Efficacy of Leukadherin-1 in the Prevention of Hyperoxia-Induced Lung Injury in Neonatal Rats.

Lung inflammation plays a key role in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. The challenge in BPD management is the lack of effective and safe antiinflammatory agents. Leukadherin-1 (LA1) is a novel agonist of the leukocyte surface integrin CD11b/CD18 that enhances leukocyte adhesion to ligands and vascular endothelium and thus reduces leukocyte transendothelial migration and influx to the injury sites. Its functional significance in preventing hyperoxia-induced neonatal lung injury is unknown. We tested the hypothesis that administration of LA1 is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) and received twice-daily intraperitoneal injection of LA1 or placebo for 14 days. Hyperoxia exposure in the presence of the placebo resulted in a drastic increase in the influx of neutrophils and macrophages into the alveolar airspaces. This increased leukocyte influx was accompanied by decreased alveolarization and angiogenesis and increased pulmonary vascular remodeling and pulmonary hypertension (PH), the pathological hallmarks of BPD. However, administration of LA1 decreased macrophage infiltration in the lungs during hyperoxia. Furthermore, treatment with LA1 improved alveolarization and angiogenesis and decreased pulmonary vascular remodeling and PH. These data indicate that leukocyte recruitment plays an important role in the experimental model of BPD induced by hyperoxia. Targeting leukocyte trafficking using LA1, an integrin agonist, is beneficial in preventing lung inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting integrin-mediated leukocyte recruitment and inflammation may provide a novel strategy in preventing and treating BPD in preterm infants.

PM2.5 exposure and household income are associated with lung function abnormalities in children with sickle cell disease.

RATIONALE: Cardiopulmonary dysfunction is a major contributor to mortality among persons with sickle cell disease (pwSCD). Despite this, little is known regarding environmental drivers of lung function decline. OBJECTIVE: We hypothesized that environmental and socioeconomic variables have a significant effect on lung function in pwSCD that can be detected by spirometry. METHODS: We retrospectively analyzed all spirometry results from pwSCD followed in the Pediatric Pulmonology clinic at the Children's Hospital of Philadelphia since 1 January 2016. RESULTS: The study included 349 spirometry tests from 128 patients, primarily "Black or African American" (88%) and male (61%). More frequent exposure to PM2.5 above 25 µg/m3 was associated with higher odds of obstruction. Specifically, when compared to incidence of exposure to PM2.5 above 25 µg/m3 <25th percentile, both pwSCD exposed to 25th-75th percentile and pwSCD >75th percentile had higher odds of obstruction on spirometry (25th-75th: odds ratio [OR]: 9.6, p = .017; >75th: OR: 31.85, p = .002) despite correction for potential confounders. Similarly, median household income below the mean was associated with higher odds of restriction (OR: 4.37; p = .009). CONCLUSIONS: We report higher odds of obstruction in pwSCD frequently exposed to PM2.5 concentrations above 25 µg/m3 and higher odds of restriction in pwSCD with lower household income. Our findings link spirometry patterns to modifiable risk factors indicating that there may opportunities for early intervention in pwSCD that have been referred to a pulmonology clinic. Further research is needed to assess if these findings can be generalized to the wider population of pwSCD.

Phenotype wide association study links bronchopulmonary dysplasia with eosinophilia in children.

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Despite this, genetic drivers of BPD are poorly understood. The objective of this study is to better understand the impact of single nucleotide polymorphisms (SNPs) previously associated with BPD by examining associations with other phenotypes. We drew pediatric subjects from the biorepository at the Center for Applied Genomics to identify associations between these SNPs and 2,146 imputed phenotypes. Methylation data, external cohorts, and in silico validation methods were used to corroborate significant associations. We identified 60 SNPs that were previously associated with BPD. We found a significant association between rs3771150 and rs3771171 and mean eosinophil percentage in a European cohort of 6,999 patients and replicated this in external cohorts. Both SNPs were also associated with asthma, COPD and FEV1/FVC ratio. These SNPs displayed associations with methylation probes and were functionally linked to ST2 (IL1RL1) levels in blood and lung tissue. Our findings support a genetic justification for the epidemiological link between BPD and asthma. Given the well-established link between ST2 and type 2 inflammation in asthma, these findings provide a rationale for future studies exploring the role of type 2 inflammation in the pathogenesis of BPD.

