were increases in children presenting with new onset diabetes in DKA (395 to 566, 43%), severe DKA (141 to 252, 79%) and admissions to intensive care (38 to 72, 89%). Increased severity was reflected in biochemical and physiological parameters and administration of fluid boluses. Time to presentation from symptom onset for children presenting with new onset diabetes and DKA were similar across both years; healthcare seeking delay did not appear to be the sole contributing factor to DKA during the pandemic. Patterns of presentation changed in the pandemic year and seasonal variation was lost. Children with pre-existing diabetes presented with fewer episodes of decompensation.
Conclusions There were increases in new onset diabetes in children and a higher risk of DKA in the first COVID pandemic year.
- Diabetes
- Covid-19
- Emergency Care
Data availability statement
Data are available upon reasonable request. Not applicable.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Incidence of new onset diabetes and diabetic ketoacidosis (DKA) has been reported to have increased in children during the COVID-19 pandemic.
Proposed reasons for the increased incidence of new onset diabetes and DKA at diagnosis were delay in presentation and SARS-CoV-2 infection.
WHAT THIS STUDY ADDS
The Diabetes Mellitus in Children and Young People in the SARS-CoV-2 Pandemic study describes this pattern in a large patient population.
The study adds detailed data on presentation, severity of illness, diagnostic intervals and documented delay in presentation in both new onset and pre-existing diabetes.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
We may see further high incidence years with new onset diabetes, especially if SARS-CoV-2 has triggered the process of seroconversion in susceptible children.
Studies to characterise DKA in new onset diabetes are important to understand the factors for the high incidence of DKA despite public awareness campaigns.
Resource allocation and planning services will be key combined with a targeted approach of raising awareness for early identification of new onset diabetes in children.
Introduction
While paediatric emergency department (ED) attendances declined during the COVID-19 pandemic, the proportion of severely unwell patients presenting to ED increased.1 Among the high acuity presentations, an unseasonal spike in new onset paediatric diabetes and diabetic ketoacidosis (DKA) presenting to ED was observed during the first pandemic wave.
While this increase has been reported for both new onset diabetes2–4 and DKA2–8 at diagnosis, speculation on contributing factors has varied. Some hypothesise that the rise in DKA may be due to a direct effect of SARS-CoV-2 infection,2 3 while others speculate that delay in presentation was the main reason.5–7 Studies have also proposed an association between new onset diabetes and SARS-CoV-2.9–11 While studies reported that hospitalised adults with COVID-19 developed new-onset diabetes,12 13 evidence of a similar association between new onset diabetes and SARS-CoV-2 in children varied.2–8 Children generally present with mild or asymptomatic COVID-19, and selection bias in testing for SARS-CoV-2 existed as only symptomatic and hospitalised children were tested. Combined with a paucity of testing for SARS-CoV-2 antibodies in the first pandemic year, it was difficult to establish whether a relationship existed between new onset diabetes and SARS-CoV-2.
In the DIMPLES study, we aimed to describe the characteristics of new onset and decompensation of existing diabetes in children presenting to paediatric EDs during the COVID-19 pandemic and compare this to the prepandemic era.
Methods
Study design
This retrospective medical record review was conducted across 49 paediatric EDs who were member sites of Paediatric Emergency Research in the UK & Ireland (PERUKI).14 Participating sites included tertiary paediatric and general hospitals seeing both adults and children. Two distinct time periods were studied in order to compare the pandemic and prepandemic eras: 1 March 2020–28 February 2021 (year 2) and 1 March 2019–28 February 2020 (year 1). Data were collected between 1 May and 31 December 2021, and the study is reported in line with the Strengthening the Reporting of Observational Studies in Epidemiology statement (online supplemental appendix).
Supplemental material
Study population
Participants were eligible for inclusion if they were aged 6 months–16 years at the time of attending ED with (1) any new onset diabetes or (2) decompensation of existing diabetes resulting in DKA. Inclusion was at an individual attendance level; data from more than one attendance were captured provided severity criteria were satisfied at each attendance. Patients were identified by site study leads through searches of electronic clinical coding systems using International Classification of Diseases, 10th Revision codes for diabetes and DKA; this cohort was screened through review of medical notes to confirm eligibility. DKA was defined as a pH less than 7.3 or bicarbonate of <15 mmol and severe DKA as a pH less than 7.1 or serum bicarbonate of <5 mmol and ketones of >3.0 mmol/L in line with national and international guidance.15
Procedures
Data were collected according to standard methods for retrospective chart reviews, with all study variables in keeping with international definitions. Data were extracted by site investigators from the clinical records directly into an electronic case report form. All study staff underwent training delivered by the chief investigator prior to study commencement. Data included demographics, presence and duration of symptoms, physical examination findings, physiological parameters at presentation, family history, comorbidities, laboratory results (including COVID testing, HbA1c and pancreatic autoantibodies at diagnosis), duration and type of hospital admission and factors contributing to any delay in presentation. Diagnostic intervals were calculated from the period of reported symptoms of diabetes to the date of presentation to the hospital.
Data management
Study data were collected and managed using Research Electronic Data Capture tools (REDCap), hosted at University Hospitals Bristol and Weston NHS Foundation Trust and University College Dublin. REDCap is a secure, web-based software platform designed to support data capture for research studies.16 Data entry was monitored for quality and completeness by the data manager. Prior to analysis, data were checked for completeness and accuracy, and queries on missing or potentially erroneous data were resolved by the site study lead using data quality checks.
Sample size
All ED visits that met the criteria for ‘new onset diabetes’ or DKA (‘decompensation’) were included for both the pre-COVID-19 pandemic period and the COVID-19 pandemic period.
Outcomes
The primary outcomes were to describe the incidence, clinical and biochemical characteristics of new onset paediatric diabetes presenting to EDs during the pandemic and to evaluate whether a relationship to SARS-CoV-2 existed. Secondary outcomes were to establish whether there was any change in the incidence and severity of DKA during the pandemic in cases of new onset and decompensated disease, compared with pre-COVID historical data.
Statistical analyses
Variables are expressed as absolute numbers and relative frequencies, or median with IQR (or range) where appropriate. χ2 analyses were used for categorical and dichotomous variables, and Fisher’s exact test was used when ≤5 cases were present; non-parametric Wilcoxon rank-sum tests were used for non-normally distributed continuous variables; and Student’s t-test was used for normally distributed continuous variables. All analyses were planned a priori; no post hoc analyses were undertaken. Missing data were treated as missing; no imputation was performed. All analyses were performed in R statistical software V.4.0.0.
Results
Incidence and cohort characteristics
In total, 2618 individuals were identified during the study period. There was a 17% increase in new onset diabetes from 1015 in year 1 to 1183 in year 2, 97% of which were type 1 diabetes and 2% were type 2 diabetes (table 1 and online supplemental table A,B). There was a 27.8% reduction in attendances during the pandemic year (year 2) for patients with DKA due to decompensation of existing diabetes (online supplemental table C, D). Participant demographic characteristics did not differ significantly between the 2 years (table 1 and online supplemental table C). The normal seasonal pattern of new onset type 1 diabetes cases (winter peak with summer trough) was disrupted in year 2 (figure 1).
Characteristics of patients with new-onset diabetes in the Diabetes Mellitus in Children and Young People in the SARS-CoV-2 Pandemic cohort
Number of cases of new onset diabetes in the Diabetes Mellitus in Children and Young People in the SARS-CoV-2 Pandemic study.
Severity of presentations
Presenting symptoms, severity, treatment and outcomes of patients with new onset diabetes are demonstrated in table 2. On comparing severity of new onset disease during year 2 to that of year 1, we found there was a 43% increase in DKA (from 395 to 566, figures 1 and 2). This was most marked in severe DKA, which increased by 79% (from 141 to 252, p<0.001 (table 2) and intensive care admissions, which increased by 89% (from 38 to 72, p<0.05). The number of children with DKA who received a fluid bolus in ED of 20 mL/kg or more increased from 64 to 161 (p<0.001) (table 2). Increased severity of new-onset disease was also reflected in other biochemical and physiological parameters, including pH, tachycardia and tachypnoea (all p<0.001) (table 2 and online supplemental table D).
Severity and outcomes of patients with new-onset diabetes in cohort
Number of cases of diabetic ketoacidosis in children with new onset diabetes in the Diabetes Mellitus in Children and Young People in the SARS-CoV-2 Pandemic study
SARS-CoV-2 testing
In children with new onset and pre-existing diabetes, 1028 were negative for SARS-CoV-2 on nasopharyngeal swabs (reverse transcription polymerase chain reaction), while 316 children were not tested. Of 12 children with new onset diabetes who tested positive for SARS-CoV-2 on nasopharyngeal swab, 10 presented in DKA (online supplemental table E). Four of 155 children with pre-existing diabetes tested positive for SARS-CoV-2 on nasopharyngeal swab; all four presented in DKA. In total, 37 children were tested for SARS-CoV-2 antibodies, of which eight were positive (online supplemental table F).
Delays in presentations
Median symptom duration before attendance for new-onset diabetes in year 2 (14 days, IQR 7–28) was similar to year 1 (14 days, IQR 7–30) (online supplemental table D). There was no documented delay in 92% of children presenting with new onset diabetes in the pandemic year, similar to the prepandemic year (tables 3 and 4). Across both years, most instances of documented delay related to referral from primary care to EDs in children with new onset diabetes.
