Faculty Bibliography

Rationale: Macrolide antibiotics, specifically azithromycin, have antimicrobial and immunomodulatory effects and, despite not having proven effect on spirometry, have been shown to prevent exacerbations in patients with moderate to severe chronic obstructive disease (COPD). We have previously shown that in asymptomatic smokers with early emphysema identified by computed tomography, distal lung dysfunction is an early marker of subclinical lung inflammation. Thus, we hypothesized that in early emphysema, treatment with azithromycin will impact both distal lung function and biomarkers of airway inflammation. Methods: Emphysema subjects were identified from the NYU Lung Cancer Biomarker Center CT-Scan Screening Cohort. Ten subjects (7M/3F) with emphysema were enrolled for pulmonary function evaluation and research bronchoscopy pre and post eight weeks 250mg/day azithromycin therapy. Physiologic assessment included spirometry, plethysmography, and diffusing capacity. Distal lung function was assessed (pre and post bronchodilator) with impulse oscillometry (IOS). Pre and post bronchodilator exhaled nitric oxide (NO) was measured at variable flow rates to determine airway and alveolar NO concentration. Results: Subjects were 65+/-4 years age. All had history of smoking with emphysema identified on computed tomography. Subjects were asymptomatic with GOLD 0 spirometry in 9/10. Lung volumes (FRC, RV and TLC) and diffusing capacity were within normal limits in all subjects. In contrast, baseline IOS revealed abnormal resistance spectrum in 5/10 and abnormal reactance spectrum in 8/10, consistent with dysfunction in the distal lung. Post bronchodilator there was significant reduction in frequency dependence of resistance and in the reactance spectrum (R5-20 = 3.88 [3.39, 5.85] vs. 3.39 [3.26, 5.06] cmH2O/L/s, p = 0.022; X5 = -1.40 [-2.02, -1.01] vs. -1.03 [-1.47, -0.90] cmH2 O/L/s, p = 0.022; resonant frequency 16.2 [13.2, 20.1] vs. 13.6 [10.9, 16.2] Hz, p = 0.007). Following azithromycin therapy, IOS demonstrated no change in resistance; however, improved reactance was seen in 8 patients (p<0.04) and bronchodilator responsiveness was no longer present. Alveolar NO normalized in all subjects post azithromycin (baseline range 1.2-9.9 vs. 0-3.6 PPB post azithromycin, p=0.06 ) despite lack of change in airway NO. (Figure presented) Conclusions: In patients with early emphysema, azithromycin administration was associated with improved oscillometry reactance but not resistance parameters and improved alveolar rather than airway NO. These data support a beneficial effect of azithromycin on distal lung function and inflammation that may not be detected by routine tests

BACKGROUND: The present study (1) characterizes a physiologic phenotype of restrictive dysfunction due to airway injury and (2) compares this phenotype to the phenotype of interstitial lung disease (ILD). METHODS: This is a retrospective study of 54 persistently symptomatic subjects following World Trade Center (WTC) dust exposure. Inclusion criteria were reduced vital capacity (VC), FEV1/VC > 77%, and normal chest roentgenogram. Measurements included spirometry, plethysmography, diffusing capacity of lung for carbon monoxide (Dlco), impulse oscillometry (IOS), inspiratory/expiratory CT scan, and lung compliance (n = 16). RESULTS: VC was reduced (46% to 83% predicted) because of the reduction of expiratory reserve volume (43% +/- 26% predicted) with preservation of inspiratory capacity (IC) (85% +/- 16% predicted). Total lung capacity (TLC) was reduced, confirming restriction (73% +/- 8% predicted); however, elevated residual volume to TLC ratio (0.35 +/- 0.08) suggested air trapping (AT). Dlco was reduced (78% +/- 15% predicted) with elevated Dlco/alveolar volume (5.3 +/- 0.8 [mL/mm Hg/min]/L). IOS demonstrated abnormalities in resistance and/or reactance in 50 of 54 subjects. CT scan demonstrated bronchial wall thickening and/or AT in 40 of 54 subjects; parenchymal disease was not evident in any subject. Specific compliance at functional residual capacity (FRC) (0.07 +/- 0.02 [L/cm H2O]/L) and recoil pressure (Pel) at TLC (27 +/- 7 cm H2O) were normal. In contrast to patients with ILD, lung expansion was not limited, since IC, Pel, and inspiratory muscle pressure were normal. Reduced TLC was attributable to reduced FRC, compatible with airway closure in the tidal range. CONCLUSIONS: This study describes a distinct physiologic phenotype of restriction due to airway dysfunction. This pattern was observed following WTC dust exposure, has been reported in other clinical settings (eg, asthma), and should be incorporated into the definition of restrictive dysfunction.

