Chest X-ray lung imaging features in pediatric COVID-19 and comparison with viral lower respiratory infections in young children.

RATIONALE: Chest radiography (CXR) is a noninvasive imaging approach commonly used to evaluate lower respiratory tract infections (LRTIs) in children. However, the specific imaging patterns of pediatric coronavirus disease 2019 (COVID-19) on CXR, their relationship to clinical outcomes, and the possible differences from LRTIs caused by other viruses in children remain to be defined. METHODS: This is a cross-sectional study of patients seen at a pediatric hospital with polymerase chain reaction (PCR)-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 95). Patients were subdivided in infants (0-2 years, n = 27), children (3-10 years, n = 27), and adolescents (11-19 years, n = 41). A sample of young children (0-2 years, n = 68) with other viral lower respiratory infections (LRTI) was included to compare their CXR features with the subset of infants (0-2 years) with COVID-19. RESULTS: Forty-five percent of pediatric patients with COVID-19 were hospitalized and 20% required admission to intensive care unit (ICU). The most common abnormalities identified were ground-glass opacifications (GGO)/consolidations (35%) and increased peribronchial markings/cuffing (33%). GGO/consolidations were more common in older individuals and perihilar markings were more common in younger subjects. Subjects requiring hospitalization or ICU admission had significantly more GGO/consolidations in CXR (p < .05). Typical CXR features of pediatric viral LRTI (e.g., hyperinflation) were more common in non-COVID-19 viral LRTI cases than in COVID-19 cases (p < .05). CONCLUSIONS: CXR may be a complemental exam in the evaluation of moderate or severe pediatric COVID-19 cases. The severity of GGO/consolidations seen in CXR is predictive of clinically relevant outcomes. Hyperinflation could potentially aid clinical assessment in distinguishing COVID-19 from other types of viral LRTI in young children.

Airway Remodeling Factors During Early-Life Rhinovirus Infection and the Effect of Premature Birth.

Background: Early rhinovirus (RV) infection is a strong risk factor for asthma development. Airway remodeling factors play a key role in the progression of the asthmatic condition. We hypothesized that RV infection in young children elicits the secretion of growth factors implicated in airway remodeling and asthma progression. Methods: We examined the nasal airway production of remodeling factors in children ( ≤ 2 years old) hospitalized due to PCR-confirmed RV infection. Airway remodeling proteins included: MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, TIMP-2, EGF, Angiopoietin-2, G-CSF, BMP-9, Endoglin, Endothelin-1, Leptin, FGF-1, Follistatin, HGF, HB-EGF, PLGF, VEGF-A, VEGF-C, VEGF-D, FGF-2, TGF-ß1, TGF-ß2, TGF-ß3, PDGF AA, PDGF BB, SPARC, Periostin, OPN, and TGF-α. Results: A total of 43 young children comprising RV cases (n = 26) and uninfected controls (n = 17) were included. Early RV infection was linked to (1) enhanced production of several remodeling factors (e.g., HGF, TGFα), (2) lower MMP-9/TIMP-2 and MMP-2/TIMP-2 ratios, and (3) increased MMP-10/TIMP-1 ratios. We also found that relative to term infants, severely premature children had reduced MMP-9/TIMP-2 ratios at baseline. Conclusion: RV infection in young children elicits the airway secretion of growth factors implicated in angiogenesis, fibrosis, and extracellular matrix deposition. Our results highlight the potential of investigating virus-induced airway remodeling growth factors during early infancy to monitor and potentially prevent chronic progression of respiratory disorders in all ages.

Central breathing abnormalities in children with trisomy 21: Effect of age, sex, and concomitant OSA.

BACKGROUND: Trisomy 21 (TS21) is a condition with a high risk for sleep apnea. In the pediatric population, the risk also includes central breathing disorders. The aim of this study was to define the clinical and polysomnographic characteristics of central apnea in infants, children, and adolescents with TS21. METHODS: Retrospective review of baseline polysomnograms (PSGs) in children with TS21 in the sleep center at Children's National Medical Center in Washington DC. RESULTS: We included a total of 158 infants, children, and adolescents (0-18 years) with TS21 in this study. The median age was 4.82 years and 62% were male. The primary findings of the study are that (1) 12% of all pediatric subjects with TS21 included had a central apnea index (CAI) > 2/h; (2) the proportion of TS21 individuals with central breathing abnormalities progressively decreased with age being common in young individuals (≤2 years of age) but rare after 10 years of age; (3) additional sleep breathing disturbances (e.g., OSA and/or hypoxemia) are often present in children with TS21 and central apnea; and (4) the prevalence of central breathing abnormalities in TS21 is influenced by sex, being more likely to persist beyond early childhood (>2 years of age) in females than in males. CONCLUSION: Central breathing abnormalities are common in TS21 among young children (≤2 years of age) and in females older than 2 years of age. Central apnea is often associated with concomitant obstructive sleep apnea and/or hypoxemia in children with TS21.

