Graves Disease (GD) is the most common cause of thyrotoxicosis in pediatric age, although it is considered a rare disease with an incidence of 0.3-14/100.000. The management of GD in pediatric age is still controversial and many questions remain on the duration of the medical approach with ATD and on when definitive treatment should be considered. Most Authors report lower remission rates than adults (15-40% vs 40-85%) with patients relapsing mainly in the first 6-12 months after ATD discontinuation. Younger age, large goiter size, higher fT4 and fT3 levels, higher TRAb titration, and duration of ATD treatment itself, are believed to be important predictive factors [9–13]. The availability of predictive factors in GD is important as tools that can drive the pediatric endocrinologist in choosing between short-term medical treatment and subsequent definitive approach, long-term medical treatment or the direct definitive approach. Choosing the right treatment at the right time is of primary importance in pediatric GD, considering the low rate of remission reported and the poor quality of life of children and adolescents during the thyrotoxic state.
To date, few data are available on the correlation of lymphocyte parameters and the outcome of GD in pediatric age. Chen et al observed a higher CD4+/CD8+ ratio, lower percentages of CD3+CD8+ T cells and higher percentages of CD3- CD19+ cells in children and adolscents with Grave’s ophthalmoopathy (GO), although non independent after excluding effect of the TRAb titre . In another study no correlation was observed between peripheral blood naive T lymphocyte and levels of TRAb or fT4 levels, but the increase in transient and pre-naive mature B lymphocytes was related to plasma levels of fT4 . The correlation between TRAb levels and B lymphocytes was confirmed, whereas no correlation has been found between TRAb levels and the percentage of lymphocyte subpopulations in thyroid tissue [15–16]
In our study the CD4+/CD8+ ratio was the only lymphocyte parameter significantly related to the disease severity as subjects whom underwent to thyroidectomy after two years of follow-up showed higher ratio with respect of subjects with disease remission and long-term medical treatment approach. A positive correlation was observed between CD4+/CD8+ ratio and fT3 levels and diagnosis and TRAb titre at diagnosis and after 6, 12 and 24 months. The same trend was also observed for thyroid volume and the daily dose of ATD. Subjects with a higher CD4+/CD8+ ratio also had a higher risk of having a thyroid volume greater than 2 SDS and a higher ATD dose. Patients with higher ratio seem to be at higher risk of definitive treatment after two years of follow-up or to follow the long-term treatment approach, even if this hypothesis need to be confirmed in larger multicentric studies with greater cohorts, given the rarity of GD. We believe that this lymphocyte subset parameter should be considered as predictive for outcome, along with other factors actually considered, such as age, sex, fT3 and TRAb levels at diagnosis and thyroid volume. To our knowledge, this is the first study in pediatric age reporting the relation of CD4+/CD8+ ratio to disease severity. Lymphocyte subgroups should be evaluated at the time of GD diagnosis as methimazole and other ATD drugs interfere with the immune system.
The limitations of the present study lie mainly in the size of the cohort which limits the statistical strength of our data, although the rarity of GD in pediatric age must be considered.
Among the parameters of the lymphocyte population, the elevated CD4+/CD8+ ratio appears to be positively correlated with higher fT3 levels and goiter size at diagnosis, higher TRAb titre in the first two years, and higher ATD dose in the first year after the diagnosis. Thus, this ratio could be considered as a promising predictive tool, together with the other prognostic factors to better manage pediatric GD, even if these preliminary data need to be confirmed over a longer follow-up period and in larger cohorts.