Incidence of Type 1 diabetes and factors associated with presence and severity of ketoacidosis at onset in children.

BACKGROUND AND AIM: To assess the incidence of Type 1 Diabetes Mellitus (T1DM) during the period 2012-2017, the frequency and severity of ketoacidosis (DKA) at diabetes onset, and the factors associated with DKA in children and adolescents younger than 18 years old in the Abruzzo region, Italy.
METHODS: All incident cases of T1DM (0-17 years old) diagnosed between January 2012 and December 2017 were included. Data about the patients were obtained from two independent sources; insulin prescriptions and medical records. Clinical data at diabetes onset, as well as demographic and non-demographic data, including center of first hospitalization, distance to regional reference center and number of pediatricians (per 1000 residents younger than 18 years) were collected and evaluated.
RESULTS: During 2012-2017 period, 177 patients were diagnosed with T1DM. In 2012, T1DM incidence was 15.6 per 100,000/year; in 2013, 16.4 per 100,000/year; in 2014, 11.6 per 100,000/year; in 2015, 14.2 per 100,000/year; in 2016, 16.2 per 100,000/year and in 2017, 12.2 per 100,000/year. DKA was present in 29.3% of patients, 6.9% with severe DKA. The DKA presence was correlated to age (p<0.02), ethnicity (p<0.04), being transferred to a specialist center instead of being directly admitted to one (p<0.002) and the number of pediatricians in the population (p<0.01). The DKA severity was associated with the delay of transfer (p<0.04).
CONCLUSIONS: Being admitted directly to a specialist center is very important and it could be expression of high alertness of pediatricians. Availability of well-trained pediatricians is necessary for the prevention of DKA. (www.actabiomedica.it).

Introduction

Type 1 Diabetes Mellitus (T1DM) is one of the major chronic diseases of childhood. Approximately, there are 80,000 new cases (under 15 years of age) worldwide every year (1). The incidence of T1DM varies greatly between different countries, but also within them. The highest incidence rates are observed in Finland, Northern Europe, and Canada (2). The overall pattern is one of an approximately 3% per annum increase, though in some high-incidence countries such as Finland (3) and Norway (4) the incidence rate of T1DM seems to show a temporary deceleration (5).

It is well established that unrecognized and untreated T1DM leads to ketoacidosis (DKA), with an increased risk of cerebral edema, cognitive deficits, or even death. Overall mortality in children with DKA varies from 0.15% to 0.35% in developed countries (6). Even subtle cerebral injury may occur, with deficits in attention, spatial memory, executive function and other cognitive function (7-9). Furthermore, the costs of DKA-related hospital admission are high.

The frequency of DKA at T1DM onset varies from 12.8% to 80% worldwide (10). The lowest rates are found in Canada and the Scandinavian countries, the highest in Saudi Arabia (11). The frequency of DKA is lower in countries where the background incidence of T1DM is higher (10, 12-13). There is evidence regarding the association of DKA with the increased awareness of the disease and having a first-degree relative with T1DM (14-15). Younger age, lower socioeconomic status, lower parental education (16) and living in smaller cities (17) confer an increased risk of DKA at onset of disease. Higher rates of DKA are more common in countries with lower development index (11).

Having a regular healthcare provider is associated with a reduced risk of DKA at diabetes onset (17). Other factors related with a decreased risk of DKA are the development of specialist pediatric diabetes services and the widespread availability of glucose meters (12). However, the beneficial effect of additional factors, including direct admission to a specialist center (18-19), prevention campaigns and raising public awareness (20-23) has not been always confirmed (20, 24).

Italy is one of the countries with the greatest variability in T1DM incidence. The highest rate is observed in Sardinia (25). In the 1990-2003 period, the incidence rate in peninsular Italy (0-14 years) was 12.26/100,000 with an increasing temporal trend of 2.94% per year. In the Veneto region, an incidence rate of 16.5 per 100,000 person-years was reported (26). DKA frequency at onset of T1DM in Italy is increasing (38.5% to 47.6%) (24).

