Faculty Bibliography

INTRODUCTION: Impulse oscillometry (IOS) has been used to demonstrate distal airway dysfunction in symptomatic WTC exposed patients despite normal spirometry. However, it remains to be determined whether the respiratory symptoms can be attributed to the observed functional abnormalities. The present study was designed to assess the simultaneous relationship between the onset of respiratory symptoms and IOS abnormalities in patients undergoing bronchoprovocation for diagnostic evaluation. METHODS: Methacholine challenge testing (MCT) was performed in 113 symptomatic WTC dust exposed patients with normal spirometry that were enrolled WTC Environmental Health Center treatment program. In addition to spirometry, the MCT protocol included performance of IOS and assessment of respiratory symptoms (cough, dyspnea, chest tightness). IOS parameters included resistance at 5 and 20Hz (R⁵ and R₂₀) and frequency dependence of resistance assessed as the difference between these parameters (R_5-20). The PC20 for FEV₁, was used to categorize bronchial hyperreactivity (BHR) as negative (>16mg/ml), borderline (4-16mg/ml) or positive (<4mg/ml). RESULTS: The cohort was 58% female with mean age 49+/-12yr and BMI 29+/-5 kg/m². Baseline spirometry was within normal limits (FEV₁ 98+/-13% predicted, FEV₁/FVC 80+/-4%). Approximately 58% demonstrated abnormal baseline R₅ or R_5-20 indicating respiratory dysfunction despite normal spirometry. MCT revealed BHR, as assessed by spirometry, in 49/113 patients (43%). An additional 27 patients became symptomatic at methacholine doses <4mg/ml despite minimal change in FEV₁ (<5% decrement). All of these patients demonstrated increased R₅, R₂₀ and R_5-20 that coincided with onset of symptoms; median (IQR) increases were 23% (16-41), 13% (7-20), and 92% (39-138), respectively. Following bronchodilator administration, respiratory symptoms resolved and IOS parameters returned towards baseline. CONCLUSIONS: During bronchoprovocation, development of symptoms may coincide with development of distal airway dysfunction as assessed by IOS, even in absence of change in FEV₁. Findings reversed with bronchodilator administration reinforcing the link between symptoms and distal airway dysfunction

Rationale: Early COPD is characterized by inflammation leading to lung destruction. Recent data supports that enrichment of the lung microbiome with supraglottic characteristic taxa (SCT) is associated with inflammation. We hypothesize that in subjects with early COPD, areas at higher risk for microaspiration (right) or with greater degree of parenchymal abnormalities will be enriched with SCT or potential pathogenic taxa (PPT) compared to their contralateral lung segment. Methods: Subjects with early emphysema were enrolled for research bronchoscopy from the NYU/EDRN cohort. An independent radiologist semiquantitatively assessed all Chest CT scans: six-point score based on the presence of parenchymal damage in three zones (upper, middle, and lower). Broncho-alveolar lavages (BAL) were obtained from the right middle lobe and lingula segments. Sequencing 16S rDNA performed with 454 pyrosequence. Results: A total of 15 subjects with early COPD were studied. CT scans demonstrated n=7 with normal lower zones and n=8 with symmetrical or asymmetrical emphysema in the lower zones (p=ns). We used Wilcoxon paired comparisons to analyze the microbiome in areas of greater degree of parenchymal abnormalities (if asymmetric) or right compared to the contralateral lung segment. Data showed that the areas of greater abnormalities or right were associated with increased relative abundance (RA) of Haemophilus (RA 0.00170+/-0.002 vs. 0.00084+/-0.001, p=0.04), Neisseria (RA 0.0048+/-0.005 vs. 0.0023+/-0.003, p=0.028), Parvimonas (RA 0.017+/-0.003 vs. 0.0002+/-0.0008, p=0.05), and Serratia (RA 0.0122+/-0.02 vs. 0.0033+/-0.003, p=0.03) compared with the contralateral segment. Streptococcus appeared not to have a predilection for at-risk segments at the genus level. However, at the OTU level, Streptococcus mitis and Streptococcus pneumoniae species were higher in lung segments with more emphysema or right lung segments. Conclusions: Our data shows that areas of greater parenchymal damage or at higher risk for microaspiration (right) are enriched with potentially pathogenic taxa, such as Parvimonas, Neisseria, Haemophilus, Serratia, and Streptococcus. These taxa are known to be in high relative abundance in the oral and supraglottic region. Some of these taxa have been found to be at higher RA after viral infections, suggesting that enrichment of these low relative abundance taxa may play a critical role in disease. However, other supraglottic characteristic taxa such as Prevotella and Veillonella were not increased in these regions. These observations suggest a distinct selection pressure between the upper and lower airway microbiome

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 lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils. RESULTS: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, alpha, or beta diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022). CONCLUSION: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.

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.

BACKGROUND: This section of the guidelines is intended to provide an evidence-based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer. METHODS: The current guidelines and medical literature applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee. RESULTS: The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (Dlco). Predicted postoperative (PPO) lung functions should be calculated. If the % PPO FEV1 and % PPO Dlco values are both > 60%, the patient is considered at low risk of anatomic lung resection, and no further tests are indicated. If either the % PPO FEV1 or % PPO Dlco are within 60% and 30% predicted, a low technology exercise test should be performed as a screening test. If performance on the low technology exercise test is satisfactory (stair climbing altitude > 22 m or shuttle walk distance > 400 m), patients are regarded as at low risk of anatomic resection. A cardiopulmonary exercise test is indicated when the PPO FEV1 or PPO Dlco (or both) are < 30% or when the performance of the stair-climbing test or the shuttle walk test is not satisfactory. A peak oxygen consumption (V O2peak) < 10 mL/kg/min or 35% predicted indicates a high risk of mortality and long-term disability for major anatomic resection. Conversely, a V O2peak > 20 mL/kg/min or 75% predicted indicates a low risk. CONCLUSIONS: A careful preoperative physiologic assessment is useful for identifying those patients at increased risk with standard lung cancer resection and for enabling an informed decision by the patient about the appropriate therapeutic approach to treating his or her lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment of this disease.

MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.