Reasons for delay and coexisting diagnoses in patients with new onset diabetes
Reasons for delay and coexisting diagnoses in patients with decompensation of pre-existing diabetes
Discussion
We have demonstrated an increase in new onset diabetes and severity of DKA during the first year of the COVID pandemic, in the context of unchanged patient demographics and symptom duration. Increased severity was reflected in biochemical and physiological parameters, administration of fluid boluses, and increases in severe DKA and intensive care admissions. This was contrasted by a reduction in decompensation of established disease during the pandemic year. Rates of delayed presentation to EDs were not different between study years in either new onset or decompensated diabetes. The seasonal variation of a peak in winter and a trough in summer reported in the prepandemic years17 was lost in the COVID-19 pandemic year.
Comparison to existing literature
The 17% increase in new onset diabetes in the first year of the COVID pandemic appears to represent a true rise, unique to this year. The population incidence of new onset diabetes in children over the past 5 years is 3%–5%, as reported from the National Paediatric Diabetes audit (NPDA).18 This is also supported by similar findings of a 20.7% rise in the first pandemic year reported from NPDA18 A further study showed an increase of 57% in children diagnosed with type 1 diabetes mellitus (T1DM) during the first pandemic year versus the previous 5 years.4
The DIMPLES study is a unique study from the ED that has demonstrated that DKA at presentation in new onset diabetes was greater during the pandemic era compared with the previous year. Children were at higher risk of DKA both during lockdown and during the period of partial restrictions in the pandemic year (figure 2). There were increases in the number of children with DKA who received a fluid bolus of 20 mL/kg. Eighty seven per cent of children who received a fluid bolus of 20 mL/kg or more in the pandemic year had severe DKA. During the study period, national guidance (British Society of Paediatric Endocrinology and Diabetes) changed in regard to fluid management, which could have also contributed.
Proposed reasons for increased frequency and severity of DKA diagnosis in children with new onset diabetes during the COVID pandemic have included delay in presentation.5–7 We therefore included the duration of symptoms before diagnosis to evaluate this relationship, and the comparable median duration across both years suggests that delay was unlikely to be the sole factor contributing to the increased severity seen in our cohort.
There is growing evidence that increased incidence of new onset diabetes is related to previous SARS-CoV-2 infection.2–4 A study of two large US databases of more than 2.5 million children reported that those with active/prior COVID-19 exhibited higher risk of new-onset diabetes than those without COVID-19.2 Several observational and registry studies also showed evidence of a link between COVID-19 and severity of DKA.3 4 8–11
From our data, the corelation with previous SARS-CoV-2 infection and new onset diabetes could not be tested as there was a paucity of testing for SARS-CoV-2 antibodies. It was also not possible to determine whether incidence of new onset diabetes or risk of decompensation was increased during acute SARS-CoV-2 infection due to the low volume of positive RT-PCR tests. The peaks of new-onset diabetes we have demonstrated followed surges of COVID-19 by approximately 3 months (figure 1). We hypothesise that there may be an association between COVID-19 and new-onset diabetes that cannot be captured by acute SARS-CoV-2 testing, akin to the late temporal association with PIMS-TS (Paediatric multisystem inflammatory syndrome temporally associated with COVID-19)
The DIMPLES data demonstrates a reduction in ED presentations for children with decompensated pre-existing diabetes during the pandemic, a phenomenon which has not previously been reported. Additionally, the DIMPLES study showed that there was no increase in severity of DKA or duration of hospital stay in children with pre-existing diabetes. Children with DKA usually present through ED; hence, the reduction in numbers is likely to be a true reduction. However, some participating institutions created alternative pathways for children with diabetes and implemented new ways of managing these patients effectively and safely. DKA in children with pre-existing type 1 diabetes is usually precipitated by insulin omission, concurrent illness or both. The pandemic offered opportunities for virtual diabetes clinics which may have contributed to increased engagement.19 The NPDA audit also reported better glycaemic control in the pandemic compared with previous years.18 Young people and families were managing their pre-existing diabetes and emergencies well with better implementation of sick day rules, resulting in reduced DKA. Learning from this and finding a system that allows flexibility between virtual and hospital clinics and is responsive to clinical needs may be of benefit and cost effective in the management of chronic diseases.
Implications for clinical practice and future research
Awareness of the increased incidence of new onset paediatric diabetes and the severity of DKA in the pandemic among both healthcare professionals and parents is vital. A targeted approach of educating people who will be in most contact with children (families, teachers and primary care clinicians) may help in increasing vigilance, recognising subtle symptoms, early identification of new onset diabetes and reducing the incidence of DKA.
The estimated incidence of new-onset T1DM in children was 3%–5% annually in the prepandemic period; an increase of 17% placed unexpected pressure on services. It is possible that we may see further high incidence years with new onset diabetes. Resource allocation and planning services are vital. Capture of pancreatic autoantibodies in all children with new onset diabetes is important.