RATIONALE: Analysis of local in vivo inflammation is relevant to the understanding of pathogenesis and disease progression in emphysema. Bronchial reactivity is an early marker of disease in asthma but the relevance of reactivity to the natural history of emphysema is not understood. We hypothesize that bronchial reactivity is a phenotype of early emphysema that might be related to the degree of inflammation in the lung. METHODS: Normal subjects were enrolled as part of a normal volunteer protocol. Emphysema subjects were identified from the NYU Lung Cancer Biomarker Center CT-scan screening cohort. All patients underwent spirometry, plethysmography, diffusion, and oscillometry, as well as bronchoscopy with bronchoalveolar lavage (BAL). Bronchial reactivity was assessed by changes in FEV1, V50 and R5 . From the BAL fluid, cell count differential was obtained, as well as measurement of 39 cytokines in concentrated BAL fluid with Luminex using Human Cytokine Panel I (Millipore). Results amongst the groups were compared with ANOVA and post-hoc LSD comparison. RESULTS: Twenty patients were available for analysis: Six subjects in the control group, 6 emphysema subjects without bronchial reactivity (BR-), and 8 emphysema subjects with bronchial reactivity (BR+). Baseline demographics and pertinent spirometry/oscillometry are listed in Table 1. Emphysema subjects were all GOLD stage 0 or 1. Post-bronchodilator spirometric and oscillometric parameters were not significantly different between BR- and BR+ emphysema groups. There were 28/39 cytokines with reliably measurable levels. Both emphysema groups had elevated neutrophils and higher degree of inflammation as compared to controls (significant data shown Table 1). However, the BR+ emphysema group evidenced higher degree of neutrophils, IL-6, IL-8, G-CSF, Eotaxin, GRO and Fractalkine as compared with the BR- emphysema group. CONCLUSION: These data suggest that in early emphysema a phenotype of proximal and/or distal bronchial reactivity is associated with an increased degree of inflammation as assessed by neutrophils and in vivo inflammatory cytokines. In contrast with early asthma, the phenotype of bronchial reactivity in early emphysema may be characterized by neutrophilic inflammation produced by increased IL-8 in the lung. The role of IL-6, G-CSF, Eotaxin, GRO and Fractalkine in producing emphysema related bronchial reactivity requires further investigation. (Table Presented)

BACKGROUND: Obesity is frequently associated with respiratory symptoms despite normal large airway function as assessed by spirometry. However, reduced functional residual capacity and expiratory reserve volume are common and might reflect distal airway dysfunction. Impulse oscillometry (IOS) might identify distal airway abnormalities not detected using routine spirometry screening. Our objective was to test the hypothesis that excess body weight will result in distal airway dysfunction detected by IOS that reverses after bariatric surgery. The setting was a university hospital. METHODS: A total of 342 subjects underwent spirometry, plethysmography, and IOS before bariatric surgery. Of these patients, 75 repeated the testing after the loss of 20% of the total body weight. The data from 47 subjects with normal baseline spirometry and complete pre- and postoperative data were analyzed. RESULTS: IOS detected preoperative distal airway dysfunction despite normal spirometry findings by an abnormal airway resistance at an oscillation frequency of 20 Hz (4.75 +/- 1.2 cm H(2)O/L/s), frequency dependence of resistance from 5 to 20 Hz (2.20 +/- 1.6 cm H(2)O/L/s), and reactance at 5 Hz (-3.47 +/- 2.1 cm H(2)O/L/s). Postoperatively, the subjects demonstrated 57% +/- 15% excess weight loss. The body mass index decreased (from 44 +/- 6 to 32 +/- 5 kg/m(2), P < .001). Improvements in functional residual capacity (from 59% +/- 11% to 75% +/- 20% predicted, P < .001) and expiratory reserve volume (from 41% +/- 20% to 75% +/- 20% predicted, P < .001) were demonstrated. Distal airway function also improved: airway resistance at an oscillation frequency of 20 Hz (3.91 +/- .9, P < .001), frequency dependence of resistance from 5 to 20 Hz (1.17 +/- .9, P < .001), and reactance at 5 Hz (-1.85 +/- .9, P < .001). CONCLUSION: The present study detected significant distal airway dysfunction despite normal preoperative spirometry findings. The effect of increased body weight was likely the main mechanism for these abnormalities. However, the inflammatory state of obesity or associated respiratory disease could also be invoked. These abnormalities improved significantly toward normal after weight loss. The results of the present study highlight the importance of bariatric surgery as an effective intervention in reversing these respiratory abnormalities.