Abruzzo is a region of central-eastern Italy; it is divided in 4 provinces (L’Aquila; Chieti; Pescara; Teramo). During 1990-1995 period, the overall age-adjusted incidence rate (0-14 years) in the Abruzzo region was 9.34 (95% CI 7.76-10.95) (27).

In Abruzzo region, the model of territorial and hospital healthcare delivery consists of 4 autonomous areas. During the study period, T1DM management in the region was mostly managed by a regional reference center for T1DM in childhood and a small peripheral healthcare unit, necessary for the orographic characteristics of the region.

The aim of this study was to assess the incidence of T1DM during the period 2012-2017 as well as the frequency and severity of DKA at diabetes onset in children and adolescents younger than 18 years in the Italian region of Abruzzo. We wanted to investigate the possible factors associated with DKA. We also evaluated the factors affecting DKA severity. By identifying modifiable risk factors, it would be possible to reduce the rate and severity of DKA through targeted interventions.

Methods

Study population

Children and adolescents aged <18 years old at diagnosis of T1DM were included in the study. All incident cases between January 2012 and December 2017 were considered. T1DM diagnosis was established based on clinical and biological parameters. Clinical diagnoses of T1DM were validated through the presence of at least one diabetes autoantibody (Islet Cell cytoplasmic Autoantibodies - ICA, Insulinoma-Associated-2 Autoantibodies - IA2, Antibodies to Glutamic Acid Decarboxylase - Anti GAD); the clinical judgment of a specialist in pediatric diabetology was also used (2). All children with Maturity Onset Diabetes of the Young, Type 2 Diabetes Mellitus, Cystic Fibrosis-related Diabetes, Neonatal Diabetes or other forms were excluded.

DKA presence at onset and its severity were defined according to the International Society for Pediatric and Adolescent Diabetes Guidelines (28) (mild: pH <7.3, bicarbonate <15 mmol/l; moderate: pH <7.2, bicarbonate <10mmol/l; severe: pH<7.1, bicarbonate <5 mmol/l). Ketone levels were not consistently reported.

Data about the patients were obtained from two independent sources. The primary source was territorial pharmaceutical insulin prescriptions (2012-2017). As a secondary source, medical records of patients were consulted. Completeness of registration was assessed by capture–recapture method (29). Population data from the Italian National Institute for Statistics (http://dati.istat.it/) were used for the calculation of the incidence.

Data collected from patients’ files included: gender, date of diagnosis, age at onset, place of residence, laboratory data [blood glucose concentration, pH, bicarbonate, c-peptide, hemoglobin A1c (HbA1c), autoimmunity for diabetes (ICA, IA2, Anti GAD)], presence of first-degree relative with T1DM, personal medical history (including duration of symptoms and/or recent infections), ethnicity, first hospitalization in specialist center or transfer to it. The study population was divided into four age groups: 0-4 years, 5-9 years, 10-14 years and 15-17 years old group.

The distance from patient’s residence to regional reference specialist center was measured by online distance calculator (https://maps.google.it/). The number of inhabitants (<10000, 10-50000, 50-250000 inhabitants) and degree of urbanization (densely populated, intermediate density, rural) of each municipality of residence was determined according to Eurostat classification (https://www.istat.it/it/archivio/156224).

Moreover, the number of pediatricians (per 1000 residents younger than 18 years) was calculated for each province using data from the Italian National Institute for Statistics.

Data analysis

Statistical analyses were performed using SPSS 16.0 for windows software (SPSS Inc, Chicago, IL, USA). Variables were assessed for normal distribution. Descriptive statistics were described as means ± standard deviations for continuous variables and as frequencies for categorical variables. The incidence of Type 1 diabetes was evaluated as punctual and 95% confidence interval (95% CI). Student’s t test and the χ2 test or fisher exact test were used to evaluate the differences between patients with and without DKA at T1DM diagnosis. Stepwise logistic regression was applied to determine independent risk factors for DKA occurrence at onset. Comparison between continuous variables to assess the factors contributing to DKA severity was performed using one-way analysis of variance (ANOVA). A p value< 0.05 was considered statistically significant.

Ethical approval

This study was carried out in accordance with the Declaration of Helsinki and approved by the local Ethics Committee, University of Chieti-Pescara, Italy.

