Innate Immune Gene Polymorphisms and COVID-19 Prognosis.

COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211, and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host's genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708, and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.

Outpatient management of established bronchopulmonary dysplasia: An update.

As the incidence of infants with bronchopulmonary dyspasia (BPD) has continued to rise, so has their rate of survival. Their medical management is often complex and requires the use of numerous therapies such as steroids, bronchodilators, diuretics and modalities to deliver supplemental oxygen and positive pressure. It also requires multi-disciplinary care to ensure adequate growth and to optimize neurodevelopmental outcomes. This review aims to discuss the most widely used therapies in the treatment of patients with established BPD. The focus will be on ongoing outpatient (post-neonatal intensive care) management of children with BPD. Since many of the mentioned therapies lack solid evidence to support their use, more high quality research, such as randomized controlled trials, is needed to assess their effectiveness using defined outcomes.

Respiratory Outcomes for Ventilator-Dependent Children With Bronchopulmonary Dysplasia.

OBJECTIVES: To describe outpatient respiratory outcomes and center-level variability among children with severe bronchopulmonary dysplasia (BPD) who require tracheostomy and long-term mechanical ventilation. METHODS: Retrospective cohort of subjects with severe BPD, born between 2016 and 2021, who received tracheostomy and were discharged on home ventilator support from 12 tertiary care centers participating in the BPD Collaborative Outpatient Registry. Timing of key respiratory events including time to tracheostomy placement, initial hospital discharge, first outpatient clinic visit, liberation from the ventilator, and decannulation were assessed using Kaplan-Meier analysis. Differences between centers for the timing of events were assessed via log-rank tests. RESULTS: There were 155 patients who met inclusion criteria. Median age at the time of the study was 32 months. The median age of tracheostomy placement was 5 months (48 weeks' postmenstrual age). The median ages of hospital discharge and first respiratory clinic visit were 10 months and 11 months of age, respectively. During the study period, 64% of the subjects were liberated from the ventilator at a median age of 27 months and 32% were decannulated at a median age of 49 months. The median ages for all key events differed significantly by center (P ≤ .001 for all events). CONCLUSIONS: There is wide variability in the outpatient respiratory outcomes of ventilator-dependent infants and children with severe BPD. Further studies are needed to identify the factors that contribute to variability in practice among the different BPD outpatient centers, which may include inpatient practices.

Validation of an outpatient questionnaire for bronchopulmonary dysplasia control.

INTRODUCTION: Despite bronchopulmonary dysplasia (BPD) being a common morbidity of preterm birth, there is no validated objective tool to assess outpatient respiratory symptom control for clinical and research purposes. METHODS: Data were obtained from 1049 preterm infants and children seen in outpatient BPD clinics of 13 US tertiary care centers from 2018 to 2022. A new standardized instrument was modified from an asthma control test questionnaire and administered at the time of clinic visits. External measures of acute care use were also collected. The questionnaire for BPD control was validated in the entire population and selected subgroups using standard methodology for internal reliability, construct validity, and discriminative properties. RESULTS: Based on the scores from BPD control questionnaire, the majority of caregivers (86.2%) felt their child's symptoms were under control, which did not differ by BPD severity (p = 0.30) or a history of pulmonary hypertension (p = 0.42). Across the entire population and selected subgroups, the BPD control questionnaire was internally reliable, suggestive of construct validity (albeit correlation coefficients were -0.2 to -0.4.), and discriminated control well. Control categories (controlled, partially controlled, and uncontrolled) were also predictive of sick visits, emergency department visits, and hospital readmissions. CONCLUSION: Our study provides a tool for assessing respiratory control in children with BPD for clinical care and research studies. Further work is needed to identify modifiable predictors of disease control and link scores from the BPD control questionnaire to other measures of respiratory health such as lung function testing.

Daycare Attendance is Linked to Increased Risk of Respiratory Morbidities in Children Born Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To test the hypothesis that daycare attendance among children with bronchopulmonary dysplasia (BPD) is associated with increased chronic respiratory symptoms and/or greater health care use for respiratory illnesses during the first 3 years of life. STUDY DESIGN: Daycare attendance and clinical outcomes were obtained via standardized instruments for 341 subjects recruited from 9 BPD specialty clinics in the US. All subjects were former infants born preterm (<34 weeks) with BPD (71% severe) requiring outpatient follow-up between 0 and 3 years of age. Mixed logistic regression models were used to test for associations. RESULTS: Children with BPD attending daycare were more likely to have emergency department visits and systemic steroid usage. Children in daycare up to 3 years of age also were more likely to report trouble breathing, having activity limitations, and using rescue medications when compared with children not in daycare. More severe manifestations were found in children attending daycare between 6 and 12 months of chronological age. CONCLUSIONS: In this study, children born preterm with BPD who attend daycare were more likely to visit the emergency department, use systemic steroids, and have chronic respiratory symptoms compared with children not in daycare, indicating that daycare may be a potential modifiable risk factor to minimize respiratory morbidities in children with BPD during the preschool years.

