Background
The first reported case of CoronaVirus Disease 2019 (COVID-19) was in Wuhan City, China in December 2019 [
1]. The median age of infected patients was approximately 62 years variable according to the country and period of the study. Interestingly, only 1.5% of patients diagnosed with Severe Acute Resporatory Syndrome-CoronaVirus 2 (SARS-CoV-2) are aged 0–18 years [
2]. On March 9
th a state of epidemic was announced in Italy and the lockdown period started. Afterwards, the World Health Organization declared a pandemic on March 11, 2020. The Italian Government imposed on March 2020 a national lockdown with travel restriction, closing of school, and suspending elective hospital activities. These recommendations have a strong consequence on different aspects of life such as on management of public health service. Therefore, the accesses to emergency room were strongly recommended to be limited to life-threatening conditions [
3]. In addition, the health-care resources and workforce were focused on the growing COVID-19 pandemic with limited access to general pediatrician outpatient. All these changes have led to divert attention from other diseases non COVID-19 related, such as paediatric type 1 diabetes causing delayed identification of new onset diabetes with an increased risk of severe diabetic ketoacidosis (DKA) [
4].
Type 1 diabetes (T1D) is one of the most common chronic autoimmune disease during childhood accounting for about 5–10% of all diabetes forms [
5]. In the last decades the incidence of disease has increasing in many countries with estimated overall annual increase at around 3% with geographic differences [
6]. DKA is one of the most important life-threatening complications of diabetes [
7] and is generally the consequence of a misdiagnosis [
5] which can be strongly modified by appropriate educational campaigns. In fact, Italian studies have shown a reduction in frequency of DKA following educational campaigns directed to targeting schools and primary healthcare physicians [
8]. Therefore, all changes related to the current pandemic period could strongly affect the disease having a strong impact on the management of it as well as other chronic diseases. In this study we aimed to evaluate the impact of COVID-19 pandemic on the frequency and severity of DKA in comparison to five previous years.
Discussion
In this study we demonstrated a significant increased risk of DKA at presentation in newly diagnosed type 1 diabetes during COVID-19 pandemic and particularly an increased prevalence of severe form of DKA compared to the previous five years. We also demonstrated in newly diagnosed subjects with type 1 diabetes during COVID-19 pandemic but not in those diagnosed during the previous five years that pH values significantly correlated positively with HDL values and indirectly with Triglycerides and TG/HDL cholesterol ratio suggesting an additional effect of lifestyle changes beside the delay in the diagnosis and these correlations were also confirmed by logistic regression analysis.
Diabetes is one of the most common chronic disease during childhood [
15,
16]. Diabetic ketoacidosis is an acute and life-threatening complication of diabetes commonly associated to newly diagnosed subjects. The SEARCH for Diabetes in Youth (SEARCH) study previously reported that the DKA prevalence is one third of patients with newly onset type 1 diabetes [
17]. The DKA reflects more severe pancreatic β-cell destruction and is associated with increased morbidity and mortality risk, longer hospitalization, higher insulin requirement and a worsening glycemic control over time [
18]. Cherubini et colleagues showed that the worldwide prevalence of DKA at type 1 diabetes onset was increased and it is estimated around 29.9% with differences between countries; in addition, the one of the highest prevalence was highlighted in Italy (about 41%) [
19,
20]. Of note, this temporal trend seems to be additionally affected by COVID-19 pandemic, as suggested by few recent studies. In particular, a Polish study found increased DKA frequency and severity during the pandemic lockdown from March 2020 until May 2020 in comparison to the same previous year [
21]. On the other hand, different studies conducted in Italy during COVID-19 pandemic have described cases of delayed diagnosis of new-onset type 1 diabetes (T1D) and consequently severe DKA [
22].
