Introduction Rubinstein‐Taybi syndrome (RSTS) is a rare genetic syndrome caused primarily by a mutation in the CREBBP gene found on chromosome 16. Patients with RSTS are at greater risk for a variety of medical problems, including upper airway obstruction and aspiration. Childhood interstitial lung disease (ILD) thus far has not been definitively linked to RSTS. Here we present three patients with RSTS who developed ILD and discuss possible mechanisms by which a mutation in CREBBP may be involved in the development of ILD. Methods Routine hematoxylin and eosin staining was performed on lung biopsy tissue for histological analysis. Immunofluorescent staining was performed on lung biopsy tissue for markers of fibrosis, surfactant deficiency and histone acetylation. Cases 1 and 2 had standard clinical microarray analysis. Case 3 had whole exome sequencing. Bioinformatics analyses were performed to identify possible causative genes using ToppGene. Results Computed tomography images in all cases showed consolidated densities overlying ground glass opacities. Lung histopathology revealed accumulation of proteinaceous material within alveolar spaces, evidence of fibrosis, and increased alveolar macrophages. Immunofluorescent staining showed increase in surfactant protein C staining, patchy areas of increased anti‐smooth muscle antibody staining, and increased staining for acetylated histone 2 and histone 3 lysine 9. Discussion Clinical characteristics, radiographic imaging, lung histopathology, and immunofluorescent staining results shared by all cases demonstrated findings consistent with ILD. Immunofluorescent staining suggests two possible mechanisms for the development of ILD: abnormal surfactant metabolism and/or persistent activation of myofibroblasts. These two pathways could be related to dysfunctional CREBBP protein.
Particulate matter exposure is a risk factor for lower respiratory tract infection in children. Here, we investigated the geospatial patterns of community-acquired pneumonia and the impact of PM2.5 (particulate matter with an aerodynamic diameter ≤2.5 µm) on geospatial variability of pneumonia in children. We performed a retrospective analysis of prospectively collected population-based surveillance study data of community-acquired pneumonia hospitalizations among children <18 years residing in the Memphis metropolitan area, who were enrolled in the Centers for Disease Control and Prevention sponsored Etiology of Pneumonia in the Community (EPIC) study from January 2010 to June 2012. The outcome measure, residence in high- and low-risk areas for community-acquired pneumonia, was determined by calculating pneumonia incidence rates and performing cluster analysis to identify areas with higher/lower than expected rates of community-acquired pneumonia for the population at risk. High PM2.5 was defined as exposure to PM2.5 concentrations greater than the mean value (>10.75 μg/m3), and low PM2.5 is defined as exposure to PM2.5 concentrations less than or equal to the mean value (≤10.75 μg/m3). We also assessed the effects of age, sex, race/ethnicity, history of wheezing, insurance type, tobacco smoke exposure, bacterial etiology, and viral etiology of infection. Of 810 (96.1%) subjects with radiographic community-acquired pneumonia, who resided in the Memphis metropolitan area and had addresses which were successfully geocoded (Supplementary Figure F2), 220 (27.2%) patients were identified to be from high- ( n = 126) or low-risk ( n = 94) community-acquired pneumonia areas. Community-acquired pneumonia in Memphis metropolitan area had a non-homogenous geospatial pattern. PM2.5 was associated with residence in high-risk areas for community-acquired pneumonia. In addition, children with private insurance and bacterial, as opposed to viral, etiology of infection had a decreased risk of residence in a high-risk area for community-acquired pneumonia. The results from this paper suggest that environmental exposures as well as social risk factors are associated with childhood pneumonia.
Exposure to elevated levels of particulate matter (PM) is associated with adverse respiratory health and increased risk of morbidity and mortality due to respiratory tract viral infections in infants. Our previous studies demonstrated combustion derived PM (CDPM) induced immunosuppression allowing for enhanced influenza disease severity and mortality in neonatal mice. Current studies are aimed at understanding the underlying mechanisms. Neonatal mice (3 day old) were acutely exposed to Air or DCB230 (CDPM), and infected with influenza virus (Flu), Air/Flu and DCB/Flu respectively. Pulmonary T cell profile and immunosuppressive cytokines were analyzed. At 10 days-post exposure, a significant increase in pulmonary Tregs and IL10 coinciding with decrease in protective T helper 1 (Th1) and cytotoxic T cell (Tc1) responses was observed in DCB/Flu mice compared to Air/Flu mice. Further, depletion of Tregs (using anti-CD25 antibody) in DCB mice prior to flu infection increased both Th1 and Tc1 cells, whereas adoptive transfer of DCB-induced Tregs into Air mice and later infection with flu suppressed these responses. To elucidate the role of IL10 in DCB/Flu mice, Air exposed neonatal mice were treated with recombinant IL10 (rIL10) and subsequently infected with flu (rIL10/Flu). rIL10/Air/Flu mice had increased morbidity and pulmonary viral load compared to Air/Flu mice, whereas, IL10 deficient DCB/Flu mice exhibited reduction in pulmonary viral load and morbidity compared to wild-type mice indicative of enhanced protection against flu. Together, these studies demonstrate that PM- induced Tregs and their effector cytokine, IL10, suppress adaptive T cell responses leading to increased influenza severity in infected neonatal mice.
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