Results

Incidence of T1DM

The total number of children aged 0-17 years-old diagnosed with T1DM in the Abruzzo region during 2012-2017 was 177 (male: 56.3%; mean age at diagnosis: 9.77 ± 4.38 years); three patients were excluded from the analysis for incomplete data.

Thirty-two new cases of T1DM were identified in 2012 (incidence: 15.58 per 100,000/year; 95% CI 11.02-22.04), thirty-four new cases were identified in 2013 (incidence: 16.39 per 100,000/year; 95% CI 11.72-22.95) and twenty-four new cases were identified in 2014 (incidence: 11.64 per 100,000/year; 95% CI 7.81-17.38). Twenty-nine, thirty-three and twenty-five new cases were identified in 2015 (incidence: 14.20 per 100,000/year; 95% CI 9.80-20.40), 2016 (incidence: 16.16 per 100,000/year; 95% CI 11.49-22.73) and 2017 (incidence: 12.24 per 100,000/year; 95% CI 8.27-18.12), respectively.

The majority of patients (88.5%) were of Italian origin. The distribution of the residence at disease onset among the provinces was as follows: 19.5% in L’Aquila province, 32.2% in Chieti province, 27.6% in Pescara province, 20.7% in Teramo province. The highest number of patients was distributed along the coast of the region.

According to age, the T1DM incident cases were distributed as follows: 13.2% in 0-4 years old group, 27.6% in 5-9 years old group, 40.2% in 10-14 years old group, 19% in 15-17 years old group.

Of the total patients, 23% were diagnosed in spring, 21.3% in summer, 29.3% in autumn, and 26.4% in winter, so more patients were diagnosed during the autumn, but the difference was not significant (p=0.442).

Diabetes onset-Presence and severity of DKA and associated factors

The mean blood glucose concentration at the onset was 431 ± 157.32 mg/dl. The mean HbA1c level was 11.80 ± 2.33% (105 ± 25.6 mmol/mol), the mean c-peptide level was 0.47 ±0.44 ng/ml. Patients with first-degree relative with T1DM accounted for 8.6% of cases. The presence of infection before diagnosis was reported in 20.07% of cases. The mean duration between the first symptoms and the diagnosis was 16.20 ± 18.74 days. In 67.2% of cases, patients were admitted first in a specialist center for the management of Type 1 diabetes. Of those who were transferred (57 patients), 70.71% were transferred on the same day.

DKA was present in 51 patients (29.3%) (male: 63%; mean age: 8.86 ± 4.73 years). The frequency of mild and moderate DKA was 11.5% and 10.9%, respectively. The frequency of severe DKA was 6.9% (male: 50%; mean age: 9.28 ± 4.24 years). Cerebral edema following DKA treatment was not observed. One patient experienced a hyperglycemic hyperosmolar state at onset of T1DM (for the purposes of the study, this patient was considered without DKA). The characteristics of patients according to the presentation at onset are shown in Table 1.

Table 1.

Characteristics of patients according to the presentation at the onset of diabetes.

