Main text
Type 1 diabetes mellitus (T1D) is one of the most frequent chronic diseases in children; it is due to an autoimmune destruction of the insulin-producing β-cells in the islets of Langerhans within the pancreas [
1]. Patients with T1D lose blood glucose control, which can result in both acute conditions (ketoacidosis and severe hypoglycemia) and chronic complications (retinopathy, nephropathy, neuropathy, and cardiovascular diseases). The pathogenesis of the T1D involves environmental factors (e.g. enteroviral infection) and polygenic predisposition.
The incidence of T1D has increased dramatically over the last five decades, especially in children younger than five years [
2]. Those under the age of 18 years are most often affected, but an equal number of adults over 18 are thought to develop the disease. Currently there is no cure to T1D, therefore the patients are destined for a lifelong insulin treatment and, in most cases, the development of disease-related complications. Additionally, T1D has a huge economic burden on the patients, their families and the health systems globally [
3]. Numerous studies have shown that new technologies improve glycaemic control and long-term outcomes in children and adolescents with type 1 diabetes. Furthermore, these devices have improved quality of life and have patient satisfaction [
4].
Here we discuss the main unmet needs in type 1 diabetes and the opportunity presented by population screening.
Diabetic ketoacidosis at clinical onset of diabetes
A recent international study showed that the frequency of DKA at diabetes diagnosis was between 20.7% and 48.7% in the years 2006–2019 with a huge increase during the COVID-19 pandemic, exceeding 55% of cases [
5]. DKA is a clinical emergency associated with serious complications including cerebral edema, increased mortality rates, prolonged hospital stays, excessive costs, and poor long-term metabolic control [
6] [
7] [
8]. A single episode of moderate/severe DKA in young children at diagnosis is sufficient to cause cognitive impairment and impaired brain growth [
9]. The presence of DKA suggests delayed or unrecognized symptoms by parents or caregivers. DKA awareness campaigns are effective in reducing the frequency of DKA at the clinical onset of type 1 diabetes in children and adolescents [
10]. However, large-scale implementation of prevention campaigns requires considerable effort and their diffusion is still limited today. Very interesting results on the reduction of DKA at the diagnosis of diabetes have been reported by the screening program of the general population using anti-beta-cell autoantibodies [
11].
Screening of type 1 diabetes
The onset of clinical type 1 diabetes is preceded by a long non-symptomatic prodromal period characterized by well-defined stages, which allow the progression towards the symptomatic disease, defined as stage 3, to be predicted [
20]. In stage 1, individuals have two or more beta-cell autoantibodies with normal blood sugar, in stage 2, two or more autoantibodies and dysglycemia or glucose intolerance. Given the reduced level of β-cell numbers at the time of diagnosis, the ability to stage type 1 diabetes before clinical onset presents an opportunity to preserve functional residual β-cell mass and prevent the onset of clinical symptoms [
21]. The islet-specific autoantibodies are anti-insulin antibodies (IAA), glutamate decarboxylase (GAD), islet antigen 2 (IA-2) and islet-specific zinc transporter (ZnT8). Children with two or more islet autoantibodies in stage 1 have a 5-year risk of clinical T1D of 44%, and a 15-year risk of 80-90%; children with two or more islet autoantibodies in stage 2 have a 5-year risk of clinical T1D of 75% and a lifetime risk of 100% [
22]. A child with only one islet autoantibody should be also followed up since could be transient or could develop other autoantibodies and then clinical T1D.
Antibody screening has been used extensively in first-degree relatives of patients with type 1 diabetes (siblings, children, parents), including the TrialNet study, which identified potential subjects for prevention studies and provided information on the natural history of the disease [
23]. However, it is known that nearly 90% of children with newly diagnosed T1D have no family history of type 1 diabetes, so simply screening this population misses many cases.
There are many reasons to suggest population screening in Europe [
24] and Italy. First, a large number of children have diabetic ketoacidosis at the diagnosis of type 1 diabetes, this number of patients has dramatically increased during the COVID-19 pandemic both in Italy and in the rest of the world [
25] [
5]. DKA is a serious and life-threatening event associated with short- and long-term sequelae, including significant neurocognitive outcomes, shorter remission phase, lower C-peptide reserve, worse glycaemic control, increased risk of vascular complications, and costs.