Ambient Air Pollution and Outpatient Morbidities in Bronchopulmonary Dysplasia.

Rationale: Bronchopulmonary dysplasia (BPD) is the most common long-term complication of prematurity. Although socioeconomic status is associated with BPD morbidities, the drivers of this association are poorly understood. In the United States, ambient air pollution (AAP) exposure is linked to both race/ethnicity and socioeconomic status. Furthermore, AAP exposure is known to have a detrimental effect on respiratory health in children. Objectives: To assess if AAP exposure is linked to BPD morbidity in the outpatient setting. Methods: Participants with BPD were recruited from outpatient clinics at Johns Hopkins University and the Children's Hospital of Philadelphia between 2008 and 2021 (N = 800) and divided into low, moderate, and high AAP exposure groups, based on publicly available U.S. Environmental Protection Agency data. Clinical data were obtained by chart review and caregiver questionnaires. Results: Non-White race, home ventilator use, and lower median household income were associated with higher degrees of air pollution exposure. After adjustment for these factors, moderate and high air pollution exposure were associated with requiring systemic steroids (odds ratio, 1.78 and 2.17, respectively) compared with low air pollution. Similarly, high air pollution exposure was associated with emergency department visits (odds ratio, 1.59). Conclusions: This study demonstrates an association between AAP exposure and BPD morbidity after initial hospital discharge. AAP exposure was closely linked to race and median household income. As such, it supports the notion that AAP exposure may be contributing to health disparities in BPD outcomes. Further studies directly measuring exposure and establishing a link between biomarkers of exposure and outcomes are prerequisites to developing targeted interventions protecting this vulnerable population.

GWAS reveals Genetic Susceptibility to Air Pollution-Related Asthma Exacerbations in Children of African Ancestry.

Background: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, mitigation efforts have yielded mixed results, potentially due to genetic variability in the response to AAP. We hypothesize that common single nucleotide polymorphisms (SNPs) are linked to AAP sensitivity and test this through a Genome Wide Association Study (GWAS). Methods: We selected a cohort of pediatric asthma patients frequently exposed to AAP. Patients experiencing exacerbations immediately following AAP spikes were deemed sensitive. A GWAS compared sensitive versus non-sensitive patients. Findings were validated using data from the All of Us program. Results: Our study included 6,023 pediatric asthma patients. Due to the association between AAP exposure and race, GWAS analysis was feasible only in the African ancestry cohort. Seven risk loci reached genome-wide significance, including four non-intergenic variants. Two variants were validated: rs111970601 associated with sensitivity to CO (odds ratio [OR], 6.58; PL=L1.63L×L10-8; 95% CI, 3.42-12.66) and rs9836522 to PM2.5 sensitivity (OR 0.75; PL=L3,87 ×L10-9; 95% CI, 0.62-0.91). Interpretation: While genetic variants have been previously linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. The identified variants implicate genes with a known role in asthma and established links to AAP. Future research should explore how clinical interventions interact with genetic risk to mitigate the effects of AAP, particularly to enhance health equity for vulnerable populations. What is already known on this topic: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, efforts to mitigate the impact of AAP on children with asthma have yielded mixed results, potentially due to genetic variability in response to AAP. What this study adds: Using publicly available AAP data, we identify which children with asthma experience exacerbations immediately following spikes in AAP. We then conduct a Genome Wide Association Study (GWAS) comparing these patients with those who have no temporal association between AAP spikes and asthma exacerbations, identifying several Single Nucleotide Polymorphisms (SNPs) significantly associated with AAP sensitivity. How this study might affect research practice or policy: While genetic variants have previously been linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. This creates a framework for identifying children especially at risk when exposed to AAP. These children should be targeted with policy interventions to reduce exposure and may require specific treatments to mitigate the effects of ongoing AAP exposure in the interim.

Outpatient inhaled corticosteroid use in bronchopulmonary dysplasia.

