Burden of severe bronchiolitis in children up to 2 years of age in Spain from 2012 to 2017.

Bronchiolitis represents a heavy burden of disease in children under 2 years of age in our society due to the high infectivity of the Respiratory Syncytial Virus [RSV] and the vulnerability of the youngest children.The objective of this retrospective epidemiological study was to show the burden of severe bronchiolitis in Spain through population-based estimates of hospitalizations due to bronchiolitis in children up to 24 months old during a 6-year period (2012-2017).A total of 100,115 cases of bronchiolitis required hospitalization in Spain from 2012 to 2017. Most cases of bronchiolitis that required hospitalization were in infants under 3 months of age. The hospitalization rate for bronchiolitis for children under 1 year of age was 3,838.27 per 100,000 healthy children. During the 6-year study period, a total of 82 deaths due to bronchiolitis were reported among hospitalized infants. Among these deaths, more than 50% were in patients younger than 3 months of age. The annual average cost to the National Health Care System was €58 M, with a mean hospitalization cost of €3,512 per case.

Identification of Resistance to Exogenous Thyroxine in Humans.

Background: Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity. Dio2(-/-) mice show central resistance to exogenous T4. Patients with resistance to exogenous thyroxine (RETH) have not been described. The aim of this study was to identify hypothyroid patients with thyrotropin (TSH) unresponsiveness to levothyroxine (LT4) and to characterize the clinical, hormonal, and genetic features of human RETH. Methods: We investigated hypothyroid patients with elevated TSH under LT4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3, and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4, and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-ß (THRB) mutations. DIO2, including the Ala92-D2 polymorphism, selenocysteine binding protein 2 (SECISBP2), and THRB were fully sequenced. Results: Eighteen hypothyroid patients (nine of each sex, 3-59 years) treated with LT4 showed elevated TSH (15.5 ± 4.7 mU/L; reference range [RR]: 0.4-4.5), fT4 (20.8 ± 2.4 pM; RR: 9-20.6), and TSH/fT4 ratio (0.74 ± 0.25; RR: 0.03-0.13). Despite increasing LT4 doses from 1.7 ± 1.0 to 2.4 ± 1.7 µg/kg/day, TSH remained elevated (6.9 ± 2.7 mU/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9 ± 3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2 ± 2.4, RR: 11.3-15.3 and 2.5 ± 1.4, RR: 7.5-8.5, respectively) whereas rT3/T4 was increased (0.6 ± 0.2; RR: 0.43-0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but the allele dose did not correlate with RETH. Conclusions: Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germline DIO2 mutations suggests that aberrant post-translational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.