The Child Opportunity Index 2.0 and exacerbation-prone asthma in a cohort of urban children.

RATIONALE: Social determinants of health underlie disparities in asthma. However, the effects of individual determinants likely interact, so a summary metric may better capture their impact. The Child Opportunity Index 2.0 (COI) is one such tool, yet its association with exacerbation-prone (EP) asthma is unknown. OBJECTIVE: To investigate the association between the COI and EP asthma and clinical measures of asthma severity in children. METHODS: We analyzed data from two prospective observational pediatric asthma cohorts (n = 193). Children were classified as EP (≥1 exacerbation in the past 12 months) or exacerbation-null (no exacerbations in the past 5 years). Spirometry, exhaled nitric oxide, IgE, and Composite Asthma Severity Index (CASI) were obtained. The association between COI and EP status was assessed with logistic regression. We fit linear and logistic regression models to test the association between COI and each clinical measure. RESULTS: A 20-point COI decrease conferred 40% higher odds of EP asthma (OR 1.4; 95%CI 1.1-1.76). The effect was similar when adjusted for age and sex (OR 1.38, 95%CI 1.1-1.75) but was attenuated with additional adjustment for race and ethnicity (OR 1.19, 95%CI 0.92-1.54). A similar effect was seen for the Social/Economic and Education COI domains but not the Health/Environment Domain. A 20-point COI decrease was associated with an increase in CASI of 0.34. COI was not associated with other clinical measures. CONCLUSIONS: Lower COI was associated with greater odds of EP asthma. This highlights the potential use of the COI to understand neighborhood-level risk and identify community targets to reduce asthma disparities.

Breathing zone pollutant levels are associated with asthma exacerbations in high-risk children.

Background: Indoor and outdoor air pollution levels are associated with poor asthma outcomes in children. However, few studies have evaluated whether breathing zone pollutant levels associate with asthma outcomes. Objective: Determine breathing zone exposure levels of NO 2 , O 3 , total PM 10 and PM 10 constituents among children with exacerbation-prone asthma, and examine correspondence with in-home and community measurements and associations with outcomes. Methods: We assessed children's personal breathing zone exposures using wearable monitors. Personal exposures were compared to in-home and community measurements and tested for association with lung function, asthma control, and asthma exacerbations. Results: 81 children completed 219 monitoring sessions. Correlations between personal and community levels of PM 10 , NO 2 , and O 3 were poor, whereas personal PM 10 and NO 2 levels correlated with in-home measurements. However, in-home monitoring underdetected brown carbon (Personal:79%, Home:36.8%) and ETS (Personal:83.7%, Home:4.1%) personal exposures, and detected black carbon in participants without these personal exposures (Personal: 26.5%, Home: 96%). Personal exposures were not associated with lung function or asthma control. Children experiencing an asthma exacerbation within 60 days of personal exposure monitoring had 1.98, 2.21 and 2.04 times higher brown carbon (p<0.001), ETS (p=0.007), and endotoxin (p=0.012), respectively. These outcomes were not associated with community or in-home exposure levels. Conclusions: Monitoring pollutant levels in the breathing zone is essential to understand how exposures influence asthma outcomes, as agreement between personal and in-home monitors is limited. Inhaled exposure to PM 10 constituents modifies asthma exacerbation risk, suggesting efforts to limit these exposures among high-risk children may decrease their asthma burden. CLINICAL IMPLICATIONS: In-home and community monitoring of environmental pollutants may underestimate personal exposures. Levels of inhaled exposure to PM 10 constituents appear to strongly influence asthma exacerbation risk. Therefore, efforts should be made to mitigate these exposures. CAPSULE SUMMARY: Leveraging wearable, breathing-zone monitors, we show exposures to inhaled pollutants are poorly proxied by in-home and community monitors, among children with exacerbation-prone asthma. Inhaled exposure to multiple PM 10 constituents is associated with asthma exacerbation risk.

Prediction of lung cancer risk based on age and smoking history.

