Publications by authors named "Leopoldo N Segal"

50 Publications

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

medRxiv 2021 Feb 26. Epub 2021 Feb 26.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
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http://dx.doi.org/10.1101/2021.02.23.21252221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924286PMC
February 2021

Crossing Kingdoms: Host-Microbial Endotyping and the Quest to Understand Treatable Traits in COPD.

Am J Respir Crit Care Med 2021 Mar 2. Epub 2021 Mar 2.

University of Michigan, 1259, Pulmonary/Critical Care, Ann Arbor, Michigan, United States;

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http://dx.doi.org/10.1164/rccm.202101-0169EDDOI Listing
March 2021

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases.

J Allergy Clin Immunol 2021 Jan 22. Epub 2021 Jan 22.

Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, TX 78229; Foundation for Advancing Veterans' Health Research, South Texas Veterans Health Care System, San Antonio, TX 78229; Department of Microbiology, Immunology & Molecular Genetics, UT Health San Antonio, San Antonio, TX 78229; Department of Medicine, UT Health San Antonio, San Antonio, TX 78229; Departments of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, TX 78229. Electronic address:

Background: Signifying the two-compartments/one-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (e.g., house dust mites (HDMs)). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resistance or adaptation.

Objective: Determine if ARC/AA severity relates to maladaptive responses to disease triggers.

Methods: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber; associated mechanistic traits were identified.

Results: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity correlated with CD8+ T-cells, whereas airway inflammation correlated with CD8+ T-cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased NK and CD8+ cells, lower CD4+ MAIT cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models.

Conclusions: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

Clinical Implications: The wide variation in allergic rhinoconjunctivitis disease severity may be underpinned by an imbalance in epithelial integrity and inflammation manifesting as maladaptation to disease triggers such as house dust mites.
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http://dx.doi.org/10.1016/j.jaci.2021.01.008DOI Listing
January 2021

Functional lower airways genomic profiling of the microbiome to capture active microbial metabolism.

Eur Respir J 2021 Jan 14. Epub 2021 Jan 14.

Division of Pulmonary, Critical Care, & Sleep Medicine, Department of Medicine, New York University School of Medicine, NY, USA

Rationale: Microbiome studies of the lower airway based on bacterial 16S rRNA gene sequencing assess microbial community structure but can only infer functional characteristics. Microbial products, such as short chain fatty acids (SCFAs), in the lower airways have significant impact on the host's immune tone. Thus, functional approaches to the analyses of the microbiome are necessary.

Methods: Here we used upper and lower airway samples from a research bronchoscopy smoker cohort. In addition, we validated our results in an experimental mouse model.

Measurements: We extended our microbiota characterisation beyond 16S rRNA gene sequencing with the use of whole genome (WGS) and RNA metatranscriptome sequencing. Short chain fatty acids (SCFA) were also measured in lower airway samples and correlated with each of the sequencing datasets. In the mouse model, 16S rRNA gene and RNA metatranscriptome sequencing were performed.

Main Results: Functional evaluations of the lower airway microbiota using inferred metagenome, WGS and metatranscriptome were dissimilar. Comparison with measured levels of SCFAs shows that the inferred metagenome from the 16S rRNA gene sequencing data was poorly correlated, while better correlations were noted when SCFAs levels were compared with WGS and metatranscriptome. Modelling lower airway aspiration with oral commensals in a mouse model showed that the metatranscriptome most efficiently captures transient active microbial metabolism, which was overestimated by 16S rRNA gene sequencing.

Conclusions: Functional characterisation of the lower airway microbiota through metatranscriptome identify metabolically active organisms capable of producing metabolites with immunomodulatory capacity such as SCFAs.
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http://dx.doi.org/10.1183/13993003.03434-2020DOI Listing
January 2021

Lower Airway Dysbiosis Affects Lung Cancer Progression.

Cancer Discov 2021 Feb 11;11(2):293-307. Epub 2020 Nov 11.

Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York.

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB-IV tumor-node-metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858243PMC
February 2021

Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary Th17 Response that Mitigates Susceptibility to .

Am J Respir Crit Care Med 2020 Nov 9. Epub 2020 Nov 9.

New York University, Pulmonary and Critical Care Medicine, New York, New York, United States;

Rationale Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with increased Th17 inflammatory phenotype. In this study we evaluated the microbial and host immune response dynamics after aspiration with a oral commensals using a preclinical mouse model. Methods Aspiration with a mixture of human oral commensals (MOC; Prevotella melaninogenica, Veillonella parvula, and Streptococcus mitis) was modeled in mice followed by variable time of sacrifice. Genetic background of mice included WT, MyD88 knock out and STAT3C. Measurements 16S rRNA gene sequencing characterized changes in microbiota. Flow cytometry, cytokine measurement via Luminex and RNA host transcriptome sequencing was used to characterize host immune phenotype. Main Results While MOC aspiration correlated with lower airway dysbiosis that resolved within five days, it induced an extended inflammatory response associated with IL17-producing T-cells lasting at least 14 days. MyD88 expression was required for the IL-17 response to MOC aspiration, but not for T-cell activation or IFN-γ expression. MOC aspiration prior to a respiratory challenge with S. pneumoniae led to a decreased in host's susceptibility to this pathogen. Conclusions Thus, in otherwise healthy mice, a single aspiration event with oral commensals are rapidly cleared from the lower airways, but induce a prolonged Th17 response that secondarily decreased susceptibility to respiratory pathogens. Translationally, these data implicate an immuno-protective role of episodic microaspiration of oral microbes in the regulation of the lung immune phenotype and mitigation of host susceptibility to infection with lower airway pathogens.
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http://dx.doi.org/10.1164/rccm.202005-1596OCDOI Listing
November 2020

