When inflammation meets lung development-an update on the pathogenesis of bronchopulmonary dysplasia.

Even more than 50 years after its initial description, bronchopulmonary dysplasia (BPD) remains one of the most important and lifelong sequelae following premature birth. Tremendous efforts have been undertaken since then to reduce this ever-increasing disease burden but a therapeutic breakthrough preventing BPD is still not in sight. The inflammatory response provoked in the immature lung is a key driver of distorted lung development and impacts the formation of alveolar, mesenchymal, and vascular structures during a particularly vulnerable time-period. During the last 5 years, new scientific insights have led to an improved pathomechanistic understanding of BPD origins and disease drivers. Within the framework of current scientific progress, concepts involving disruption of the balance of key inflammatory and lung growth promoting pathways by various stimuli, take center stage. Still today, the number of efficient therapeutics available to prevent BPD is limited to a few, well-established pharmacological interventions including postnatal corticosteroids, early caffeine administration, and vitamin A. Recent advances in the clinical care of infants in the neonatal intensive care unit (NICU) have led to improvements in survival without a consistent reduction in the incidence of BPD. Our update provides latest insights from both preclinical models and clinical cohort studies and describes novel approaches to prevent BPD.

Oxygen Toxicity to the Immature Lung-Part II: The Unmet Clinical Need for Causal Therapy.

Oxygen toxicity continues to be one of the inevitable injuries to the immature lung. Reactive oxygen species (ROS) production is the initial step leading to lung injury and, subsequently, the development of bronchopulmonary dysplasia (BPD). Today, BPD remains the most important disease burden following preterm delivery and results in life-long restrictions in lung function and further important health sequelae. Despite the tremendous progress in the pathomechanistic understanding derived from preclinical models, the clinical needs for preventive or curative therapies remain unmet. This review summarizes the clinical progress on guiding oxygen delivery to the preterm infant and elaborates future directions of research that need to take into account both hyperoxia and hypoxia as ROS sources and BPD drivers. Many strategies have been tested within clinical trials based on the mechanistic understanding of ROS actions, but most have failed to prove efficacy. The majority of these studies were tested in an era before the latest modes of non-invasive respiratory support and surfactant application were introduced or were not appropriately powered. A comprehensive re-evaluation of enzymatic, antioxidant, and anti-inflammatory therapies to prevent ROS injury is therefore indispensable. Strategies will only succeed if they are applied in a timely and vigorous manner and with the appropriate outcome measures.

Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants-"The OPTTIMMAL-Trial"-Optimizing PEEP To The IMMAture Lungs: study protocol of a randomized controlled trial.

BACKGROUND: Nasal continuous positive airway pressure (CPAP) applies positive end-expiratory pressure (PEEP) and has been shown to reduce the need for intubation and invasive mechanical ventilation in very low birth weight infants with respiratory distress syndrome. However, CPAP failure rates of 50% are reported in large randomized controlled trials. A possible explanation for these failure rates is the application of insufficient low levels of PEEP during nasal CPAP treatment to maintain adequate functional residual capacity shortly after birth. The optimum PEEP level to treat symptoms of respiratory distress in very low birth weight infants has not been assessed in clinical studies. The aim of the study is to compare two different PEEP levels during nasal CPAP treatment in preterm infants. METHODS: In this randomized multicenter trial, 216 preterm infants born at 26 + 0-29 + 6 gestational weeks will be allocated to receive a higher (6-8 cmH2O) or a lower (3-5 cmH2O) PEEP during neonatal resuscitation and the first 120 h of life. The PEEP level within each group will be titrated throughout the intervention based on the FiO2 (fraction of inspired oxygen concentration) requirements to keep oxygenation within the target range. The primary outcome is defined as the need for intubation and mechanical ventilation for > 1 h or being not ventilated but reaching one of the two pre-defined CPAP failure criteria (FiO2 > 0.5 for > 1 h or pCO2 ≥ 70 mmHg in two consecutive blood gas analyses at least 2 h apart). DISCUSSION: Based on available data from the literature, the optimum level of PEEP that most effectively treats respiratory distress syndrome in preterm infants is unknown, since the majority of large clinical trials applied a wide range of PEEP levels (4-8 cmH2O). The rationale for our study hypothesis is that the early application of a higher PEEP level will more effectively counteract the collapsing properties of the immature and surfactant-deficient lungs and that the level of inspired oxygen may serve as a surrogate marker to guide PEEP titration. Finding the optimum noninvasive continuous distending pressure during early nasal CPAP is required to improve CPAP efficacy and as a consequence to reduce the exposure to ventilator-induced lung injury and the incidence of chronic lung disease in this vulnerable population of very preterm infants. TRIAL REGISTRATION: drks.de DRKS00019940 . Registered on March 13, 2020.