BACKGROUND AND OBJECTIVE: The CISNET models provide predictions for dying of lung cancer in any year of life as a function of age and smoking history, but their predictions are quite variable and the models themselves can be complex to implement. Our goal was to develop a simple empirical model of the risk of dying of lung cancer that is mathematically constrained to produce biologically appropriate probability predictions as a function of current age, smoking start age, quit age, and smoking intensity. METHODS: The six adjustable parameters of the model were evaluated by fitting its predictions of cancer death risk versus age to the mean of published predictions made by the CISNET models for the never smoker and for six different scenarios of lifetime smoking burden. RESULTS: The mean RMS fitting error of the model was 6.16 × 10 -2 (% risk of dying of cancer per year of life) between 55 and 80 years of age. The model predictions increased monotonically with current age, quit age and smoking intensity, and decreased with increasing start age. CONCLUSIONS: Our simple model of the risk of dying of lung cancer in any given year of life as a function of smoking history is easily implemented and thus may serve as a useful tool in situations where the mortality risks of smoking need to be estimated.

Airwave oscillometry to measure lung function in children with Down syndrome.

BACKGROUND: Children with Down syndrome are at risk for significant pulmonary co-morbidities, including recurrent respiratory infections, dysphagia, obstructive sleep apnea, and pulmonary vascular disease. Because the gold standard metric of lung function, spirometry, may not be feasible in children with intellectual disabilities, we sought to assess the feasibility of both airwave oscillometry and spirometry in children with Down syndrome. METHODS: Thirty-four children with Down syndrome aged 5-17 years were recruited. Participants performed airwave oscillometry and spirometry before and 10 min after albuterol. Outcomes include success rates, airway resistance and reactance pre- and post-bronchodilator, and bronchodilator response. RESULTS: Participants were median age 9.2 years (interquartile range 7.2, 12.0) and 47% male. Airwave oscillometry was successful in 26 participants (76.5%) and 4 (11.8%) were successful with spirometry. No abnormalities in airway resistance were detected, and 16/26 (61.5%) had decreased reactance. A positive bronchodilator response by oscillometry was observed in 5/23 (21.7%) of those with successful pre- and post-bronchodilator testing. CONCLUSIONS: Measures of pulmonary function were successfully obtained using airwave oscillometry in children with Down syndrome, which supports its use in this high-risk population. IMPACT: Children with Down syndrome are at risk for significant pulmonary co-morbidities, but the gold standard metric of lung function, spirometry, may not be feasible in children with intellectual disabilities. This may limit the population's enrollment in clinical trials and in standardized clinical care. In this prospective study of lung function in children with Down syndrome, airwave oscillometry was successful in 76% of participants but spirometry was successful in only 12%. This study reinforces that measures of pulmonary function can be obtained successfully using airwave oscillometry in children with Down syndrome, which supports its use in this high-risk population.

Three Alveolar Phenotypes Govern Lung Function in Murine Ventilator-Induced Lung Injury.

Mechanical ventilation is an essential lifesaving therapy in acute respiratory distress syndrome (ARDS) that may cause ventilator-induced lung injury (VILI) through a positive feedback between altered alveolar mechanics, edema, surfactant inactivation, and injury. Although the biophysical forces that cause VILI are well documented, a knowledge gap remains in the quantitative link between altered parenchymal structure (namely alveolar derecruitment and flooding), pulmonary function, and VILI. This information is essential to developing diagnostic criteria and ventilation strategies to reduce VILI and improve ARDS survival. To address this unmet need, we mechanically ventilated mice to cause VILI. Lung structure was measured at three air inflation pressures using design-based stereology, and the mechanical function of the pulmonary system was measured with the forced oscillation technique. Assessment of the pulmonary surfactant included total surfactant, distribution of phospholipid aggregates, and surface tension lowering activity. VILI-induced changes in the surfactant included reduced surface tension lowering activity in the typically functional fraction of large phospholipid aggregates and a significant increase in the pool of surface-inactive small phospholipid aggregates. The dominant alterations in lung structure at low airway pressures were alveolar collapse and flooding. At higher airway pressures, alveolar collapse was mitigated and the flooded alveoli remained filled with proteinaceous edema. The loss of ventilated alveoli resulted in decreased alveolar gas volume and gas-exchange surface area. These data characterize three alveolar phenotypes in murine VILI: flooded and non-recruitable alveoli, unstable alveoli that derecruit at airway pressures below 5 cmH2O, and alveoli with relatively normal structure and function. The fraction of alveoli with each phenotype is reflected in the proportional changes in pulmonary system elastance at positive end expiratory pressures of 0, 3, and 6 cmH2O.