INTRODUCTION: The incidence of asthma may be increased in patients with obesity. However, recognition of airway disease is confounded by abnormal lung physiology seen in obesity per se. Healthy obese patients with normal spirometry have elevated resistance (oscillometry) similar to non-obese patients with obstructive spirometry. However, in obese patients elevated resistance is associated with decreased FRC (mass loading), whereas FRC is normal-high in non-obese patients with airway obstruction. We hypothesize that obese patients with obstructive dysfunction can be distinguished from obese patients without airway disease by relating oscillometry findings to resting lung volume (FRC). METHODS: 183 obese subjects (BMI 30-73 kg/m²) were divided into 3 groups. Group 1: healthy obese (non-smoker, no history of lung disease, normal FEV₁/FVC; n= 62) Group 2: obstructive airway disease (reduced FEV₁/FVC; n= 40) Group 3: reported diagnosis of asthma with normal airflow (normal FEV₁/FVC; n= 81). All subjects underwent spirometry and plethysmography. Oscillometry was performed at baseline and repeated during voluntary inflation to predicted FRC to minimize the confounding effect of reduced lung volume on airway resistance. Oscillometry parameters included resistance at 5 and 20Hx (R₅, R₂₀). RESULTS: VC, IC, and ERV were similar in Groups 1 and 2 (Table 1). FRC was reduced in all subjects of Group 1; in Group 2 higher values were seen extending into normal range despite obesity. R₅ and R₂₀ were elevated in all subjects to a similar degree in Groups 1 and 2; calculation of specific conductance for R₅ and R₂₀ (SGrs5, SGrs20) distinguished Group 1 from Group 2. Based on these observations, Group 3 was divided into normal vs. reduced FRC (Table 2). To minimize the effect of lung volume on resistance in Group 3, oscillometry data were analyzed at similar lung volumes (i.e. during voluntary inflation in subjects with reduced FRC vs. at baseline in remaining subjects with normal FRC). Subjects with normal FRC demonstrated higher values for R₅ and R₂₀ compared to subjects with reduced FRC. Response to bronchodilator was only noted in those subjects with normal FRC. CONCLUSIONS: Preservation of FRC occurred in obese patients with known airway disease and reduced FEV₁/FVC. In patients with normal airflow despite self reported asthma, increased airway resistance was associated with normal FRC. Therefore, whereas a reduction in FRC is expected in healthy obese subjects, a normal FRC may reflect pseudo-normalization as a manifestation of airway disease even when FEV₁/FVC is normal. (Table Presented)

There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5,) R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment

Introduction: Airway dysfunction has been detected by oscillometry in obese subjects despite normal large airway function as assessed by spirometry. This has been attributed to lung/airway compression as reflected by reduced FRC; we previously demonstrated improvement of abnormalities towards normal upon voluntary inflation to predicted FRC (AJRCCM 2010; 181:A2532). However, other causes of airway dysfunction such as inflammation or concomitant intrinsic airway disease may coexist and could not be excluded. The present study re-evaluated these subjects following bariatric surgery induced weight loss to evaluate for residual abnormality. Methods: 22 morbidly obese subjects without history of smoking and/or cardiopulmonary disease, underwent evaluation pre/post bariatric surgery (20% reduction in weight). Spirometry, plethysmography and impulse oscillometry (IOS) were performed. IOS parameters included resistance at 5Hz (R5), resistance at 20Hz (R20) frequency dependence of resistance (R5-20) and reactance at 5Hz (X5).IOS was also performed at an elevated lung volume (~1 liter) targeted to restore FRC to predicted values. All IOS measurements were repeated post bronchodilator. Results: Baseline weight and BMI were 256+/-43 kg and 46+/-7 kg/m², respectively. All subjects lost >20% of body weight, but obesity persisted in all subjects (weight 182 kg, BMI 33 kg/ m2). FEV /FVC was normal at baseline and remained unchanged post weight loss 1 (81+/-3% vs 83+/-4%) indicating normal large airway function. FRC and ERV improved post weight loss but values remained abnormal (FRC from 60+/-12 to 77+/-21% predicted, ERV from 46+/-16 to 75+/-38% predicted, p<0.05). Although IOS parameters improved following weight loss, data remained above the upper limit of normal (R5 from 6.8+/-1.8 to 5.1+/-1.4 cmH₂O/l/s, R₂₀ from 4.7+/-1.1 to 3.9+/-0.9 cmH₂O/l/s, R_5-20 from 2.1+/-1.1 to 1.2+/-0.9 cmH_2O /l/s, X₅ from -3.2+/-1.7 to -1.8+/-0.9 cmH₂O /l/s, p<0.05). Since FRC remained abnormal following weight loss, IOS was repeated following voluntary lung inflation (FRC 142+/-30%). While R20 corrected to normal at the elevated FRC (R₂₀ 3.1+/-1.0 cmH₂ O/l/s), R5, R5-20 and X5 remained abnormal indicating residual distal airway dysfunction (R₅ 4.2+/-1.4 cmH₂O/l/s, , R_5-20 1.1+/-0.7 cmH₂O /l/s, X₅ -2.0+/-0.8 cmH₂O /l/s); these residual oscillometric abnormalities were present in 11/22 subjects. Residual airway dysfunction was demonstrated by low specific conductance (assessed at 5HZ) despite restoration of FRC to supranormal values. Conclusions: Distal airway dysfunction persisted following weight loss and was not attributable to persistent mass loading in a subgroup of patients without clinical evidence of airway disease. These abnormalities may represent either functional abnormalities due to persistent obesity and/or intrinsic airway disease