Monitoring of omalizumab therapy by measuring free IgE using a bedside immunoassay.

BACKGROUND: The monoclonal anti-IgE antibody omalizumab is used as add-on therapy for improved asthma control in patients with severe persistent allergic bronchial asthma. The aim of the study was to examine the effectiveness of omalizumab and to demonstrate the hitherto unavailable possibilities for treatment monitoring by means of a bedside immunoassay. METHODS: In the prospective longitudinal study, 9 patients aged 8 to 15 years with severe persistent allergic asthma received add-on treatment with omalizumab. Besides the parameters of general physical examination, recordings of exacerbation rate, asthma control and lung function (FEV1), and total IgE concentrations in serum were determined after 6 and 12 months; free IgE was measured using the Milenia QuickLine immunoassay. RESULTS: The mean duration of treatment was 56 ± 7.5 months. After 12 months, omalizumab showed good tolerability and effectiveness with a reduced exacerbation rate, a significant improvement of asthma control (ACT; p < 0.001) and FEV1 (p < 0.01). Already after six months of therapy, a significant reduction in total IgE from 1253 ± 407 IU/mL to 466 ± 120 IU/mL (p < 0.01) was observed. Free IgE levels were below the detection limit in all patients during treatment with omalizumab, even following dose reduction; they increased only after cessation of the treatment. CONCLUSIONS: Our data 1) confirmed good therapeutic effectiveness of omalizumab in patients with severe persistent asthma and 2) indicated that a quick and easy-to-use immunoassay to measure free IgE together with thorough clinical assessment may be a potential instrument for monitoring omalizumab treatment.

Immunoglobulin E monitoring and reduction of omalizumab therapy in children and adolescents.

Omalizumab, a monoclonal anti-immunoglobulin E (IgE) antibody, is being successfully used as supplementary therapy to improve asthma control in children with severe persistent allergic asthma from the age of ≥6 years. Because the majority of commercially available IgE assays measure free as well as omalizumab-bound IgE, a rise in total IgE is believed to occur in the course of therapy. We aimed at testing the therapeutic monitoring regime based on total IgE measurements in patients treated with omalizumab over a period of 12-60 months. We report on 10 patients aged 8-17 years who were given omalizumab to treat severe allergic bronchial asthma. Total IgE in serum (sandwich immunoassay ADVIA Centaur; Siemens Healthcare Diagnostics GmbH, Eschborn, Germany) was determined before injection of omalizumab. In two patients, the dose of omalizumab was reduced during the treatment once the patients' total IgE was in the normal range. Six months after the start of treatment with omalizumab, all patients showed a marked drop in total IgE levels compared with baseline (p < 0.003). All patients tolerated omalizumab well. The dose reduction in two patients with normal total IgE levels caused no clinical deterioration. The rise in total IgE levels after treatment with omalizumab, which has been reported in the literature, was not confirmed in the present study. Extensive elimination of IgE by omalizumab influences the immune system and IgE regulation. This will be an important aspect of dosage in long-term therapy. Patients undergoing treatment with omalizumab must be monitored at close intervals.