Using injury cost functions from a predictive single-compartment model to assess the severity of mechanical ventilator-induced lung injuries.

Identifying safe ventilation patterns for patients with acute respiratory distress syndrome remains challenging because of the delicate balance between gas exchange and selection of ventilator settings to prevent further ventilator-induced lung injury (VILI). Accordingly, this work seeks to link ventilator settings to graded levels of VILI to identify injury cost functions that predict injury by using a computational model to process pressures and flows measured at the airway opening. Pressure-volume loops were acquired over the course of ~2 h of mechanical ventilation in four different groups of BALB/c mice. A cohort of these animals were subjected to an injurious bronchoalveolar lavage before ventilation. The data were analyzed with a single-compartment model that predicts recruitment/derecruitment and tissue distension at each time step in measured pressure-volume loops. We compared several injury cost functions to markers of VILI-induced blood-gas barrier disruption. Of the cost functions considered, we conclude that mechanical power dissipation and strain heterogeneity are the best at distinguishing between graded levels of injury and are good candidates for forecasting the development of VILI. NEW & NOTEWORTHY This work uses a predictive single-compartment model and injury cost functions to assess graded levels of mechanical ventilator-induced lung injury. The most promising measures include strain heterogeneity and mechanical power dissipation.

Linking lung function to structural damage of alveolar epithelium in ventilator-induced lung injury.

Understanding how the mechanisms of ventilator-induced lung injury (VILI), namely atelectrauma and volutrauma, contribute to the failure of the blood-gas barrier and subsequent intrusion of edematous fluid into the airspace is essential for the design of mechanical ventilation strategies that minimize VILI. We ventilated mice with different combinations of tidal volume and positive end-expiratory pressure (PEEP) and linked degradation in lung function measurements to injury of the alveolar epithelium observed via scanning electron microscopy. Ventilating with both high inspiratory plateau pressure and zero PEEP was necessary to cause derangements in lung function as well as visually apparent physical damage to the alveolar epithelium of initially healthy mice. In particular, the epithelial injury was tightly associated with indicators of alveolar collapse. These results support the hypothesis that mechanical damage to the epithelium during VILI is at least partially attributed to atelectrauma-induced damage of alveolar type I epithelial cells.

Alveolar leak develops by a rich-get-richer process in ventilator-induced lung injury.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition for which there are currently no medical therapies other than supportive care involving the application of mechanical ventilation. However, mechanical ventilation itself can worsen ARDS by damaging the alveolocapillary barrier in the lungs. This allows plasma-derived fluid and proteins to leak into the airspaces of the lung where they interfere with the functioning of pulmonary surfactant, which increases the stresses of mechanical ventilation and worsens lung injury. Once such ventilator-induced lung injury (VILI) is underway, managing ARDS and saving the patient becomes increasingly problematic. Maintaining an intact alveolar barrier thus represents a crucial management goal, but the biophysical processes that perforate this barrier remain incompletely understood. To study the dynamics of barrier perforation, we subjected initially normal mice to an injurious ventilation regimen that imposed both volutrauma (overdistension injury) and atelectrauma (injury from repetitive reopening of closed airspaces) on the lung, and observed the rate at which macromolecules of various sizes leaked into the airspaces as a function of the degree of overall injury. Computational modeling applied to our findings suggests that perforations in the alveolocapillary barrier appear and progress according to a rich-get-richer mechanism in which the likelihood of a perforation getting larger increases with the size of the perforation. We suggest that atelectrauma causes the perforations after which volutrauma expands them. This mechanism explains why atelectrauma appears to be essential to the initiation of VILI in a normal lung, and why atelectrauma and volutrauma then act synergistically once VILI is underway.

Linking Ventilator Injury-Induced Leak across the Blood-Gas Barrier to Derangements in Murine Lung Function.

