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Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate COPD

Sulaiman, Imran; Wu, Benjamin G; Chung, Matthew; Isaacs, Bradley; Tsay, Jun-Chieh J; Holub, Meredith; Barnett, Clea R; Kwok, Benjmain; Kugler, Matthias C; Natalini, Jake G; Singh, Shivani; Li, Yonghua; Schluger, Rosemary; Carpenito, Joseph; Collazo, Destiny; Perez, Luisanny; Kyeremateng, Yaa; Chang, Miao; Campbell, Christina D; Hansbro, Philip M; Oppenheimer, Beno W; Berger, Kenneth I; Goldring, Roberta M; Koralov, Sergei B; Weiden, Michael D; Xiao, Rui; D'Armiento, Jeanine; Clemente, Jose C; Ghedin, Elodie; Segal, Leopoldo N
RATIONALE/BACKGROUND:Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality and health care costs. Cigarette smoke is a causative factor, however not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advance stages. OBJECTIVE:Here we investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. METHODS:We recruited 57 patients with >10 pack year smoking history: 26 had physiological evidence of COPD, 31 had normal lung function (smoker controls). Bronchoscopy sampled the upper airways (UA), lower airways (BAL) and environmental background (BKG). Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. MEASUREMENTS/MAIN RESULTS/RESULTS:Compared with smoker controls, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1 and MUC4 in mild-to-moderate COPD. Finally, in a pre-clinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury revealing transcriptomic signatures similar to those observed in human COPD subjects. CONCLUSIONS:Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.
PMID: 37677136
ISSN: 1535-4970
CID: 5573582

Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy

Morris, Alan H; Horvat, Christopher; Stagg, Brian; Grainger, David W; Lanspa, Michael; Orme, James; Clemmer, Terry P; Weaver, Lindell K; Thomas, Frank O; Grissom, Colin K; Hirshberg, Ellie; East, Thomas D; Wallace, Carrie Jane; Young, Michael P; Sittig, Dean F; Suchyta, Mary; Pearl, James E; Pesenti, Antinio; Bombino, Michela; Beck, Eduardo; Sward, Katherine A; Weir, Charlene; Phansalkar, Shobha; Bernard, Gordon R; Thompson, B Taylor; Brower, Roy; Truwit, Jonathon; Steingrub, Jay; Hiten, R Duncan; Willson, Douglas F; Zimmerman, Jerry J; Nadkarni, Vinay; Randolph, Adrienne G; Curley, Martha A Q; Newth, Christopher J L; Lacroix, Jacques; Agus, Michael S D; Lee, Kang Hoe; deBoisblanc, Bennett P; Moore, Frederick Alan; Evans, R Scott; Sorenson, Dean K; Wong, Anthony; Boland, Michael V; Dere, Willard H; Crandall, Alan; Facelli, Julio; Huff, Stanley M; Haug, Peter J; Pielmeier, Ulrike; Rees, Stephen E; Karbing, Dan S; Andreassen, Steen; Fan, Eddy; Goldring, Roberta M; Berger, Kenneth I; Oppenheimer, Beno W; Ely, E Wesley; Pickering, Brian W; Schoenfeld, David A; Tocino, Irena; Gonnering, Russell S; Pronovost, Peter J; Savitz, Lucy A; Dreyfuss, Didier; Slutsky, Arthur S; Crapo, James D; Pinsky, Michael R; James, Brent; Berwick, Donald M
How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.
PMID: 36125018
ISSN: 1527-974x
CID: 5335342