Characteristic	With DKA	Without DKA	p Value
Year of diagnosis (n, %) 2012 2013 2014 2015 2016 2017	7 (21.88%)11 (32.35%)6 (25%)8 (27.59%)11 (33.33%)8 (36.36%)	25 (78.12%)23 (67.65%)18 (75%)21 (72.41%)22 (66.67%)14 (63.64%)	0.842
Season of diagnosis (n, %) Spring Summer Autumn Winter	9 (22.5%)11 (29.75%)18 (25.25%)13 (28.26%)	25 (78.12%)23 (67.65%)33 (64.75%)33 (71.74%)	0.614
Age at onset (years) (mean ± SD)	8.86 ± 4.73	10.15 ± 4.18	0.077
Age group (n, %) 0-4 years old 5-9 years old 10-14 years old 15-17 years old	13 (56.52%)9 (18.75%)21 (30%)8 (24.24%)	10 (43.48%)39 (81.25%)49 (70%)25 (75.76%)	0.01
Glucose concentration (mg/dL) (mean ± SD)	491.18 ± 152.97	406.82 ± 152.98	0.001
HbA 1 c % (mmol/mol) (mean ± SD)	12.55 ± 1.93(114 ± 21.2)	11.48 ± 2.40(102 ± 26.5)	0.005
c-peptide (ng/ml) (mean ± SD)	0.29 ± 0.25	0.54 ± 0.48	0.001
First-degree relative with T1DM (n, %) No Yes	49 (30.82%)2 (13.34%)	110 (69.18%)13 (86.66%)	0.115
Presence of infection (before diagnosis) (n, %) No Yes	36 (26.09%)15 (41.67%)	102 (73.91%)21 (58.33)	0.067
Caucasian Italians (n. %) No Yes	10 (50%)41 (26.62%)	10 (50%)113 (73.38%)	0.031
First hospitalization in specialist center at the onset (n, %) No Yes	27 (47.37%)24 (20.51%)	30 (52.63%)93 (79.49%)	0.000
Specific symptoms duration (days) (mean ± SD)	15.73 ± 16.60	16.39 ± 19.62	0.832
Province of residence (n, %) Aquila Chieti Pescara Teramo	15 (44.12%)12 (21.43%)11 (22.92%)13 (36.12%)	19 (55.88%)44 (78.57%)37 (77.08%)23 (63.88%)	0.071
Distance from the patient’s residence to the regional reference center (Km) (mean ± SD)	63.53 ± 33.99	49.19 ± 32.88	0.010
Number of inhabitants (n, %) <10000 10-50000 50-250000	23 (35.94%)19 (32.02%)9 (17.65%)	41 (46.06%)40 (67.98%)42 (82.35%)	0.084
Degree of urbanization (n, %) Densely populated Intermediate density Rural	1 (5.88%)28 (31.46%)22 (32.35%)	16 (94.12%)61 (68.54%)46 (67.56%)	0.082
Pediatricians/1000 residents/province (mean ± SD)	0.85 ± 0.68	0.88 ± 0.66	0.009

The characteristics according to the DKA severity are shown in Table 2.

Table 2.

Characteristics of patients presenting DKA at the onset according to severity.

Characteristic	Mild DKA	Moderate DKA	Severe DKA	p Value
Year of diagnosis (n) 2012 2013 2014 2015 2016 2017	153443	341263	322212	0.808
Season of diagnosis (n) Spring Summer Autumn Winter	5375	3484	1434	0.749
Age at onset (years) (mean ± SD)	9.21 ± 5.06	8.22 ± 4.84	9.28 ± 4.24	0.766
Age group (n) 0-4 years old 5-9 years old 10-14 years old 15-17 years old	3449	5284	1254	0.484
Glucose concentration (mg/dL) (mean ± SD)	498.40 ± 173.22	493 ± 140.34	475 ± 148.05	0.917
HbA 1 c % (mmol/mol) (mean ± SD)	12.59 ± 1.88(114 ± 20.7)	12.51 ± 1.81(114 ± 20.5)	12.57 ± 2.27(114 ± 25)	0.992
c-peptide (ng/ml) (mean ± SD)	0.32 ± 0.25	0.28 ± 0.26	0.24 ± 0.22	0.637
First-degree relative with T1DM (n) No Yes	191	190	111	0.483
Presence of infection (before diagnosis) (n) No Yes	155	145	75	0.565
Caucasian Italians (n) No Yes	119	619	39	0.09
First hospitalization in specialist center at the onset (n) No Yes	812	109	93	0.158
Delay of transfer (days) (mean ± SD)	0.45 ± 0.60	0.68 ± 0.74	1.33 ± 1.43	0.035
Specific symptoms duration (days) (mean ± SD)	15.5 ± 13.74	14.16 ± 10.17	18.85 ± 27.29	0.775
Province of residence (n) Aquila Chieti Pescara Teramo	7553	7534	1236	0.32
Distance from the patient’s residence to the regional reference center (Km) (mean ± SD)	61.42 ± 40.33	66.95 ± 28.48	61.65 ± 32.89	0.863
Number of inhabitants (n) <10000 10-50000 50-250000	974	793	732	0.756
Degree of urbanization (n) Densely populated Intermediate density Rural	0128	0127	147	0.243
Pediatricians/1000 residents/province (mean ± SD)	0.85 ± 0.71	0.84 ± 0.69	0.85 ± 0.067	0.864