Mechanical ventilation is vital to the management of acute respiratory distress syndrome, but it frequently leads to ventilator-induced lung injury (VILI). Understanding the pathophysiological processes involved in the development of VILI is an essential prerequisite for improving lung-protective ventilation strategies. The goal of this study was to relate the amount and nature of material accumulated in the airspaces to biomarkers of injury and the derecruitment behavior of the lung in VILI. Forty-nine BALB/c mice were mechanically ventilated with combinations of tidal volume and end-expiratory pressures to produce varying degrees of overdistension and atelectasis while lung function was periodically assessed. Total protein, serum protein, and E-Cadherin levels were measured in bronchoalveolar lavage fluid (BALF). Tissue injury was assessed by histological scoring. We found that both high tidal volume and zero positive end-expiratory pressure were necessary to produce significant VILI. Increased BALF protein content was correlated with increased lung derecruitability, elevated peak pressures, and histological evidence of tissue injury. Blood derived molecules were present in the BALF in proportion to histological injury scores and epithelial injury, reflected by E-Cadherin levels in BALF. We conclude that repetitive recruitment is an important factor in the pathogenesis of VILI that exacerbates injury associated with tidal overdistension. Furthermore, the dynamic mechanical behavior of the injured lung provides a means to assess both the degree of tissue injury and the nature and amount of blood-derived fluid and proteins that accumulate in the airspaces.

Predicting the Mortality Benefit of CT Screening for Second Lung Cancer in a High-Risk Population.

Patients who survive an index lung cancer (ILC) after surgical resection continue to be at significant risk for a metachronous lung cancer (MLC). Indeed, this risk is much higher than the risk of developing an ILC in heavy smokers. There is currently little evidence upon which to base guidelines for screening at-risk patients for MLC, and the risk-reward tradeoffs for screening this patient population are unknown. The goal of this investigation was to estimate the maximum mortality benefit of CT screening for MLC. We developed a computational model to estimate the maximum rates of CT detection of MLC and surgical resection to be expected in a given population as a function of time after resection of an ILC. Applying the model to a hypothetical high-risk population suggests that screening for MLC within 5 years after resection of an ILC may identify only a very small number of treatable cancers. The risk of death from a potentially resectable MLC increases dramatically past this point, however, suggesting that screening after 5 years is imperative. The model also predicts a substantial detection gap for MLC that demonstrates the benefit to be gained as more sensitive screening methods are developed.

Predicting ventilator-induced lung injury using a lung injury cost function.

Managing patients with acute respiratory distress syndrome (ARDS) requires mechanical ventilation that balances the competing goals of sustaining life while avoiding ventilator-induced lung injury (VILI). In particular, it is reasonable to suppose that for any given ARDS patient, there must exist an optimum pair of values for tidal volume (VT) and positive end-expiratory pressure (PEEP) that together minimize the risk for VILI. To find these optimum values, and thus develop a personalized approach to mechanical ventilation in ARDS, we need to be able to predict how injurious a given ventilation regimen will be in any given patient so that the minimally injurious regimen for that patient can be determined. Our goal in the present study was therefore to develop a simple computational model of the mechanical behavior of the injured lung in order to calculate potential injury cost functions to serve as predictors of VILI. We set the model parameters to represent normal, mildly injured, and severely injured lungs and estimated the amount of volutrauma and atelectrauma caused by ventilating these lungs with a range of VT and PEEP. We estimated total VILI in two ways: 1) as the sum of the contributions from volutrauma and atelectrauma and 2) as the product of their contributions. We found the product provided estimates of VILI that are more in line with our previous experimental findings. This model may thus serve as the basis for the objective choice of mechanical ventilation parameters for the injured lung.

Modeling the Progression of Epithelial Leak Caused by Overdistension.

Mechanical ventilation is necessary for treatment of the acute respiratory distress syndrome but leads to overdistension of the open regions of the lung and produces further damage. Although we know that the excessive stresses and strains disrupt the alveolar epithelium, we know little about the relationship between epithelial strain and epithelial leak. We have developed a computational model of an epithelial monolayer to simulate leak progression due to overdistension and to explain previous experimental findings in mice with ventilator-induced lung injury. We found a nonlinear threshold-type relationship between leak area and increasing stretch force. After the force required to initiate the leak was reached, the leak area increased at a constant rate with further increases in force. Furthermore, this rate was slower than the rate of increase in force, especially at end-expiration. Parameter manipulation changed only the leak-initiating force; leak area growth followed the same trend once this force was surpassed. These results suggest that there is a particular force (analogous to ventilation tidal volume) that must not be exceeded to avoid damage and that changing cell physical properties adjusts this threshold. This is relevant for the development of new ventilator strategies that avoid inducing further injury to the lung.