In a recent study conducted in Italy it is showed a different diabetes presentation as well as its severity; the study counted a fewer number of cases of type 1 diabetes onset during pandemic but a major number of children presenting with severe DKA [
23]. A survey conducted in UK between March 2020 and June 2020 demonstrated an increased incidence and severity of DKA consequent to delayed medical intervention while no differences were found for the incidence of new onset type 1 diabetes [
24]. In addition to these studies, by evaluating data obtained during a longer period, we demonstrated relevant differences in clinical presentation of newly cases of type 1 diabetes in children and adolescents. In fact, during COVID-19 lockdown we have documented a significant increased risk of DKA and particularly we demonstrated an increase of 19-percentage in DKA frequency among children with type 1 diabetes onset diagnosed during COVID-19 pandemic compared to the previous five years. More importantly, we also demonstrated that the severity of DKA is higher among children and adolescents diagnosed during this period. In fact, compared to those subjects diagnosed during the previous five years, newly diagnosed patients with type 1 diabetes during COVID-19 pandemic showed a significantly higher percentage of severe form of DKA (22.5% vs. 8.4%). There are fewer data about the severity of COVID-19 disease among children with type 1 diabetes [
25]. It is known that DKA is strongly related to several factors and particularly to delayed diagnosis [
26], which might be supposed to be certainly affected during COVID-19 pandemic. The possible causes of diagnostic delay are various; among these, there was a major attention of healthcare on COVID-19 related problems; moreover, parents avoided conducting the child to hospital and to general pediatricians for fear of acquired COVID-19 infection as demonstrated by the lower emergency room accesses during lockdown period [
3]; indeed we must also considered the difficulties of moving related to the lockdown itself. These considerations strongly affect the key point of screening programmes for diabetes as well as publicity campaigns which are considered to be effective in reducing DKA prevalence at type 1 diabetes diagnosis [
27,
28]. Therefore to counteract diagnostic delay, a greater awareness of type 1 diabetes [
29] and health care programmes need to be supported also during those state of pandemic or long lasting emergency [
30,
31]. In a recent Italian systematic review with meta-analysis was demonstrated the effectiveness of the awareness campaigns (e.g. posters, explicative letter, newspapers and magazines, mass media spots etc.) in reducing the frequency of DKA at the diagnosis of T1D in children and adolescents and are important tool for pediatricians and others to intervene in a timely manner [
32].
It is known that children with type 1 diabetes are at increased risk for autoimmune diseases compared to the general population. Approximately 25% of patients are diagnosed with another autoimmune disease, being thyroid disease the most common followed by celiac disease. Compared to previous studies evaluating newly diagnosed children with type 1 diabetes [
21,
23], in our study we were able to characterize several laboratory findings at diagnosis including autoimmune panel. In details, concerning thyroid autoantibodies, no significant difference was found between the two groups, although a trend toward a major percentage of subjects with autoantibodies positivity was documented in Group II. Regarding celiac disease screening, we documented a significantly higher percentage of positivity for the tTgA IgA and IgG antibodies in Group II; on the other hand, no significant difference was found for EMA antibodies. Although interesting, these findings need to be evaluated in a longitudinal setting in order to characterize any possible difference in the risk of developing other autoimmune diseases later on in life.
Previous studies have characterized lipid profile in newly diagnosed children reporting an association between impairment of lipid profile and type 1 diabetes [
33]. In addition, researches have reported a correlation between TG/HDL-C and incidence of diabetes [
34]. In our study, triglycerides values were significantly higher in those children with type 1 diabetes diagnosed during COVID-19 pandemic compared to Group I; similarly, a trend toward lower concentrations of HDL cholesterol levels was documented although it did not reach significant values. In addition, by performing a correlation analysis in the entire population we showed a significant association between pH and TG/HDL cholesterol ratio but not with other variables of interest. More importantly after dividing the population into the two groups according to the period of diagnosis, pH values significantly and positively correlated with HDL and negatively with triglycerides and TG/HDL cholesterol ratio in Group II but not in Group I. More importantly, these results were also confirmed by using a regression analysis thus showing a correlation between pH and lipid profile in Group II. It might be supposed that these findings might be related to the effects of lifestyle changes during COVID 19 pandemic. Relatively recent studies have shown that the Tg/HDL cholesterol ratio represents a good marker of insulin resistance in a multi-ethnic cohort of obese and overweight children being associated with both OGTT (Oral Glucose Tolerance Test) and clamp derived measures of insulin sensitivity. Therefore, further studies evaluating this marker of insulin sensitivity at diabetes onset are needed to better characterize this interesting feature. In addition, further investigations are necessary both in type 1 diabetes subjects and in all children in order to clarify the association between lifestyle habits and changes of this cardiovascular risk factor during pandemic.
The need for social isolation might increase sedentary habits and reduce physical exercise together with diet changes which are directly related to obesity and its comorbidities. In fact, during COVID 19 pandemic, recent studies have shown in children and adolescents an increased risk of obesity [
35], a well-known risk factor for impaired lipid profile and increased insulin sensitivity [
36]. Indeed, nutritional habits as well as physical activity may significantly influence factors related to the risk of developing DKA at diagnosis. Further and larger studies are needed to confirm our data.
One of the major limits of this study is that it is not a population-based study; consequently, the data do not reflect the general population but only a small part of it, affected by the disease. Therefore, the small sample size is due to the fact that data were obtained in a single center. The availability of new multicenter studies might further confirm our data. In addition, metabolic decompensation during DKA should be confounding factor and these data should be re-evaluated and results confirmed after achieving glycemic control. One of the major strengths of the study is the availability of data evaluating subjects with newly diagnosed type 1 diabetes during the five years before. In addition, a relevant strength is the availability of a complete laboratory assessment which added novel information in the analysis of the correlation of diabetes with other autoimmune disease.
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