Secondly, the screening is cost-effectively. Early detection of T1D in children might possibly reduce the risk or even prevent the deterioration of metabolic function. This would eventually decrease the risk of long-term complications, including brain damage associated with hyperglycaemia and hypoglycaemia, as well as vascular complications. In fact, the analysis of two databases from Sweden, The Swedish Paediatric Diabetes Quality Registry (SWEDIABKIDS) and the Swedish National Diabetes Registry (NDR), found that patients with better metabolic control at the time of stage 3 clinical T1D diagnosis had better metabolic control later in adult life [
26]. Other studies have confirmed that lower HbA1c values at diagnosis and early preservation of C-peptide reserve are associated with better metabolic control later in life and reduced risk of long-term complications [
27][
28]. In addition, early screening for T1D in children could become cost-effective due to cheaper antibody screening methods, prevention of DKA hospitalization and the expected reduction in the incidence and economic impact of diabetes complications [
29]. In fact, the Fr1da study aiming to screen 200,000 children aged 3–4 years showed that DKA prevention in about 200 patients may cover a third of the study cost [
11]. In Colorado, patients with DKA at diagnosis have had HbA1c 1.4% higher than in those without DKA, for up to 15 years after diagnosis [
7]. Moreover, the Autoimmunity Screening for Kids (ASK) has demonstrated that prevention of DKA at diagnosis, combined with persistently lower HbA1c in patients without DKA and reduced incidence of diabetes complications, makes general population screening cost-effective [
29].
Thirdly, it should also not forget that early diagnosis of stage 1 or stage 2 T1D could offer children and their families an opportunity to participate in clinical trials, with the aim of delay the clinical manifestations of the disease. There are several trials available in Europe, USA and elsewhere in the world and some drugs have shown promising results in postponing the progression to clinical T1D [
30][
31][
32]. In individuals with a first-degree relative with T1D, one of these drugs (teplizumab, an anti-CD3 monoclonal antibodies) has shown to prolong a diabetes-free time of up to 6 years; this drug has been approved by the Food and Drug Administration (FDA) on November 2022 and it should be soon available in clinical practice.
The advantage of knowing in advance the possibility that a child has T1D and delaying the diagnosis with a drug must be balanced with the anxiety that this information produces in families, and with the efforts and organizational costs that screening requires (Table
1). It has been argued that screening for T1D could induce considerable psychological stress in children diagnosed with pre-symptomatic T1D and their parents (either at risk or in the general population). Natural history studies that have monitored children positive for islet autoantibodies [
33][
34][
35] have reported that parental distress was moderately increased, but returned to baseline levels with an appropriate education and monitoring. Islet autoantibody screening and diagnosis of pre-symptomatic T1D appear unlikely to induce parental psychological stress, which is comparable to that observed in families of children diagnosed with clinical T1D. Data from the Fr1da Study have shown that, when appropriately informed and educated, parents and families of children with two or more autoantibodies had positive feelings toward an early identification of T1D [
36].
Table 1
Pros and cons of screening for type 1 diabetes
Possible prevention of DKA at onset of diabetes | Potential increased anxiety in parents/carers |
Opportunity for time to adjust to diagnosis | High numbers of individuals genetically at risk, but who don’t develop T1D |
Genetic testing for high-risk genes/genetic risk scores possible at birth for use in combination with autoantibodies | If using IAb alone: - Likely need testing more than once - Will miss those diagnosed before screening and those who seroconvert after screening |
IAb detectable with fingerprick test, easy to administer, sensitive and specific | Treatment of early hyperglycaemia can be challenging |
May be intervention studies to delay development or prevent T1D | Cost/effectveness still a matter of debate |
New drug (teplizumab) available to delay the onset of T1D in high-risk individuals | No drug licensed to definitively prevent diabetes |
There has been a change towards a more screening-friendly position in recent years, in part because screening for multiple diseases is now possible with broad genetic testing such as exome sequencing. Recently, the European Society of Pediatric Endocrinology (ESPE) approved a Position Statement on Screening for T1D in the general population, hoping that other countries could also support these wishes [
37]. The Italian Society of Pediatric Endocrinology and the Italian Society of Pediatrics approved and endorsed this Position Statement, in the meetings of 24 October 2022 and 18 January 2023, respectively. Health authorities would like to see if there is a clear added value, health benefit, and low burden of diagnosing asymptomatic diseases; effective medical care should be available that at least partly prevents or delays symptomatic disease and reduces complications; screening and monitoring need to be cost effective and competitive with respect to other health needs and priorities; and there must be convincing evidence that the false-positive rate is low and identification of false-positive cases does not cause relevant harm. How does screening for beta-cell autoimmunity meet these criteria? Ongoing and future studies will provide information on the prevalence of asymptomatic beta-cell autoimmunity in the general population, program efficacy to prevent DKA and reduce family burden, and precise estimates of the rate of progression to symptomatic disease (i.e., the value predictive positive) or the return to autoantibody negativity (i.e., false positive rate) in children in the general population. Experiences from European countries and the United States, data on the added value of improved long-term care and the reduction of complications, and long-term data on the burden and social implications for families are essential. We will soon have a treatment that delays the disease (teplizumab) available in clinical practice, however the economic benefit of such a treatment is still unknown. If the authorities and insurers accept the screening and treatment of children at risk, organizational efforts and urgent investments will be required [
24] [
38]. In any case, the voice of patients and their families must be recognized and considered in the decision-making process.
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