RATIONALE: In the outpatient setting, inhaled corticosteroids (ICS) are frequently given to children with bronchopulmonary dysplasia (BPD) for treatment of respiratory and asthma-associated symptoms. In this study we sought to determine if correlations existed between ICS use and ICS initiation and patient characteristics and outpatient respiratory outcomes. METHODS: This study included children with the diagnosis of BPD (n = 661) who were seen in outpatient pulmonary clinics at the Children's Hospital of Philadelphia between 2016 and 2021. Chart review was used to determine patient demographics, use and timing of ICS initiation, asthma diagnosis, and acute care usage following initial hospital discharge. RESULTS: At the first pulmonary visit, 9.2% of children had been prescribed an ICS at NICU discharge, 13.9% had been prescribed an ICS after NICU discharge but before their first pulmonary appointment, and 6.9% were prescribed an ICS at the completion of initial pulmonary visit. Children started on an ICS as outpatients had a higher likelihood of ER visits (adjusted odds ratio: 2.68 ± 0.7), hospitalizations (4.81 ± 1.16), and a diagnosis of asthma (3.58 ± 0.84), compared to children never on an ICS. Of those diagnosed with asthma, children prescribed an ICS in the outpatient setting received the diagnosis at an earlier age. No associations between NICU BPD severity scores and ICS use were found. CONCLUSIONS: This study identifies an outpatient BPD phenotype associated with ICS use and ICS initiation independent of NICU severity score. Additionally, outpatient ICS initiation correlates with a subsequent diagnosis of asthma and acute care usage in children with BPD.

Ambient air pollution sensitivity and severity of pediatric asthma.

BACKGROUND: Ambient air pollution exposure increases the incidence and severity of pediatric asthma. Despite this, we lack effective therapies to protect patients from the impact of ambient air pollution exposure. A roadblock is the inability to identify patients that are affected by air pollution. OBJECTIVE: To examine the association between AAP sensitivity determined by individual exposure prior to asthma exacerbations and the severity of asthma in pediatric patients. METHODS: We assess the association between spikes in ambient air pollution and asthma exacerbations. Patients were considered sensitive to a specific pollutant if they experienced an asthma exacerbation immediately following a spike in the concentration of that pollutant. Cut off values for these spikes were determined as two standard deviations above the mean concentration two weeks prior and two weeks post the days leading up to an asthma exacerbation. RESULTS: We included 8129 pediatric patients with over 34,346 associated asthma exacerbations. In a multinomial log-linear logistic regression model comparing patients with mild asthma to patients with moderate or severe asthma, sensitivity to Ozone, SO2, PM2.5 and PM10 was significantly associated to severe as opposed to mild asthma (OR 1.39 with CI 1.08-1.78, 1.58 with CI 1.12-2.23, 1.37 with CI 1.07-1.76, and 1.63 with CI 1.12-2.37 respectively). Furthermore, moderate as opposed to mild asthma was significantly associated with sensitivity to SO2 and PM2.5 (OR 1.24 with CI 1.06-1.44 and 1.26 with CI 1.12-1.43, respectively). IMPACT STATEMENT: There is a subpopulation of pediatric asthma patients that experience asthma exacerbations just following spikes in ambient air pollution. This subgroup of patients has more severe asthma despite correction for significant confounders. The presented work is the first to reveal the clinically significant impact of variation in ambient air pollution sensitivity in pediatric asthma, highlighting the importance of accounting for variable sensitivity in the study of the effects of ambient air pollution exposure on pediatric asthma.

Year in review 2021: Neuromuscular diseases.

In this years' review of neuromuscular respiratory medicine, there were a series of articles on home mechanical ventilation, real-world studies assessing the impact of nusinersen, and studies describing upper airway dysfunction. Beyond this, we highlight two excellent reviews regarding cardiac dysfunction in neuromuscular diseases.

The role of gene-ambient air pollution interactions in paediatric asthma.

Globally, asthma prevention and treatment remain a challenge. Ambient air pollution (AAP) is an environmental risk factor of special interest in asthma research. AAP is poorly defined and has been subdivided either by the origin of the air pollution or by the specific bioactive compounds. The link between AAP exposure and asthma exacerbations is well established and has been extensively reviewed. In this narrative review, we discuss the specific genetic variants that have been associated with increased AAP sensitivity and impact in paediatric asthma. We highlight the relative importance of variants associated with genes with a role in oxidant defences and the nuclear factor-κB pathway supporting a potential central role for these pathways in AAP sensitivity.

