Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Diffusing Capacity and Mortality in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) mortality risk is often estimated using the BODE (body mass index, obstruction, dyspnea, exercise capacity) index, including body mass index, forced expiratory volume in 1 second, dyspnea score, and 6-minute walk distance. Diffusing capacity of the lung for carbon monoxide (DlCO) is a potential predictor of mortality that reflects physiology distinct from that in the BODE index. Objectives: This study evaluated DlCO as a predictor of mortality using participants from the COPDGene study. Methods: We performed time-to-event analyses of individuals with COPD (former or current smokers with forced expiratory volume in 1 second/forced vital capacity < 0.7) and DlCO measurements from the COPDGene phase 2 visit. Cox proportional hazard methods were used to model survival, adjusting for age, sex, pack-years, smoking status, BODE index, computed tomography (CT) percent emphysema (low attenuation areas below -950 Hounsfield units), CT airway wall thickness, and history of cardiovascular or kidney diseases. C statistics for models with DlCO and BODE scores were used to compare discriminative accuracy. Results: Of 2,329 participants, 393 (16.8%) died during the follow-up period (median = 4.9 yr). In adjusted analyses, for every 10% decrease in DlCO percent predicted, mortality increased by 28% (hazard ratio = 1.28; 95% confidence interval, 1.17-1.41, P < 0.001). When compared with other clinical predictors, DlCO percent predicted performed similarly to BODE (C statistic DlCO = 0.68; BODE = 0.70), and the addition of DlCO to BODE improved its discriminative accuracy (C statistic = 0.71). Conclusions: Diffusing capacity, a measure of gas transfer, strongly predicted all-cause mortality in individuals with COPD, independent of BODE index and CT evidence of emphysema and airway wall thickness. These findings support inclusion of DlCO in prognostic models for COPD.

Risk of Atherosclerotic Cardiovascular Disease Hospitalizations after COPD Hospitalization among Older Adults.

BACKGROUND: Meta-analyses have suggested the risk of atherosclerotic cardiovascular disease (ASCVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, these studies have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. METHODS: We assessed the risk of ASCVD hospitalizations after COPD hospitalization compared to before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016-2019 in the US. The primary outcome was risk of a ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery by-pass graft surgery, stroke, or transient ischemic attack) in the 1 year after-COPD hospitalization relative to the 1 year before-COPD hospitalization. Time from discharge to a composite ASCVD hospitalization outcome was modeled using an extension of the Cox Proportional-Hazards model, the Anderson-Gill model with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups and risk factors associated with the composite ASCVD hospitalization outcome. RESULTS: Among 920,550 patients (mean age, 73 years) the hazard ratio estimate (HR; 95% CI) for the composite ASCVD hospitalization outcome after-COPD hospitalization vs before-COPD hospitalization was 0.99 (0.97, 1.02; p = 0.53) following adjustment. We observed 3 subgroups that were significantly associated with higher risk for ASCVD hospitalizations after COPD hospitalization: 76+ years old, women, COPD hospitalization severity. Among the 19 characteristics evaluated, 10 were significantly associated with higher risk of CVD events 1 year after COPD hospitalization with hyperlipidemia (2.78; 2.67, 2.90) and history of cardiovascular disease (1.77; 1.72 1.83) associated with the greatest risk. CONCLUSION: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalizations was not significantly increased after COPD-hospitalization relative to before-COPD hospitalization. Although, we identified age 76+ years old, female sex, and COPD hospitalization severity as high risk subgroups and 10 risk factors associated with increased risk of ASCVD events after-COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia.

Patients with mutations in the ectodysplasin receptor signalling pathway genes - the X-linked ligand ectodysplasin-A (EDA), the receptor EDAR or the receptor adapter EDARADD - have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains Tabby (EdaTa ) and downless (Edardl-J/dl-J ) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in EdaTa mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired (swh) rat strain carries a mutation in the Edaradd gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaraddswh/swh than those in unaffected heterozygous Edaraddswh/+ rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children.

