Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. In this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research. 1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed. 2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes.

Objectives: To identify success and failure prognostic signs of noninvasive ventilation in pediatric acute respiratory failure. Noninvasive ventilation constitutes an alternative treatment for pediatric acute respiratory failure. However, tracheal intubation should not be delayed when considered necessary. Design: Prospective, noncontrolled, clinical study. Setting: Pediatric intensive care unit in a university hospital. Patients: Children (age range, 1 month−16 yrs) with moderate-to-severe acute respiratory failure who received noninvasive ventilation during a 4-year period. Failure was defined as the need for tracheal intubation. Interventions: None. Measurements and Main Results: Nine (19.1%) of 47 patients needed tracheal intubation between the third and 87th hour after the start of treatment (33.6 ± 29.6 hrs). Failure was associated with the younger age group (4 ± 3.3 yrs vs. 7.7 ± 5 yrs, p < .04), acute respiratory distress syndrome (failure/acute respiratory distress syndrome: 5 of 10 vs. failure/non acute respiratory distress syndrome: 4 of 37, p = .013), and worsening radiographic images taken at 24 hrs and/or 48–72 hrs (p = .001 and p < .001, respectively). A significant reduction in heart rate was observed between the second and fourth hour after starting noninvasive ventilation (130 ± 25.8 bpm vs. 116 ± 27.7 bpm, p < .001) and Pco₂ (54.1 ± 19.5 torr vs. 48.6 ± 14.3 torr; 7.21 ± 2.6 vs. 6.48 ± 1.91 kPa, p < .007) in the success group. The failure group had a higher rate of breathing assistance, both initial and maximal. In the multivariant analysis, only maximum mean airway pressure and Fio₂ formed part of the success/failure discriminant function with a cutoff point of 11.5 and 0.57, respectively. Conclusions: Modifications in a patient's respiratory assistance were made depending on the clinical, blood gas, and radiologic evolution of the patient. Mean airway pressure and Fio₂ values of >11.5 and 0.6, respectively, predict failure and possibly set the limit above the patient's risk of delayed intubation increases.

Background Recent investigations in animal models have revealed oxidative stress and oxidative damage in the pathogenesis of alpha-1 antitrypsin deficiency (AATD). However, no data are available on the oxidative stress status and antioxidant enzyme activity in these patients. This study was aimed to analyse the oxidative stress profile and enzymatic antioxidant defence mechanisms in children with AATD. Methods Oxidative stress parameters and the activity of the main antioxidant enzymes were prospectively measured in serum of fifty-one children diagnosed with AATD and thirty-eight control individuals. Results Oxidative stress was increased in the serum of children with intermediate- (MZ; SZ) and high-risk (ZZ) phenotypes for developing AATD-related emphysema and/or liver disease. When compared with the control group, intermediate- and high-risk groups showed significantly lower total glutathione and reduced glutathione levels, decreased catalase activity and increased glutathione peroxidase activity leading to an accumulation of hydrogen peroxide that would explain the significantly increased levels of oxidative stress biomarkers observed in these patients. No differences were observed between the control (MM) and the low-risk (MS; SS) groups. A gradation in oxidative stress parameters was observed when patients were compared among themselves, in that the expression of the Z allele produces a higher oxidative stress status in homozygous (ZZ) than in heterozygous (MZ; SZ) patients. Conclusions Increased oxidative stress, together with reduced antioxidant defence are involved in the pathophysiology of AATD at early stages, opening up a new rationale for the use of antioxidant therapies in the treatment of the disease.