Insurance coverage and respiratory morbidities in bronchopulmonary dysplasia.

INTRODUCTION: Preterm infants and young children with bronchopulmonary dysplasia (BPD) are at increased risk for acute care utilization and chronic respiratory symptoms during early life. Identifying risk factors for respiratory morbidities in the outpatient setting could decrease the burden of care. We hypothesized that public insurance coverage was associated with higher acute care usage and respiratory symptoms in preterm infants and children with BPD after initial neonatal intensive care unit (NICU) discharge. METHODS: Subjects were recruited from BPD clinics at 10 tertiary care centers in the United States between 2018 and 2021. Demographics and clinical characteristics were obtained through chart review. Surveys for clinical outcomes were administered to caregivers. RESULTS: Of the 470 subjects included in this study, 249 (53.0%) received employer-based insurance coverage and 221 (47.0%) received Medicaid as sole coverage at least once between 0 and 3 years of age. The Medicaid group was twice as likely to have sick visits (adjusted odd ratio [OR]: 2.06; p = 0.009) and emergency department visits (aOR: 2.09; p = 0.028), and three times more likely to be admitted for respiratory reasons (aOR: 3.04; p = 0.001) than those in the employer-based group. Additionally, those in the Medicaid group were more likely to have nighttime respiratory symptoms (aOR: 2.62; p = 0.004). CONCLUSIONS: Children with BPD who received Medicaid coverage were more likely to utilize acute care and have nighttime respiratory symptoms during the first 3 years of life. More comprehensive studies are needed to determine whether the use of Medicaid represents a barrier to accessing care, lower socioeconomic status, and/or a proxy for detrimental environmental exposures.

Characteristics of infants or children presenting to outpatient bronchopulmonary dysplasia clinics in the United States.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is a common respiratory sequelae of preterm birth, for which longitudinal outpatient data are limited. Our objective was to describe a geographically diverse outpatient cohort of former preterm infants followed in BPD-disease specific clinics. METHODS: Seven BPD specialty clinics contributed data using standardized instruments to this retrospective cohort study. Inclusion criteria included preterm birth (<37 weeks) and respiratory symptoms or needs requiring outpatient follow-up. RESULTS: A total of 413 preterm infants and children were recruited (mean age: 2.4 ± 2.7 years) with a mean gestational age of 27.0 ± 2.8 weeks and a mean birthweight of 951 ± 429 grams of whom 63.7% had severe BPD. Total, 51.1% of subjects were nonwhite. Severe BPD was not associated with greater utilization of acute care/therapies compared to non-severe counterparts. Of children with severe BPD, differences in percentage of those on any home respiratory support (p = .001), home positive pressure ventilation (p = .003), diuretics (p < .001), inhaled corticosteroids (p < .001), and pulmonary vasodilators (p < .001) were found between centers, however no differences in acute care use were observed. DISCUSSION: This examination of a multicenter collaborative registry of children born prematurely with respiratory disease demonstrates a diversity of management strategies among geographically distinct tertiary care BPD centers in the United States. This study reveals that the majority of children followed in these clinics were nonwhite and that neither variation in management nor severity of BPD at 36 weeks influenced outpatient acute care utilization. These findings suggest that post-neonatal intensive care unit factors and follow-up may modify respiratory outcomes in BPD, possibly independently of severity.

The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children's hospitals.

OBJECTIVE: To evaluate the association between chronic diuretic exposures and enteral electrolyte use in infants developing severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: Retrospective longitudinal cohort study in infants admitted to United States children's hospitals. We identified diuretic exposures and measured enteral NaCl and KCl use during pre-defined exposure risk-interval days. We used mixed-effects logistic regression to model the association between diuretic exposures and electrolyte use. RESULTS: We identified 442,341 subject-days in 3252 infants. All common diuretic classes and class combinations were associated with increased NaCl and KCl use. Thiazide monotherapy was associated with greater electrolyte use than loop monotherapy. The addition of potassium-sparing diuretics was associated with a limited reduction in KCl use compared to thiazide monotherapy. CONCLUSIONS: Chronic diuretic exposures are associated with increased NaCl and KCl use. Presumptions about the relative impact of different diuretic classes on electrolyte derangements may be inaccurate and require further study.