Chronic otitis media is initiated by a bulla cavitation defect in the FBXO11 mouse model.

Auditory bulla cavitation defects are a cause of otitis media, but the normal cellular pattern of bulla mesenchyme regression and its failure are not well understood. In mice, neural-crest-derived mesenchyme occupies the bulla from embryonic day 17.5 (E17.5) to postnatal day 11 (P11) and then regresses to form the adult air-filled bulla cavity. We report that bulla mesenchyme is bordered by a single layer of non-ciliated epithelium characterized by interdigitating cells with desmosome cell junctions and a basal lamina, and by Bpifa1 gene expression and laminin staining of the basal lamina. At P11-P12, the mesenchyme shrinks: mesenchyme-associated epithelium shortens, and mesenchymal cells and extracellular matrix collagen fibrils condense, culminating in the formation of cochlea promontory mucosa bordered by compact non-ciliated epithelial cells. FBXO11 is a candidate disease gene in human chronic otitis media with effusion and we report that a bulla cavitation defect initiates the pathogenesis of otitis media in the established mouse model Jeff (Fbxo11Jf/+ ). Persistent mesenchyme in Fbxo11Jf/+ bullae has limited mesenchymal cell condensation, fibrosis and hyperplasia of the mesenchyme-associated epithelium. Subsequent modification forms fibrous adhesions that link the mucosa and the tympanic membrane, and this is accompanied by dystrophic mineralization and accumulation of serous effusion in the bulla cavity. Mouse models of bulla cavitation defects are important because their study in humans is limited to post-mortem samples. This work indicates new diagnostic criteria for this otitis media aetiology in humans, and the prospects of studying the molecular mechanisms of murine bulla cavitation in organ culture.

Phenotype of Spirometric Impairment in an Aging Population.

RATIONALE: The Global Lung Initiative (GLI) provides age-appropriate criteria for establishing spirometric impairment, including mild, moderate, and severe chronic obstructive pulmonary disease (COPD) and restrictive pattern, but its association with respiratory-related phenotypes has not been evaluated. OBJECTIVES: To evaluate respiratory-related phenotypes in GLI-defined spirometric impairment. METHODS: In COPDGene (N = 10,131 patients; age range, 45-81 yr; average smoking history, 44.3 pack-years), we evaluated spirometry, dyspnea (modified Medical Research Council grade, ≥2), poor respiratory health-related quality of life (St. George's Respiratory Questionnaire total score, ≥25), poor exercise performance (6-minute-walk distance, <391 m), bronchodilator reversibility (FEV1 change, >12% and ≥200 ml), and computed tomography-diagnosed emphysema and gas trapping (>5% and >15% of lung, respectively). MEASUREMENTS AND MAIN RESULTS: GLI established normal spirometry in 5,100 patients (50.3%), mild COPD in 669 (6.6%), moderate COPD in 865 (8.5%), severe COPD in 2,522 (24.9%), and restrictive pattern in 975 (9.6%). Relative to normal spirometry, graded associations with respiratory-related phenotypes were found for mild, moderate, and severe COPD, with respective adjusted odds ratios (95% confidence intervals) as follows: dyspnea-1.31 (1.10-1.56), 2.20 (1.81-2.68), and 10.73 (8.04-14.33); poor respiratory health-related quality of life-1.49 (1.28-1.75), 2.69 (2.08-3.47), and 14.61 (10.09-21.17); poor exercise performance-1.11 (0.94-1.31), 1.58 (1.33-1.88), and 4.58 (3.42-6.12); bronchodilator reversibility-2.76 (2.24-3.40), 5.18 (4.29-6.27), and 6.21 (5.06-7.62); emphysema-4.86 (3.16-7.47), 6.41 (4.09-10.05), and 17.79 (10.79-29.32); and gas trapping-3.92 (3.12-4.93), 5.20 (3.82-7.07), and 16.28 (9.71-27.30). Restrictive pattern was also associated with multiple respiratory-related phenotypes at a level similar to moderate COPD, but it was otherwise not associated with emphysema (0.89 [0.60-1.32]) or gas trapping (1.15 [0.92-1.42]). CONCLUSIONS: GLI-defined spirometric impairment establishes clinically meaningful respiratory disease, as validated by graded associations with respiratory-related phenotypes.