Clinical significance and applications of oscillometry

Kaminsky, David A; Simpson, Shannon J; Berger, Kenneth I; Calverley, Peter; de Melo, Pedro L; Dandurand, Ronald; Dellacà, Raffaele L; Farah, Claude S; Farré, Ramon; Hall, Graham L; Ioan, Iulia; Irvin, Charles G; Kaczka, David W; King, Gregory G; Kurosawa, Hajime; Lombardi, Enrico; Maksym, Geoffrey N; Marchal, François; Oostveen, Ellie; Oppenheimer, Beno W; Robinson, Paul D; van den Berge, Maarten; Thamrin, Cindy
Recently, "Technical standards for respiratory oscillometry" was published, which reviewed the physiological basis of oscillometric measures and detailed the technical factors related to equipment and test performance, quality assurance and reporting of results. Here we present a review of the clinical significance and applications of oscillometry. We briefly review the physiological principles of oscillometry and the basics of oscillometry interpretation, and then describe what is currently known about oscillometry in its role as a sensitive measure of airway resistance, bronchodilator responsiveness and bronchial challenge testing, and response to medical therapy, particularly in asthma and COPD. The technique may have unique advantages in situations where spirometry and other lung function tests are not suitable, such as in infants, neuromuscular disease, sleep apnoea and critical care. Other potential applications include detection of bronchiolitis obliterans, vocal cord dysfunction and the effects of environmental exposures. However, despite great promise as a useful clinical tool, we identify a number of areas in which more evidence of clinical utility is needed before oscillometry becomes routinely used for diagnosing or monitoring respiratory disease.
PMID: 35140105
ISSN: 1600-0617
CID: 5156832

Enabling a learning healthcare system with automated computer protocols that produce replicable and personalized clinician actions

Morris, Alan H; Stagg, Brian; Lanspa, Michael; Orme, James; Clemmer, Terry P; Weaver, Lindell K; Thomas, Frank; Grissom, Colin K; Hirshberg, Ellie; East, Thomas D; Wallace, Carrie Jane; Young, Michael P; Sittig, Dean F; Pesenti, Antonio; Bombino, Michela; Beck, Eduardo; Sward, Katherine A; Weir, Charlene; Phansalkar, Shobha S; Bernard, Gordon R; Taylor Thompson, B; Brower, Roy; Truwit, Jonathon D; Steingrub, Jay; Duncan Hite, R; Willson, Douglas F; Zimmerman, Jerry J; Nadkarni, Vinay M; Randolph, Adrienne; Curley, Martha A Q; Newth, Christopher J L; Lacroix, Jacques; Agus, Michael S D; Lee, Kang H; deBoisblanc, Bennett P; Scott Evans, R; Sorenson, Dean K; Wong, Anthony; Boland, Michael V; Grainger, David W; Dere, Willard H; Crandall, Alan S; Facelli, Julio C; Huff, Stanley M; Haug, Peter J; Pielmeier, Ulrike; Rees, Stephen E; Karbing, Dan S; Andreassen, Steen; Fan, Eddy; Goldring, Roberta M; Berger, Kenneth I; Oppenheimer, Beno W; Wesley Ely, E; Gajic, Ognjen; Pickering, Brian; Schoenfeld, David A; Tocino, Irena; Gonnering, Russell S; Pronovost, Peter J; Savitz, Lucy A; Dreyfuss, Didier; Slutsky, Arthur S; Crapo, James D; Angus, Derek; Pinsky, Michael R; James, Brent; Berwick, Donald
Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention-the starting point for delivery of "All the right care, but only the right care," an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.
PMID: 33594410
ISSN: 1527-974x
CID: 4786872

Isolated small airway dysfunction in patients with unexplained dyspnea on exertion [Meeting Abstract]

