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Early Childhood Infections May Be Related to Development of Type 1 Diabetes

High frequency of infections associated with islet cell autoimmunity and disease progression.

Both genetic and environmental factors have been associated with increasing type 1 risk. Environmental factors include: maternal overweight, vitamin D deficiency, vaccinations as well as early childhood infections and standard of hygiene, which have had conflicting evidence. Several years elapse between initial activation of the autoimmune response to beta cells, as evidenced by the appearance of islet cell autoantibodies and the onset of clinical diabetes, establishing a prediabetes stage.

Early childhood infections and exposures to microbes have been hypothesized to either promote or protect from the development of islet autoimmunity and type 1 diabetes. Furthermore, some studies have suggested that microbial exposures encountered in early childhood could help with the maturation of the immune system and suppress overactive immune responses later in life, thus contributing as a protective factor against allergic and autoimmune diseases. On the other hand, some other studies have cited viral infections (enteroviruses, rotaviruses or rubella) as triggers of beta-cell autoimmunity. Studies testing the hygiene hypothesis have reached slightly controversial conclusions, some showing that childhood infections are associated with a reduced risk of T1D. Such a small study in 1997 found that children who developed T1D spent their infancy in conditions associated with a decreased risk of common infections.(1) Another study found that exposure to infections early in life could decrease diabetes risk, particularly for children diagnosed after the age of 4 years.(2) Some other studies have reported no associations between early infections and subsequent disease risk.

An observation study conducted in three countries — Finland, Estonia, and Russia — included children born between 2008 and 2011, and had HLA DR-DQ gene alleles, which have been linked with an increased risk for type 1 diabetes. Children attended the study centers at the ages of 3, 6, 12, 18, 24, and 36 months for clinical examination and blood sampling. Full workup on nutrition, allergy signs, infections, medications, vaccinations, hospitalizations, and family’s lifestyle was recorded by the families continuously. A total of 790 eligible children were included in the study. The media age at dropout was 11.9 months among 233 children who quit the study.

During the follow-up, 6,090 infections were reported, from which 48.1% were diagnosed by clinicians. The majority were respiratory infections (76.5%) followed by GI infections (8.7%), unlocalized febrile episodes (7.9%) and other infections (6.9%). Diabetes-associated antibodies were observed in 46 children, out of which 7 developed T1D. Children with islet autoimmunity had their first infection at a younger age as compared to those who did not (3.6 vs 5 months average, p=0.005); also, children who progressed to T1D had their first infection at younger age (2.2 vs 4.1 months, p=0.016) Furthermore, children with islet autoimmunity had significantly more respiratory infections during the first 18 months of age. (p=0.001). By 3 years of age, children progressing to T1D had experienced twice as many infections as the children without diabetes. (17.5 vs 9.0, p=0.006).

This study showed that respiratory infections at an early age are associated with islet cell autoimmunity and progression to type 1 diabetes in those children with HLA-conferred disease markers. The results are consistent with previous studies, which suggested childhood respiratory infections as a risk factor for development of islet autoimmunity. Also, these findings suggest that children who have a higher risk of diabetes may be more susceptible to infections. This study was found to be opposite to the standard of hygiene hypothesis, which implies that early exposure to microbes during childhood can prevent major autoimmune disorders, including T1D. This study, however, had some limitations: only 7 children progressed to T1D, which is a relatively small pool sample and more than half of the infectious episodes were reported by parents.(3) Future studies on this topic should only include the infectious that were diagnosed by licensed physicians to provide more accurate links of association with diabetes.

 

Practice Pearls:

  • Respiratory infections at an early age are associated with islet cell autoimmunity and progression to type 1 diabetes.
  • Children with islet cell immunity may have more frequent infections during the first 18 months of life.
  • Children who are at a higher risk for diabetes may be more vulnerable to infections during the first year of life.

References:

Gibbon C, Smith T, Egger P, Betts P, Phillips D. Early infection and subsequent insulin dependent diabetes. Arch Dis Child. 1997; 77:384-385

Pundziute-Lycka A, Urbonaite B, Dahlquist G. Infections and risk of type I (insulin-dependent) diabetes mellitus in Lithuanian children. Diabetologia. 2000; 43:1229-1234.

N Mustonen, H Silijander, A Peet, V Tillmann. Early childhood infections precede development of beta-cell autoimmunity and type 1 diabetes in children with HLA-conferred disease risk. Pediatric Diabetes. 2017; 0:1-7.

 

Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy