A.M. Schiltz

Neutrophilic airway inflammation and association with bacterial lipopolysaccharide in children with asthma and wheezing.

Asthma is a leading chronic childhood illness in the US. To gain further insight into the pathophysiology of childhood asthma, we studied markers of airway inflammation and possible triggers such as bacterial lipopolysaccharide (LPS) in 18 children with chronic asthma and persistent wheezing who underwent clinically indicated bronchoscopy and bronchoalveolar lavage (BAL). We predominantly found neutrophilic airway inflammation associated with increased levels of IL‐8, metalloproteinase (MMP)‐9, tissue inhibitor of metalloproteinase (TIMP‐1) and MMP‐9/TIMP‐1 ratio. A significant correlation was found between levels of LPS in BAL and airway neutrophils in BAL from a subgroup of children who had a tendency of increased levels of MMP‐9 and TIMP‐1, suggesting that increased LPS levels in BAL may contribute to chronic airway inflammation and early remodeling. Our data highlight the importance of defining chronic triggers of early airway inflammation in children and characterizing their inflammation, considering the use of bronchoscopy and BAL. Increased knowledge of airway inflammation in children may help prevent a more severe asthma phenotype and lead to environmental control measures and new treatment strategies to intervene against the establishment of irreversible inflammation. Pediatr Pulmonol. 2008; 43:916–923.

Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children.

RATIONALE The effect of endotoxin on asthma morbidity in urban populations is unclear. OBJECTIVES To determine if indoor pollutant exposure modifies the relationships between indoor airborne endotoxin and asthma health and morbidity. METHODS One hundred forty-six children and adolescents with persistent asthma underwent repeated clinical assessments at 0, 3, 6, 9, and 12 months. Home visits were conducted at the same time points for assessment of airborne nicotine, endotoxin, and nitrogen dioxide (NO2) concentrations. The effect of concomitant pollutant exposure on relationships between endotoxin and asthma outcomes were examined in stratified analyses and statistical models with interaction terms. MEASUREMENTS AND MAIN RESULTS Both air nicotine and NO2 concentrations modified the relationships between airborne endotoxin and asthma outcomes. Among children living in homes with no detectable air nicotine, higher endotoxin was inversely associated with acute visits and oral corticosteroid bursts, whereas among those in homes with detectable air nicotine, endotoxin was positively associated with these outcomes (interaction P value = 0.004 and 0.07, respectively). Among children living in homes with lower NO2 concentrations (<20 ppb), higher endotoxin was positively associated with acute visits, whereas among those living in homes with higher NO2 concentrations, endotoxin was negatively associated with acute visit (interaction P value = 0.05). NO2 also modified the effect of endotoxin on asthma symptom outcomes in a similar manner. CONCLUSIONS The effects of household airborne endotoxin exposure on asthma are modified by coexposure to air nicotine and NO2, and these pollutants have opposite effects on the relationships between endotoxin and asthma-related outcomes.

Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab

Background Atopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross‐linking inhibits critical virus‐induced IFN‐&agr; responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma. Objective We sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN‐&agr; responses in inner‐city children with asthma. Methods PBMCs and pDCs isolated from children with exacerbation‐prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross‐linking. IFN‐&agr; levels were measured in supernatants, and mRNA expression of IFN‐&agr; pathway genes was determined by using quantitative RT‐PCR (qRT‐PCR) in cell pellets. Fc&egr;RI&agr; protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT‐PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations. Results Omalizumab treatment increased rhinovirus‐ and influenza‐induced PBMC and rhinovirus‐induced pDC IFN‐&agr; responses in the presence of IgE cross‐linking and reduced pDC surface Fc&egr;RI&agr; expression. Omalizumab‐induced reductions in pDC Fc&egr;RI&agr; levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN‐&agr; responses. PBMC Fc&egr;RI&agr; mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction. Conclusions These findings indicate that omalizumab treatment augments pDC IFN‐&agr; responses and attenuates pDC Fc&egr;RI&agr; protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus‐induced asthma exacerbations.

Observed Home Dampness and Mold Are Associated with Sustained Spikes in Personal Exposure to Particulate Matter Less than 10 μm in Diameter in Exacerbation-Prone Children with Asthma

RATIONALE Home dampness and mold are associated with asthma severity and exacerbations, but little is known about the nature of these exposures in at-risk children. OBJECTIVES To test the hypothesis that observed dampness, water damage, and mold in the home are associated with higher exposure to particulate matter less than 10 μm in diameter in a cohort of at-risk children with asthma. METHODS We performed a pilot study in 8- to 16-year-old children with exacerbation-prone asthma (n = 29; Denver Asthma Panel Study). Exposure to particulate matter less than 10 μm in diameter was measured over ∼72 hours with personal wearable monitors (MicroPEM [RTI International] and iTrack Micro GPS tracker) and stationary bedroom-located monitors (PEM, MSP Corporation). Mean percentage personal monitored time was 93% (95% confidence interval, 90-96%). Mean and spikes of real-time exposure to particulate matter less than 10 μm in diameter were calculated and, for personal monitored samples, partitioned into exposure while at home, school, or other locations. We defined a sustained spike exposure as a continuous period of 20 minutes or longer during which levels were greater than 50 μg/μL over the participants minimum levels, using a 2-minute moving average of the particulate matter measurements. Mold and dampness were assessed by detailed home inspection. RESULTS Visible water damage/moisture/mold and mold/mildew were common in the homes of exacerbation-prone children: bathroom, 60% and 46%; basement, 30% and 34%; kitchen, 22% and 39%; living room, 20% and 2%; bedroom, 12% and 2%; and other rooms, 21% and 7%, respectively. Personal and bedroom filter-based levels of particulate matter less than 10 μm in diameter were associated with home cumulative measures of water damage/moisture/mold (personal r2 = 0.13, P = 0.02; bedroom r2 = 0.19, P = 0.006; analysis of variance) and mold/mildew (personal r2 = 0.11, P = 0.04; bedroom r2 = 0.18, P = 0.008). Real-time integrated particulate matter less than 10 μm in diameter during sustained spike exposures that occurred when participants were home (normalized by total duration of sustained spike exposures) was associated with cumulative drips/leaks/wet areas (r2 = 0.27; P = 0.004), mold/mildew (r2 = 0.15; P = 0.04), and water damage/moisture/mold (r2 = 0.14; P = 0.04). Other measures of exposure to particulate matter less than 10 μm in diameter from personal or stationary monitors were not associated with home dampness or mold indicators. CONCLUSIONS Although mold exposure was not directly quantified in the respirable aerosol in this study, observations of home dampness and mold were associated with sustained spikes in respirable particulate matter less than 10 μm in diameter that was measured by wearable real-time monitors. In our cohort of at-risk children, this finding could imply that mold may exert respiratory health effects via sustained spikes in exposure and help to guide future studies and interventions to reduce these spikes and improve asthma outcomes.