Sharpe, A L; Weinstein, T; Reibman, J; Goldring, R M; Liu, M; Shao, Y; Oppenheimer, B W; Bohart, I; Berger, K I
Introduction: Exertional respiratory symptoms are prominent in patients with environmental lung injury following inhalation of World Trade Center dust. Baseline pulmonary function testing in these patients is frequently normal, leaving symptoms unexplained. Although small airway dysfunction has been identified at rest, its role in producing exertional symptoms is unclear. In this study exercise evaluation with assessment of airway function was employed to uncover mechanisms for exertional dyspnea.
Method(s): 27 subjects were studied: 20 with unexplained dyspnea (normal spirometry) and 6 asymptomatic controls. Baseline pulmonary function testing was conducted along with respiratory oscillometry to assess small airway function. An incremental exercise protocol was performed that included a focused evaluation of airway function: (1) examination of tidal flow vs. volume curves during exercise to assess for dynamic hyperinflation and expiratory flow limitation; and (2) airway reactivity post-exercise using spirometry and oscillometry. Baseline: By design spirometry values were within normal limits in all subjects. Symptomatic individuals tended to have greater mean R5, R20, R5-20, and AX at baseline compared with asymptomatic controls (R5: 4.80+/-1.79 vs. 3.66+/-1.06; R20: 3.52+/-1.12 vs. 2.98+/-0.68; R5-20: 1.28+/-1.02 vs. 0.70+/-0.53; AX: 13.44+/-10.74 vs. 5.48+/-5.21). Exercise: Dyspnea was reproduced with exercise in symptomatic subjects (mean Borg dyspnea score 1.38+/-1.48 at baseline, 4.20+/-2.28 at peak exercise). Asymptomatic controls did not report significant dyspnea (mean Borg dyspnea score 0 at baseline, 1.60+/-1.14 at peak exercise). Expiratory flow limitation during exercise was noted in 13/20 symptomatic subjects compared with 0 controls. Post Exercise: Bronchial hyper-reactivity was evident in post-exercise spirometry (>10% decline in FEV1) in 3/20 symptomatic subjects vs. 1/6 controls; the fall in FEV1 was predominantly attributable to a fall in FVC, consistent with small airway dysfunction. An additional six symptomatic subjects demonstrated isolated small airway hyper-reactivity that was only revealed on oscillometry.
Conclusion(s): In patients with unexplained dyspnea and normal spirometry, symptoms were reproduced during exercise. Focused airway assessment uncovered small airway dysfunction both during and following exercise that contributed to the development of dyspnea
ISSN: 1535-4970
CID: 4915612

Respiratory impedance measured using impulse oscillometry in a healthy urban population

Berger, Kenneth I; Wohlleber, Margaret; Goldring, Roberta M; Reibman, Joan; Farfel, Mark R; Friedman, Stephen M; Oppenheimer, Beno W; Stellman, Steven D; Cone, James E; Shao, Yongzhao
This study derives normative prediction equations for respiratory impedance in a healthy asymptomatic urban population using an impulse oscillation system (IOS). In addition, this study uses body mass index (BMI) in the equations to describe the effect of obesity on respiratory impedance. Data from an urban population comprising 472 healthy asymptomatic subjects that resided or worked in lower Manhattan, New York City were retrospectively analysed. This population was the control group from a previously completed case-control study of the health effects of exposure to World Trade Center dust. Since all subjects underwent spirometry and oscillometry, these previously collected data allowed a unique opportunity to derive normative prediction equations for oscillometry in an urban, lifetime non-smoking, asymptomatic population without underlying respiratory disease. Normative prediction equations for men and women were successfully developed for a broad range of respiratory oscillometry variables with narrow confidence bands. Models that used BMI as an independent predictor of oscillometry variables (in addition to age and height) demonstrated equivalent or better fit when compared with models that used weight. With increasing BMI, resistance and reactance increased compatible with lung and airway compression from mass loading. This study represents the largest cohort of healthy urban subjects assessed with an IOS device. Normative prediction equations were derived that should facilitate application of IOS in the clinical setting. In addition, the data suggest that modelling of lung function may be best performed using height and BMI as independent variables rather than the traditional approach of using height and weight.
PMID: 33816605
ISSN: 2312-0541
CID: 4838882

Exercise-Induced Small Airway Dysfunction Detected by Oscillometry Uncovers Mechanisms for Unexplained Dyspnea [Meeting Abstract]

Sharpe, A. L.; Oppenheimer, B. W.; Goldring, R. M.; Sterman, D. H.; Addrizzo-Harris, D. J.; Weinstein, T.; Kwok, B.; Bohart, I.; Berger, K. I.
ISSN: 1073-449x
CID: 5266052

Increased Dead Space Ventilation and Refractory Hypercapnia in Patients With Coronavirus Disease 2019: A Potential Marker of Thrombosis in the Pulmonary Vasculature [Case Report]