There were no major changes in the frequency and the severity of DKA over the years (p=0.842; p=0.808) and there was no seasonality (p=0.614; p=0.749). Patients presenting with DKA were younger than patients without DKA at diagnosis (8.86 ± 4.73 years vs 10.15 ± 4.18 years) (p=0.077). DKA presence was different within various age groups (56% of children in the 0-4 years old group, 19% in the 5-9 years old group, 30% in the 10-14 years old group, and 24% in the 15-17 years old group; p<0.020). The severity of DKA was not correlated to age (p=0.484).

The mean blood glucose concentration at the onset of disease was lower in children without DKA (406.82 ± 152.98 vs 491.18 ± 152.97 mg/dl) (p<0.002). Mean HbA1c level for patients presenting in DKA was 12.55 ± 1.93% (114 ± 21.2 mmol/mol) and higher than that for patients not affected by DKA (11.48 ± 2.40%, 102 ± 26.5 mmol/mol) (p<0.010). Mean c-peptide was lower in patients with DKA at the onset of disease (p<0.002).

Having a first-degree relative with T1DM and the presence of infection were not significantly associated with DKA (p=0.115 and p=0.067, respectively). On the contrary, ethnicity other than Caucasian Italians was associated with DKA at the onset of the disease (p=0.031), but not with its severity (p=0.090). DKA was less frequent in patients admitted to specialist center directly than those transferred later (p<0.002). Delay of transfer was associated with the severity of DKA (p<0.040).

The duration of diabetes-specific symptoms (polyuria, polydipsia, weight loss) prior to the admission to the health care unit was not correlated with the DKA presence (p=0.832).

No associations were found between the province of residence at disease onset and the presence of DKA (p=0.071) or its severity (p=0.320). However, six patients of twelve with severe DKA at onset of T1DM resided in Teramo province. Moreover, the mean distance from the patient’s residence to the regional reference center was greater for patients who developed DKA (p<0.02). The distribution of residences of patients with DKA is shown in Figure 1.

Figure 1.

Distribution of the residences of the patients presenting with ketoacidosis (DKA) at the onset of diabetes according to DKA severity. The map also shows the regional reference center for pediatric Type 1 diabetes in Abruzzo, Italy.

The number of inhabitants and the degree of urbanization of each municipality of residence were not associated with DKA at onset of diabetes (p=0.084 and p=0.082, respectively).

The mean of number of pediatricians (calculated per 1000 residents younger than 18 years in each province) was lower in the group of patients affected by DKA (p<0.01).

Discussion

Published data show that the incidence rate of T1DM increases across Europe by an average of approximately 3% per annum with periods of less and more rapid rise and, in some centers, showing a cyclical pattern (5, 26, 30). It has been pointed out that T1DM incidence is very heterogeneous even in neighboring countries within a well-defined geographical region (31). Italy is one of the countries with the greatest variability (25, 26). For this reason, knowing local T1DM and DKA epidemiological data is of paramount importance for resource allocation and healthcare services provision. With this study, we can classify Abruzzo as a region with intermediate-high risk for T1DM. This is in contrast with previous studies reporting that the lowest T1DM rates in Italy were observed in the southern regions, including Abruzzo (27, 32), but in accordance with the high incidence rate of T1DM in Apulia (annual incidence of 25.2 per 100,000), another region in South Italy (33).

T1DM incidence is lower in the 0-4 years old group, increases with age, and meets the peak in children aged from 9 to 14 years, almost comparable to what was found in other countries (33-34). In the large SWEET database, seasonality at T1DM clinical onset is documented with higher percentage of incident cases in autumn and winter and lower in spring and summer (35). We have not detected a significant seasonality, with the highest percentage of incident cases seen in autumn (29.3%) and the lowest in summer (21.3%).