Phenotype of normal spirometry in an aging population.

RATIONALE: In aging populations, the commonly used Global Initiative for Chronic Obstructive Lung Disease (GOLD) may misclassify normal spirometry as respiratory impairment (airflow obstruction and restrictive pattern), including the presumption of respiratory disease (chronic obstructive pulmonary disease [COPD]). OBJECTIVES: To evaluate the phenotype of normal spirometry as defined by a new approach from the Global Lung Initiative (GLI), overall and across GOLD spirometric categories. METHODS: Using data from COPDGene (n = 10,131; ages 45-81; smoking history, ≥10 pack-years), we evaluated spirometry and multiple phenotypes, including dyspnea severity (Modified Medical Research Council grade 0-4), health-related quality of life (St. George's Respiratory Questionnaire total score), 6-minute-walk distance, bronchodilator reversibility (FEV1 % change), computed tomography-measured percentage of lung with emphysema (% emphysema) and gas trapping (% gas trapping), and small airway dimensions (square root of the wall area for a standardized airway with an internal perimeter of 10 mm). MEASUREMENTS AND MAIN RESULTS: Among 5,100 participants with GLI-defined normal spirometry, GOLD identified respiratory impairment in 1,146 (22.5%), including a restrictive pattern in 464 (9.1%), mild COPD in 380 (7.5%), moderate COPD in 302 (5.9%), and severe COPD in none. Overall, the phenotype of GLI-defined normal spirometry included normal adjusted mean values for dyspnea grade (0.8), St. George's Respiratory Questionnaire (15.9), 6-minute-walk distance (1,424 ft [434 m]), bronchodilator reversibility (2.7%), % emphysema (0.9%), % gas trapping (10.7%), and square root of the wall area for a standardized airway with an internal perimeter of 10 mm (3.65 mm); corresponding 95% confidence intervals were similarly normal. These phenotypes remained normal for GLI-defined normal spirometry across GOLD spirometric categories. CONCLUSIONS: GLI-defined normal spirometry, even when classified as respiratory impairment by GOLD, included adjusted mean values in the normal range for multiple phenotypes. These results suggest that among adults with GLI-defined normal spirometry, GOLD may misclassify normal phenotypes as having respiratory impairment.

Prediction of acute respiratory disease in current and former smokers with and without COPD.

BACKGROUND: The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown. METHODS: Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score. RESULTS: At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV1), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George's Respiratory Questionnaire score). Risks were similar for those with and without COPD. CONCLUSIONS: Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.

Ventilation and anesthetic approaches for rigid bronchoscopy.

Due to growing interest in management of central airway obstruction, rigid bronchoscopy is undergoing a resurgence in popularity among pulmonologists. Performing rigid bronchoscopy requires use of deep sedation or general anesthesia to achieve adequate patient comfort, whereas maintaining oxygenation and ventilation via an uncuffed and often open rigid bronchoscope requires use of ventilation strategies that may be unfamiliar to most pulmonologists. Available approaches include apneic oxygenation, spontaneous assisted ventilation, controlled ventilation, manual jet, and high-frequency jet ventilation. Anesthetic technique is partially dictated by the selected ventilation strategy but most often relies on a total intravenous anesthetic approach using ultra-short-acting sedatives and hypnotics for a rapid offset of action in this patient population with underlying respiratory compromise. Gas anesthetic may be used with the rigid bronchoscope, minimizing leaks with fenestrated caps placed over the ports, although persistent circuit leaks can make this approach challenging. Jet ventilation, the most commonly used ventilatory approach, may be delivered manually using a Sanders valve or via an automated ventilator at supraphysiologic respiratory rates, allowing for an open rigid bronchoscope to facilitate ease of moving tools in and out of the airway. Despite a patient population that often suffers from significant respiratory compromise, major complications with rigid bronchoscopy are uncommon and are similar among modern ventilation approaches. Choice of ventilation technique should be determined by local expertise and equipment availability. Appropriate patient selection and recognition of limitations associated with a given ventilation strategy are critical to avoid procedural-related complications.