Oppenheimer, Beno W; Bakker, Jan; Goldring, Roberta M; Teter, Katherine; Green, David L; Berger, Kenneth I
Objectives/UNASSIGNED:Mortality rates in intubated coronavirus disease 2019 patients remain markedly elevated. Some patients develop sudden refractory hypercapnia and hypoxemia not explained by worsening pulmonary parenchymal disease. This case series highlights clinical findings and management of coronavirus disease 2019 patients with refractory hypercapnia despite maximal/optimal ventilatory support. Hypercapnia could not be explained by worsening lung disease or other common factors, and thus, a pulmonary vascular etiology was suggested. The pillars of management were targeted to improve pulmonary vascular patency via aggressive anticoagulation and support right ventricular function. Data Sources/UNASSIGNED:Four consecutive patients with confirmed coronavirus disease 2019 infection with sudden hypercapnia and hypoxemia were included. Data Synthesis/UNASSIGNED:removal was discontinued in three patients over the ensuing 3 weeks, and one patient was discharged home. Conclusions/UNASSIGNED:We speculate that thromboinflammation with pulmonary microvasculature occlusion leads to a sudden increase in dead space and shunt resulting in severe hypercapnia and hypoxemia in coronavirus disease 2019 patients. Early identification of these physiologic and clinical biomarkers could trigger the institution of therapies aiming to reverse the hypercoagulable state and support right ventricular function.
PMID: 33063042
ISSN: 2639-8028
CID: 4641672

Small airway function in obese individuals with self-reported asthma

Oppenheimer, Beno W; Goldring, Roberta M; Soghier, Israa; Smith, David; Parikh, Manish; Berger, Kenneth I
Diagnosis of asthma in obese individuals frequently relies on clinical history, as airflow by spirometry may remain normal. This study hypothesised that obese subjects with self-reported asthma and normal spirometry will demonstrate distinct clinical characteristics, metabolic comorbidities and enhanced small airway dysfunction as compared with healthy obese subjects. Spirometry, plethysmography and oscillometry data pre/post-bronchodilator were obtained in 357 obese subjects in three groups as follows: no asthma group (n=180), self-reported asthma normal spirometry group (n=126), and asthma obstructed spirometry group (n=51). To assess the effects of obesity related to reduced lung volume, oscillometry measurements were repeated during a voluntary inflation to predicted functional residual capacity (FRC). Dyspnoea was equally prevalent in all groups. In contrast, cough, wheeze and metabolic comorbidities were more frequent in the asthma normal spirometry and asthma obstructed spirometry groups versus the no asthma group (p<0.05). Despite similar body size, oscillometry measurements demonstrated elevated R5-20 (difference between resistance at 5 and 20 Hz) in the no asthma and asthma normal spirometry groups (0.19±0.12; 0.23±0.13 kPa/(L·s-1), p<0.05) but to a lesser degree than the asthma obstructed spirometry group (0.34±0.20 kPa/(L·s-1), p<0.05). Differences between groups persisted post-bronchodilator (p<0.05). Following voluntary inflation to predicted FRC, R5-20 in the no asthma and asthma normal spirometry groups fell to similar values, indicating a reversible process (0.11±0.07; 0.12±0.08 kPa/(L·s-1), p=NS). Persistently elevated R5-20 was seen in the asthma obstructed spirometry group, suggesting chronic inflammation and/or remodelling (0.17±0.11 kPa/(L·s-1), p<0.05). Thus, small airway abnormalities of greater magnitude than observations in healthy obese people may be an early marker of asthma in obese subjects with self-reported disease despite normal airflow. Increased metabolic comorbidities in these subjects may have provided a milieu that impacted airway function.
PMID: 32714957
ISSN: 2312-0541
CID: 4540052

Technical Standards for Respiratory Oscillometry

King, Gregory G; Bates, Jason; Berger, Kenneth I; Calverley, Peter; de Melo, Pedro L; Dellacà, Raffaele L; Farré, Ramon; Hall, Graham L; Ioan, Iulia; Irvin, Charles G; Kaczka, David W; Kaminsky, David A; Kurosawa, Hajime; Lombardi, Enrico; Maksym, Geoffrey N; Marchal, François; Oppenheimer, Beno W; Simpson, Shannon J; Thamrin, Cindy; van den Berge, Maarten; Oostveen, Ellie
PMID: 31772002
ISSN: 1399-3003
CID: 4215932