Diagnostic and management considerations in pseudohypoaldosteronism type 1b.

Pseudohypoaldosteronism type 1B is a rare autosomal recessive disorder caused by dysfunction of amiloride-sensitive epithelial sodium channels (ENaCs). We present the case of a neonate with cardiogenic shock after cardiac arrest due to profound hyperkalaemia. Genetic testing revealed a novel homozygous variant in SCNNIA We review diagnostic considerations including the molecular mechanisms of disease, discuss treatment approaches and highlight the possible significance of the diversity of pulmonary ENaCs.

HIF-1α Pulmonary Phenotype Wide Association Study Unveils a Link to Inflammatory Airway Conditions.

Despite experimental data linking HIF-1α dysfunction to inflammatory airway conditions, the effect of single nucleotide polymorphisms within the HIF1A gene on these conditions remains poorly understood. In the current study, we complete a phenotype wide association study to assess the link between SNPs with known disease associations and respiratory phenotypes. We report two SNPs of the HIF1A gene, the intronic rs79865957 and the missense rs41508050. In these positions the A and the T allele are significantly associated with allergic rhinitis and acute bronchitis and bronchiolitis, respectively. These findings further support the role of HIF-1α in inflammatory pulmonary conditions and may serve as a basis to refine our understanding of other HIF-1α associated phenotypes.

A Pediatric Case of Sirolimus-Associated Pneumonitis After Kidney Transplantation.

Sirolimus is an immunosuppressive medication often used in solid organ transplantation. It has been associated with severe side effects, including pulmonary toxicity. In adult patients, a single center study found that 14% of those treated with sirolimus developed pulmonary pneumonitis; however, the incidence in the pediatric population is not known. Most reports in adult patients indicate that elevated drug concentrations and a prolonged duration of use are associated with pulmonary toxicity. We report a case of a 17-year-old male kidney transplant recipient who developed rapid-onset respiratory failure, necessitating mechanical ventilation and acute renal replacement therapy for ultrafiltration secondary to sirolimus-induced pneumonitis. He had been treated for acute rejection with corticosteroids 17 days prior to the development of pneumonitis. His symptoms developed within 1 week of initiation of sirolimus and with a serum concentration of 1.1 ng/mL. Sirolimus was discontinued, and, following aggressive diuresis and ventilatory support, his respiratory status returned to baseline. Sirolimus-induced pneumonitis is an important diagnosis to be considered in any transplant recipient receiving sirolimus with new onset fever, cough, or dyspnea without an identifiable source, especially if there is a preceding history of treatment with high-dose corticosteroids.

Clinical Characteristics of Infective Endocarditis in Children.

BACKGROUND: Infective endocarditis (IE) remains a diagnostic and therapeutic challenge associated with high morbidity and mortality. We evaluated the microbial profile and clinical manifestation of IE in children. METHODS: A retrospective study examining pediatric IE cases treated between 2000 and 2017 at the Department of Pediatric Cardiology, KU Leuven, was conducted. Clinical presentation, treatment, complications, outcome of IE, underlying microorganisms and congenital heart defects were reviewed. RESULTS: Fifty-three patients were diagnosed with IE. Overall, 19 patients (36%) required cardiac surgery. Seven patients (13%) died. Eighty-seven percent of patients had an underlying congenital cardiac defect. Eighteen (34%) children presented with prosthetic graft IE. A causative organism was found in 49 (92%) cases: viridans group streptococci were identified in 17 (32%), Staphylococcus aureus in 13 (25%) and coagulase-negative staphylococci in 11 (20%) children. Community-acquired (CA) IE increased significantly from 8 (33%) cases in 2000-2007 to 20 (74%) cases in 2008-2017 (P < 0.01). Even with viridans streptococci being significantly more prevalent in the CA group (P < 0.01), we did not observe an increase of streptococcal IE from 2008 to 2017. Seventeen (32%) patients presented with hospital-acquired IE during the first year of life with 14 (82%) children after surgery and a prevalence of coagulase-negative staphylococci (53%). CONCLUSIONS: The incidence of pediatric IE was similar over the investigated time period with a shift toward CA IE. Streptococci and staphylococci accounted for the majority of cases in both periods. Awareness of IE and its prevention is crucial in patients after implantation of prosthetic grafts.