In our study, the frequency of DKA at onset of T1DM is 29.3%, which is high (in Denmark 14.7%, in Sweden 18%, in Canada 18.6%) (10-11). Even so, it is lower than what is reported in other studies from Italy (38.5 - 47.6 - 56%) (24, 36-37). The frequency of severe DKA is also lower (6.9% versus 10.3% (36) and 15%) (24, 37). The frequency of DKA in Abruzzo region remains stable over the study period. Similarly, stable prevalence in DKA has also been noted in other countries (20, 38).

Although the association between mean age at onset and DKA is not significant, when divided in age groups, younger patients (0-4 years) are more likely to present with DKA (of any severity) in our region. Younger children may have more aggressive β-cell destruction (39) and less well-developed compensatory mechanisms, which could result in faster development of acidosis and dehydration (17, 40-41). Difficulties in diagnosing T1DM, as well as a wrong preliminary diagnosis (42), are a significant cause of DKA development; mostly in younger children (43).

Pediatricians have a key role in the diagnostic and therapeutic assistance of children with diabetes. They should be able to promptly identify alterations of clinical parameters (respiratory rate, state of dehydration, water balance) and T1DM symptoms, which are often nonspecific and/or masked by the presence of concomitant diseases (44, 45). Pediatricians should have a high medical index of suspicion (15) and a low threshold to check blood or urine sugar and ketone (18). They are responsible for early diagnosis and direct admission to the specialist center.

Similarly, to previous findings (15), in our study, children diagnosed with DKA have higher HbA1c and lower c-peptide, which may indicate longer duration of the preclinical disease state. Surprisingly, having a first-degree relative with T1DM and the presence of infection are not associated with DKA. Ethnicity is associated with DKA perhaps because of lack of awareness, language and cultural barriers, and practical difficulties in accessing healthcare (14). The need for appropriate provision of healthcare services for the increasing population of immigrants is key.

The mean distance from the patient’s residence to the regional reference specialist center is associated with the presence of DKA at disease onset. Our analysis shows also that DKA at diabetes onset is less frequent in patients admitted to a specialist center directly than those transferred later. Moreover, delay of transfer is associated with the severity of DKA. Malachowska et al. have shown in their region that being admitted directly to the specialist center is a protective factor against DKA regardless of the patient’s place of residence and its distance from the specialist center (19). A multicenter analysis conducted in Germany and Austria shows that patients with DKA at onset of diabetes are admitted to the nearest hospital, independent of center size (46). Hospitalization in a non-specialist department, such as an emergency room, and the delay of transfer could be justified by the more serious clinical conditions due to the diagnostic delay, probably because of a lower degree of alertness of pediatricians further away from the regional reference center. During the study period, 75% of severe DKA arrived in the most accessible emergency room, to then be transferred to the specialist center. Correct diagnostic and therapeutic management, in collaboration with specialist centers, and rapid transfer to the specialist center play a crucial role in the therapy of DKA and in the prevention of complication.

In our study, the duration of specific symptoms (polyuria, polydipsia, weight loss) before the admission to the health care unit is not correlated with the DKA presence. However, relevant data were collected retrospectively, based on patients’ reports. Province of residence, number of inhabitants, and degree of urbanization of each municipality are not associated with DKA in our analysis. The number of pediatricians (calculated per 1000 residents younger than 18 years old) is lower in Teramo and L’Aquila provinces, which are also among the areas furthest from the regional reference center. The mean number of pediatricians (per 1000 residents younger than 18 years in each province) is lower in the group of children with DKA.

In conclusion, smaller density of pediatricians and their lower accessibility to the regional reference center, as well as deferred referral of patients to a specialist center, likely expression of lower alertness levels of attending pediatricians, could account for the high incidence of DKA at T1DM diagnosis. Ethnicity could also contribute. Epidemiological registry provides information that is useful not only for clinical assessments, but also for determining health care policy. Specific resources could be earmarked for immigrant children. Multidisciplinary specialist center should be able to provide all aspects of diabetes care according to chronic care model (47), even continuing education of pediatricians and educational sessions for medical doctors (21-22). In our region, the regional reference center periodically delivers continuing medical education courses about DKA and diabetes to pediatricians. We believe it is of great importance to equip the whole region with sufficient number of well-trained pediatricians, capable of early diagnosis of diabetes and promptly admitting all children to a specialist center.