Faculty Bibliography

Alveolar hypoventilation defined by an increase in PaCO2 occurs due to either reduced minute ventilation and/or increased dead space. Mild alveolar hypoventilation may be observed in healthy subjects during sleep. Sleep hypoventilation is accentuated in disease states with potential carryover to the daytime, producing chronic hypercapnia during wakefulness due to failure of compensation during sleep and/or during wakefulness. Elevation of blood bicarbonate concentration, although appropriate to defend blood pH, provides a mechanism for perpetuation of a chronic hypercapnic state due to blunting of respiratory drive. 2014 Elsevier Inc. All rights reserved

BACKGROUND: In order to develop clinical reasoning, medical students must be able to integrate knowledge across traditional subject boundaries and multiple disciplines. At least two dimensions of integration have been identified: horizontal integration, bringing together different disciplines in considering a topic; and vertical integration, bridging basic science and clinical practice. Much attention has been focused on curriculum overhauls, but our approach is to facilitate horizontal and vertical integration on a smaller scale through an interdisciplinary case study discussion and then to assess its utility. METHODS: An interdisciplinary case study discussion about a critically ill patient was implemented at the end of an organ system-based, basic sciences module at New York University School of Medicine. Three clinical specialists-a cardiologist, a pulmonologist, and a nephrologist-jointly led a discussion about a complex patient in the intensive care unit with multiple medical problems secondary to septic shock. The discussion emphasized the physiologic underpinnings behind the patient's presentation and the physiologic considerations across the various systems in determining proper treatment. The discussion also highlighted the interdependence between the cardiovascular, respiratory, and renal systems, which were initially presented in separate units. After the session students were given a brief, anonymous three-question free-response questionnaire in which they were asked to evaluate and freely comment on the exercise. RESULTS: Students not only took away physiological principles but also gained an appreciation for various thematic lessons for bringing basic science to the bedside, especially horizontal and vertical integration. The response of the participants was overwhelmingly positive with many indicating that the exercise integrated the material across organ systems, and strengthened their appreciation of the role of physiology in understanding disease presentations and guiding appropriate therapy. CONCLUSIONS: Horizontal and vertical integration can be presented effectively through a single-session case study, with complex patient cases involving multiple organ systems providing students opportunities to integrate their knowledge across organ systems while emphasizing the importance of physiology in clinical reasoning. Furthermore, having several clinicians from different specialties discuss the case together can reinforce the matter of integration across multiple organ systems and disciplines in students' minds.

Oral flora are frequently found in normal individuals' lungs without known harm. We hypothesize that a lung microbiome enriched by oral taxa would be associated with a higher degree of inflammation. We studied 29 asymptomatic subjects (9 nonsmokers and 20 smokers) with preserved lung function. Nasal bronchoscopy was performed with two separate bronchoscopes to retrieve supraglotic and lower airway samples. Bronchoalveolar lavage (BAL) cell count, BAL cytokines (Luminex), and exhaled nitric oxide defined pulmonary inflammation. Quantitative PCR measured 16S rRNA gene concentration and 454 sequences defined the microbiome. Supraglotic samples had the highest 16S rRNA concentration, BAL was intermediate, and saline used for the BAL had the lowest concentration. Nonsmokers and smokers were similar in BAL cell differential and lung microbiome. BAL samples segregated into two distinct groups that we called pneumotypes. Pneumotype background predominant taxa (pneumotypeBPT) was similar to the saline background in rDNA concentration or microbial community. Pneumotype supraglotic-characteristic taxa (pneumotypeSCT) has higher rDNA concentration and high relative abundance of SCT, such as Prevotella and Veillonella. PneumotypeSCT was associated with multiple measures of lung inflammation, including higher BAL neutrophils, IL-8, and levels of exhaled nitric oxide. PneumotypeSCT also had higher BAL lymphocytes and fractalkine, a chemokine that correlates with T helper type 17:T regulatory cell ratio in the BAL. These data suggest that a pneumotype with high relative abundance of supraglotic bacteria, such as Prevotella and Veillonella, is associated with increased innate and cellular inflammation.

INTRODUCTION: Abnormality in distal lung function may occur in obesity due to reduction in resting lung volume; however, airway inflammation, vascular congestion and/or concomitant intrinsic airway disease may also be present. The goal of this study is to 1) describe the phenotype of lung function in obese subjects utilizing spirometry, plethysmography and oscillometry; and 2) evaluate residual abnormality when the effect of mass loading is removed by voluntary elevation of end expiratory lung volume (EELV) to predicted FRC. METHODS: 100 non-smoking obese subjects without cardio-pulmonary disease and with normal airflow on spirometry underwent impulse oscillometry (IOS) at baseline and at the elevated EELV. RESULTS: FRC and ERV were reduced (44+/-22, 62+/-14% predicted) with normal RV/TLC (29+/-9%). IOS demonstrated elevated resistance at 20 Hz (R20, 4.65+/-1.07 cmH2O/L/s); however, specific conductance was normal (0.14+/-0.04). Resistance at 5-20 Hz (R5-20, 1.86+/-1.11 cmH2O/L/s) and reactance at 5 Hz (X5, -2.70+/-1.44 cmH2O/L/s) were abnormal. During elevation of EELV, IOS abnormalities reversed to or towards normal. Residual abnormality in R5-20 was observed in some subjects despite elevation of EELV (1.16+/-0.8 cmH2O/L/s). R5-20 responded to bronchodilator at baseline but not during elevation of EELV. CONCLUSIONS: This study describes the phenotype of lung dysfunction in obesity as reduction in FRC with airway narrowing, distal respiratory dysfunction and bronchodilator responsiveness. When R5-20 normalized during voluntary inflation, mass loading was considered the predominant mechanism. In contrast, when residual abnormality in R5-20 was demonstrable despite return of EELV to predicted FRC, mechanisms for airway dysfunction in addition to mass loading could be invoked.

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