A systematic approach to analyse the sequelae of LCPD.

The analysis and treatment of hips with healed Legg-Calvé-Perthes disease (LCPD) differs substantially from the treatment in the acute phase of the disease. More specifically, the treating orthopaedic surgeon is often faced with a complex three-dimensional pathomorphology of the hip that is difficult to understand and correct. To date, none of the current classification systems provide a useful decision-making algorithm with regards to the type of surgical intervention necessary to improve hip function in patients with sequelae of LCPD. The conceptual recognition of the femoroacetabular impingement (FAI) and the ability to safely dislocate the hip have revolutionised our diagnostic and therapeutic algorithm for joint-preserving surgery of hips with structural residuals of LCPD. We present a systematic approach to analyse femoral and acetabular pathomorphologic features. The resulting pathomechanisms and the surgical treatment options are presented.

Perfluoropropane gas as a magnetic resonance lung imaging contrast agent in humans.

BACKGROUND: Fluorine-enhanced MRI is a relatively inexpensive and straightforward technique that facilitates regional assessments of pulmonary ventilation. In this report, we assess its suitability through the use of perfluoropropane (PFP) in a cohort of human subjects with normal lungs and subjects with lung disease. METHODS: Twenty-eight subjects between the ages of 18 and 71 years were recruited for imaging and were classified based on spirometry findings and medical history. Imaging was carried out on a Siemens TIM Trio 3T MRI scanner using two-dimensional, gradient echo, fast low-angle shot and three-dimensional gradient echo, volumetric, interpolated, breath-hold examination sequences for proton localizers and PFP functional scans, respectively. Respiratory waveforms and physiologic signals of interest were monitored throughout the imaging sessions. A region-growing algorithm was applied to the proton localizers to define the lung field of view for analysis of the PFP scans. RESULTS: All subjects tolerated the gas mixture well with no adverse side effects. Images of healthy lungs demonstrated a homogeneous distribution of the gas with sufficient signal-to-noise ratios, while lung images from asthmatic and emphysematous lungs demonstrated increased heterogeneity and ventilation defects. CONCLUSIONS: Fluorine-enhanced MRI using a normoxic PFP gas mixture is a well-tolerated, radiation-free technique for regionally assessing pulmonary ventilation. The inherent physical characteristics and applicability of the gaseous agent within a magnetic resonance setting facilitated a clear differentiation between normal and diseased lungs.

Chronic critical illness: the growing challenge to health care.

The chronically critically ill (CCI) comprise a rapidly growing population of patients who have survived acute critical illness, only to be left with ongoing organ dysfunctions requiring high levels of specialized care for months or years. In many ways, CCI is an "iatrogenic" process, reflecting the ability of modern life support technologies to keep patients alive for prolonged periods of time despite ongoing life threatening illness. Venues of care for the CCI patient include acute care hospitals (both ICU and step-down facilities), specialized long term acute care hospitals, and, less commonly, skilled nursing facilities, or even the home. Importantly, CCI patients transition among these venues frequently, reflecting the nature of CCI to be punctuated with episodes of acute critical illness. Management of the CCI population requires a special combination of intensive care and rehabilitative skills.

Is there a role for screening spirometry?

In obstructive lung disease, the characteristic change in spirometry is a reduction in the forced expiratory volume in the first second (FEV(1)) with respect to the vital capacity. Moreover, the severity of the obstruction can be graded by referencing spirometric measurements to age, sex, and height predicted normal values. Spirometry, however, should be considered a medical test, and not simply a vital sign that anyone can perform. Indeed, both technical issues and tester skills can profoundly affect the results and interpretations. Properly done spirometry can guide therapies and predict outcomes, but using spirometry to screen for obstructive lung disease in asymptomatic populations can be problematic, and the effects of screening spirometry on outcomes have yet to be determined. The value of spirometry is increased when it is of good quality, is interpreted properly, and is used in high-risk populations as a case-finding rather than a screening tool.