Innate IFN-lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life.

INTRODUCTION: IFN lambda (type III-IFN-λ1) is a molecule primarily produced by epithelial cells that provides an important first-line defence against viral respiratory infections and has been linked to the pathogenesis of viral-induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN-lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. METHODS: IFN-lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN-lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. RESULTS: Our in vitro experiments showed that the poly(I:C)-induced innate production of IFN lambda in human infant AECs is regulated by (a) p38-MAPK/NF-kB dependent mechanism; and (b) exposure to pro-inflammatory signals such as IL1ß. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus-induced IFN-lambda airway secretion; (b) subjects with RSV infection showed the highest IFN-lambda airway levels; and (c) individuals with the highest virus-induced IFN-lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). CONCLUSION: IFN-lambda responses to dsRNA in the human infant airway epithelium are regulated by p38-MAPK and NF-kB signalling. High in vivo IFN-lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children.

Airway mir-155 responses are associated with TH1 cytokine polarization in young children with viral respiratory infections.

BACKGROUND: MicroRNAs (miRs) control gene expression and the development of the immune system and antiviral responses. MiR-155 is an evolutionarily-conserved molecule consistently induced during viral infections in different cell systems. Notably, there is still an unresolved paradox for the role of miR-155 during viral respiratory infections. Despite being essential for host antiviral TH1 immunity, miR-155 may also contribute to respiratory disease by enhancing allergic TH2 responses and NFkB-mediated inflammation. The central goal of this study was to define how airway miR-155 production is related to TH1, TH2, and pro-inflammatory cytokine responses during naturally occurring viral respiratory infections in young children. METHODS: Normalized nasal airway levels of miR-155 and nasal protein levels of IFN-γ, TNF-α, IL-1ß, IL-13, IL-4 were quantified in young children (≤2 years) hospitalized with viral respiratory infections and uninfected controls. These data were linked to individual characteristics and respiratory disease parameters. RESULTS: A total of 151 subjects were included. Increased miR-155 levels were observed in nasal samples from patients with rhinovirus, RSV and all respiratory viruses analyzed. High miR-155 levels were strongly associated with high IFN-γ production, increased airway TH1 cytokine polarization (IFN-γ/IL-4 ratios) and increased pro-inflammatory responses. High airway miR-155 levels were linked to decreased respiratory disease severity in individuals with high airway TH1 antiviral responses. CONCLUSIONS: The airway secretion of miR-155 during viral respiratory infections in young children is associated with enhanced antiviral immunity (TH1 polarization). Further studies are needed to define additional physiological roles of miR-155 in the respiratory tract of human infants and young children during health and disease.

Validation of a new predictive model to improve risk stratification in bronchopulmonary dysplasia.

We need a better risk stratification system for the increasing number of survivors of extreme prematurity suffering the most severe forms of bronchopulmonary dysplasia (BPD). However, there is still a paucity of studies providing scientific evidence to guide future updates of BPD severity definitions. Our goal was to validate a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks postmenstrual age (PMA). We hypothesized that this approach improves BPD risk assessment, particularly in extremely premature infants. This is a longitudinal cohort of premature infants (≤32 weeks PMA, n = 188; Washington D.C). We performed receiver operating characteristic analysis to define optimal BPD severity levels using the duration of supplementary O2 as predictor and respiratory hospitalization after discharge as outcome. Internal validation included lung X-ray imaging and phenotypical characterization of BPD severity levels. External validation was conducted in an independent longitudinal cohort of premature infants (≤36 weeks PMA, n = 130; Bogota). We found that incorporating the total number of days requiring O2 (without restricting at 36 weeks PMA) improved the prediction of respiratory outcomes according to BPD severity. In addition, we defined a new severity category (level IV) with prolonged exposure to supplemental O2 (≥120 days) that has the highest risk of respiratory hospitalizations after discharge. We confirmed these findings in our validation cohort using ambulatory determination of O2 requirements. In conclusion, a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks improves risk stratification and should be considered when updating current BPD severity definitions.