Introduction: Fragmented sleep and altered circadian rhythm in critically ill patients have been linked to an increased risk of delirium. Modifiable environmental factors such as nighttime noise, light and patient-staff interactions may influence normal sleep architecture. The present study is aimed at evaluating the influence of these factors on the occurrence of delirium and perception of sleep quality in critically ill patients during the postoperative period. Methods: 38 patients admitted to the Surgical ICU were included. Noise levels, light levels and patient-staff interactions were recorded daily between 10PM and 6 AM. Sleep quality was assessed using the Richards Campell Sleep Questionnaire (RCSQ). The Confusion Assessment Method for the ICU (CAM-ICU) was performed daily to evaluate for postoperative delirium. APACHE II scores and length of stay were recorded on all patients. Results: 38 patients were studied for a total 177 patient/nights. Mean length of stay was 4.66 days and mean APACHE II score was 9.89. Patient care interactions occurred on average 16.18 times/night. Mean RCSQ score was rated at 30.67/50. The main factors perceived by patients as sleep disruptors were patient care activities (20.7% patient/nights) and noise (12.14% patient/nights). No patient reported light as a significant disruptor. In 55% of patient/nights recorded, no sleep disruptors were reported. Nighttime light levels averaged 87 Lux and light levels were greater than 100 Lux an average of 85 minutes/night. Noise peaks >80dB occurred on average 1055 times/night. Mean sound level pressure (Leq) was 56.72dBA. 9/38 patients (23.68%) developed postoperative delirium during their ICU stay. A significant correlation between APACHE II scores and occurrence of delirium was observed (p=0.008). Additionally, subjects with higher APACHE scores had greater LOS (r=0.48, p=0.002) and required more patient care activities (r=0.44, p=0.007). However, no correlation was found between the occurrence of delirium and average lux levels, time with light levels >100 lux, number of patient care activities, number of peak noise levels >80dB or Leq (p=0.52, p=0.18, p=0.16, p=0.19 and p=0.18, respectively). Similarly, no correlation was demonstrated between environmental factors and RCSQ scores or between RCSQ scores and the presence of delirium. Conclusions: This study suggests that adopting strategies aimed at limiting noise, diminishing light and regulating patient care activities may have little impact in preventing the occurrence of delirium or in improving patients' perception of sleep quality in the postoperative period. Other factors that modify sleep architecture such as disease severity seem to play a more important role

The attack on the World Trade Center (WTC) on 9/11/2001 produced a massive dust cloud with acute exposure, and the rubble pile burning over 3 months exposed more than 300,000 residents, rescue workers, and clean-up workers. Firefighters in the New York City Fire Department had significant respiratory symptoms characterized by cough, dyspnea, gastroesophageal reflux, and nasal stuffiness with a significant 1-year decline in FVC and FEV(1). Bronchial hyperreactivity measured by methacholine challenge correlated with bronchial wall thickening on CT scans. Compared with the NHANES III data for FVC and FEV(1), 32% of 2,000 WTC dust-exposed residents and clean-up workers were below the lower 5th percentile. The most common abnormality was a low FVC pattern, a finding similar to that also described for individuals in rescue and recovery activities. Among those complaining of respiratory symptoms and normal spirometry, almost half had abnormalities detected with impedance oscillometry consistent with distal airways' disease. Follow-up with the WTC Health Registry and the WTC Environmental Health Center will help discern whether treatment with anti-inflammatory medications or bronchodilators in those with respiratory symptoms may prevent the development of chronic obstructive pulmonary disease