It has historically been difficult to prove a causal relationship between viruses and T1DM due to the natural history and complexity of the disease. However, evidence exists in the form of animal studies and observational studies of new onset diabetes after viral infections to suggest that a link between these entities is likely.20 Autoimmunity and beta cell destruction start long before the clinical symptoms of T1DM, infectious triggers may accelerate the diagnosis or initiate the disease.21 Additionally, the sensitivity, the specificity and the paucity in testing for SARS-CoV-2 in children makes it difficult to associate previous SARS-CoV-2 infection and new onset diabetes.
Strengths and limitations
As a major strength, our study uniquely captures highly granular data on children with diabetes presenting to EDs affliated to the PERUKI network representing emergency care facilities from the entirety of the UK and Ireland. The large number of sites involved provides assurance that our results are reflective of actual patterns nationally. Paucity of testing for SARS-CoV-2 antibodies may have led to an underestimation of the impact of the virus on the reported outcomes. Due to missing data on deprivation and ethnicity, and it's not being missing at random, multivariable modelling was not undertaken. The DIMPLES study is a retrospective study; all characteristics of study participants could not be captured. Each centre has a defined geographical area and population providing a near 100% of new-onset diabetes from that area being captured. Population movement can still cause an occasional patient with new onset diabetes to be missed; similarly, a new onset diabetes from another area can be picked up; however, population movement during the pandemic was restricted.
Conclusions
The causes of paediatric diabetes are complex and can result from several pathogenic processes; however, given the high incidence of new onset diabetes and the incidence and severity of DKA, it is possible that SARS-CoV-2 may have a role as an accelerator or precipitator in a genetically predisposed child. Prospective studies, a priori designed, are needed to help us understand the role of SARS-CoV-2 in the pathogenesis of new onset diabetes. This is important, given the higher observed incidence and DKA severity noted in the pandemic.
Data availability statement
Data are available upon reasonable request. Not applicable.
Ethics statements
Patient consent for publication
Ethics approval
National research ethics committee approval was not necessary for this study. This was discussed and confirmed with the Health Research Authority (HRA). The study was, however, registered with, and approved by, research governance offices at the respective sites. HRA approval was obtained in Ireland. The study protocol was reviewed and approved by the HRA (IRAS 287804), and the need for patient informed consent was waived in the UK cohort on the basis that only routinely collected clinical data were being abstracted retrospectively. In Ireland, ethical approval was sought and gained from research ethics boards at participating sites.
Acknowledgments
We thank Heidi Chandler, Research and Innovation Manager for her assistance and contribution to DIMPLES. We thank Kate Honeyford, who has reviewed the statistical analysis undertaken in this paper as part of the peer-review process. We thank Mai Baquedano (UHBW), Darren Gobble (UHBW) and Kenny Lynch (Ireland) for their assistance with database design, and data management and storage.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @damian_roland, @mdlyttle
Correction notice This paper has been amended since it was first published. Some typographical errors were introduced in the headers for table 1 and these have now been removed.
Collaborators Alice Irwin, Anita Goyos, Antonia Bull, Atif Latif, Darren Ranasinghe, David Hartin, Elizabeth Dalzell, Emma Jenkinson, Fleur Cantle, Hannah Bruce-Norman, Helen Bailie, James Conroy, Jeff Morgan, Jenna Johnston, Jessica Watson, Jiske Steensma, Julie Smith, Justine Loh, Kat Priddis, Katy Rose, Lisa Kehler, Louise Budd, Lunik Sarder, Marit Ohrndorf, Meriel Tolhurst-Cleaver, Patrick Aldridge, Poppy Bennett, Rich Freeman, Ruben Willemsen, Sharryn Gardner, Simon Richardson, Sophie Keers, Steve Foster, Suzannah Johnson, Sylvester Gomes, Tim Saunders, Tom Siese, Vicky Worsnop, Victoria Agunloye, Yuva Moyo, Clodagh O’Gorman, Nida Jameel, Natasha Ferguson, Nandini Kandamany, Therese Martin, Manal Al Tareef, Catalin Soroiu, Margaret Grace, Dani Hall, Heather Grace, Marahaini Md Isa, Darren Smith, Lana Altabari and Sheena Durnin, Yvette Redpath, Kirsty Challen, Sabrina Sequeira, Gillian O'Donnell and Madison Carter.
Contributors CP, MDL, DR and RGN contributed to the design of the study. MDL and CP coordinated the running of the study in the UK, including data management and site training. MB co-ordinated the data management and running of the study in Ireland. CP, MDL and, RGN designed the electronic clinical report form RGN provided statistical expertise and performed the statistical analysis. All authors contributed to data collection and the writing of the manuscript. CP is guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.