Ventilation Strategies in Severe Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is an acquired, developmental chronic lung disease that is a consequence of premature birth. In the most severe form of the disease, infants may require prolonged periods of positive pressure ventilation. BPD is a heterogeneous disease with lung mechanics that differ from those in respiratory distress syndrome; strategies to manage the respiratory support in infants with severe BPD should take this into consideration. When caring for these infants, practitioners need to shift from the acute care ventilation strategies that use frequent blood gases and support adjustments designed to minimize exposure to positive pressure. Infants with severe BPD benefit from a chronic care model that uses less frequent ventilator adjustments and provides the level of positive support that will achieve the longer-term goal of ongoing lung growth and repair.

Lifelong pulmonary sequelae of bronchopulmonary dysplasia.

PURPOSE OF REVIEW: To summarize the current literature evaluating long-term pulmonary morbidity among surviving very preterm infants with bronchopulmonary dysplasia (BPD). RECENT FINDINGS: BPD predisposes very preterm infants to adverse respiratory signs and symptoms, greater respiratory medication use, and more frequent need for rehospitalization throughout early childhood. Reassuringly, studies also indicate that older children and adolescents with BPD experience, on average, similar functional status and quality of life when compared to former very preterm infants without BPD. However, measured deficits in pulmonary function may persist in those with BPD and indicate an increased susceptibility to early-onset chronic obstructive pulmonary disease during adulthood. Moreover, subtle differences in exercise tolerance and activity may put survivors with BPD at further risk of future morbidity in later life. SUMMARY: Despite advances in neonatal respiratory care, a diagnosis of BPD continues to be associated with significant pulmonary morbidity over the first two decades of life. Long-term longitudinal studies are needed to determine if recent survivors of BPD will also be at increased risk of debilitating pulmonary disease in adulthood.

Safety and efficacy of treatment with lumacaftor in combination with ivacaftor in younger patients with cystic fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is the most common autosomal recessive disorder among Caucasians affecting ~70,000 people worldwide. The lack of functional cystic fibrosis transmembrane conductance regulator (CFTR) causes dysregulation of epithelial fluid transport in the lungs, gastrointestinal tract, and sweat glands. Areas covered: The most common disease-causing CFTR mutation, F508del, is present in over 75% of those affected;. therapies targeting F508del function have the promise to reduce morbidity and mortality in the majority of patients with CF. The combination of lumacaftor, which corrects the aberrant intracellular trafficking of F508del, and ivacaftor, which potentiates CFTR function, is known as OrkambiTM, and is the first drug approved for the treatment of CF in patients who are F508del-homozygotes. OrkambiTM is currently approved for use in children aged 2 and older based on recent data from open-label Phase 3 clinical safety studies. Expert opinion: OrkambiTM modestly improves clinical outcomes for people with CF who are F508del-homozygotes, and does so with a reasonable safety profile. This is a major advance in therapy for CF, but further advances are needed, perhaps with the addition of a third agent to this combination small molecule therapy, in order to expand both the targeted population and beneficial effects.

Neuromuscular disorders and chronic ventilation.

Morbidity and mortality have decreased in patients with neuromuscular disease due to implementation of therapies to augment cough and improve ventilation. Infants with progressive neuromuscular disease will eventually develop respiratory complications as a result of muscle weakness and their inability to compensate during periods of increased respiratory loads. The finding of nocturnal hypercapnia is often the trigger for initiating non-invasive ventilation and studies have shown that its use not only may improve sleep-disordered breathing, but also that it may have an effect on daytime function, symptoms related to hypercapnia, and partial pressure of CO2. It is important to understand the respiratory physiology of this population and to understand the benefits and limitations of assisted ventilation.

Physiology of non-invasive respiratory support.

Non-invasive ventilation (NIV) is used in neonates to treat extrathoracic and intrathoracic airway obstruction, parenchymal lung disease and disorders of control of breathing. Avoidance of airway intubation is associated with a reduction in the incidence of chronic lung disease among preterm infants with respiratory distress syndrome. Use of nasal continuous positive airway pressure (nCPAP) may help establish and maintain functional residual capacity (FRC), decrease respiratory work, and improve gas exchange. Other modes of non-invasive ventilation, which include heated humidified high-flow nasal cannula therapy (HHHFNC), nasal intermittent mandatory ventilation (NIMV), non-invasive pressure support ventilation (NI-PSV), and bi-level CPAP (SiPAP™), have also been shown to provide additional benefit in improving breathing patterns, reducing work of breathing, and increasing gas exchange when compared with nCPAP. Newer modes, such as neurally adjusted ventilatory assist (NAVA), hold the promise of improving patient-ventilator synchrony and so might ultimately improve outcomes for preterm infants with respiratory distress.