Respiratory therapies in the critical care setting. Should aerosolized antibiotics be administered to prevent or treat ventilator-associated pneumonia in patients who do not have cystic fibrosis?

Ventilator-associated pneumonia (VAP) significantly increases intensive care unit morbidity, mortality, and costs. VAP is thought to be caused by bacterial entry into injured airways, which produces tracheobronchitis that evolves into diffuse pneumonia. The use of aerosolized antibiotics is conceptually attractive, especially when the infection is early and limited to the airway epithelium. Data show that aerosolized antibiotics kill airway bacteria and improve outcomes in cystic fibrosis. The clinical evidence for aerosolized antibiotics to prevent VAP is weak but suggestive. Concerns about the high cost, possible development of antibiotic resistance, and other potential risks of aerosolized antibiotics led several evidence-based consensus groups to recommend against routine use of aerosolized antibiotics for VAP prevention until better data are available. Importantly, the clinical evidence that aerosolized antibiotics can treat established VAP is negative, and multiple consensus groups recommend against treating established VAP with aerosolized antibiotics.

Muscle dysfunction associated with chronic obstructive pulmonary disease.

Skeletal-muscle (both respiratory and limb) abnormalities are common and can have profound effects in patients with chronic inflammatory states such as chronic obstructive pulmonary disease (COPD). Causes include direct inflammatory-mediator effects on muscle function, malnutrition, blood-gas abnormalities, compromised oxygen delivery from right-heart dysfunction, electrolyte imbalances, drugs, and comorbid states. In COPD patients, respiratory muscles are overloaded, which leads to increased fatigue potential, especially during exercise, when hyperinflation worsens. Interestingly, overloaded respiratory muscles develop structural changes that help them adapt to these conditions. In contrast, limb (especially lower extremity) muscles in COPD patients are underloaded as a consequence of disuse, and this leads to muscle atrophy. Treatment is aimed at optimizing lung function, nutritional repletion, aerobic exercise training, and (in certain patients) oxygen therapy. Resistive breathing training is more controversial. Lung-volume-reduction surgery may help with the hyperinflation effects and improve gas exchange and respiratory-muscle function in selected patients.

Corticosteroid therapy and chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is characterized in part by a chronic inflammatory state in the airways (largely from chronic noxious stimuli such as tobacco smoke), punctuated with acute inflammatory exacerbations, which are often infectious. Although pathologically and biochemically different from the inflammation of asthma, the chronic inflammation of chronic obstructive pulmonary disease, especially in subgroups with asthma-like features and especially during exacerbations, might be expected to respond to corticosteroid therapy, as does asthma. Complications from long-term corticosteroid use are important, but they appear less when the corticosteroid is given via the inhaled route. Clinical evidence is particularly strong supporting the use of inhaled corticosteroids to prevent exacerbations and oral corticosteroids to reduce the duration and impact of exacerbations.

Intrabreath analysis of carbon monoxide uptake during exercise in patients at risk for lung injury.

The single exhalation analysis of carbon monoxide, acetylene, and methane allows the determination of intrabreath (regional) DL, pulmonary capillary blood flow and ventilation inhomogeneities during rest and exercise. We reasoned that this technique might be more sensitive in detecting regional pulmonary capillary abnormalities than resting single breath DL (DL(sb)). We selected a group of breast cancer patients in high-dose chemotherapy (HDCT) protocols who were at risk for pulmonary injury. We grouped the patients into pre-HDCT and post-HDCT, and used resting DL(sb) to further categorize the latter into those with and without pulmonary injury. We found that exercise DL increases were blunted in post-HDCT patients with low resting DL(sb). More importantly, even in post-HDCT patients with normal resting DL(sb), exercise DL response was reduced in the slowest emptying lung units along with evidence for ventilation inhomogeneities (increased methane slope). We conclude that exercise assessments of DL at low lung volumes and gas mixing properties may be sensitive indicators of lung injury.