The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2021 02;203(3):339-347

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP. To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects. We prospectively recruited individuals with a CHP diagnosis ( = 110), individuals with an IPF diagnosis ( = 45), and control subjects ( = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways. Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included , , , and . However, in IPF, dominated, whereas the percentage of reads assigned to in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the burden was increased in CHP, and and burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.
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http://dx.doi.org/10.1164/rccm.202002-0460OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874329PMC
February 2021

Evidence for Environmental-Human Microbiota Transfer at a Manufacturing Facility with Novel Work-related Respiratory Disease.

Am J Respir Crit Care Med 2020 12;202(12):1678-1688

Department of Medicine and.

Workers' exposure to metalworking fluid (MWF) has been associated with respiratory disease. As part of a public health investigation of a manufacturing facility, we performed a cross-sectional study using paired environmental and human sampling to evaluate the cross-pollination of microbes between the environment and the host and possible effects on lung pathology present among workers. Workplace environmental microbiota were evaluated in air and MWF samples. Human microbiota were evaluated in lung tissue samples from workers with respiratory symptoms found to have lymphocytic bronchiolitis and alveolar ductitis with B-cell follicles and emphysema, in lung tissue samples from control subjects, and in skin, nasal, and oral samples from 302 workers from different areas of the facility. effects of MWF exposure on murine B cells were assessed. An increased similarity of microbial composition was found between MWF samples and lung tissue samples of case workers compared with control subjects. Among workers in different locations within the facility, those that worked in the machine shop area had skin, nasal, and oral microbiota more closely related to the microbiota present in the MWF samples. Lung samples from four index cases and skin and nasal samples from workers in the machine shop area were enriched with , the dominant taxa in MWF. Exposure to used MWF stimulated murine B-cell proliferation , a hallmark cell subtype found in the pathology of index cases. Evaluation of a manufacturing facility with a cluster of workers with respiratory disease supports cross-pollination of microbes from MWF to humans and suggests the potential for exposure to these microbes to be a health hazard.
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http://dx.doi.org/10.1164/rccm.202001-0197OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737585PMC
December 2020

Perspectives in lung microbiome research.

Curr Opin Microbiol 2020 08 2;56:24-29. Epub 2020 Jul 2.

Division of Pulmonary, Critical Care, & Sleep Medicine, Department of Medicine, New York University School of Medicine, NY, United States. Electronic address:

Our understanding of the existence and role of the lung microbiome has grown at a slower pace than other microbiome research areas. This is likely a consequence of the original dogma that the lung was a sterile environment although there are other barriers that are worth discussing. Here we will not be conducting an exhaustive review of the current literature on the lung microbiome, but rather we will focus on what we see as some important challenges that the field needs to face in order to improve our mechanistic understanding of the lung microbiome and its role on human health.
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http://dx.doi.org/10.1016/j.mib.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744389PMC
August 2020

Sputum neutrophil elastase associates with microbiota and in bronchiectasis.

Eur Respir J 2020 10 22;56(4). Epub 2020 Oct 22.

University of Milan, Dept of Pathophysiology and Transplantation, Milan, Italy.

Introduction: Neutrophilic inflammation is a major driver of bronchiectasis pathophysiology, and neutrophil elastase activity is the most promising biomarker evaluated in sputum to date. How active neutrophil elastase correlates with the lung microbiome in bronchiectasis is still unexplored. We aimed to understand whether active neutrophil elastase is associated with low microbial diversity and distinct microbiome characteristics.

Methods: An observational, cross-sectional study was conducted at the bronchiectasis programme of the Policlinico Hospital in Milan, Italy, where adults with bronchiectasis were enrolled between March 2017 and March 2019. Active neutrophil elastase was measured on sputum collected during stable state, microbiota analysed through 16S rRNA gene sequencing, molecular assessment of respiratory pathogens carried out through real-time PCR and clinical data collected.

Results: Among 185 patients enrolled, decreasing α-diversity, evaluated through the Shannon entropy (ρ -0.37, p<0.00001) and Pielou's evenness (ρ -0.36, p<0.00001) and richness (ρ -0.33, p<0.00001), was significantly correlated with increasing elastase. A significant difference in median levels of Shannon entropy as detected between patients with neutrophil elastase ≥20 µg·mL (median 3.82, interquartile range 2.20-4.96) neutrophil elastase <20 µg·mL (4.88, 3.68-5.80; p<0.0001). A distinct microbiome was found in these two groups, mainly characterised by enrichment with in the high-elastase group and with in the low-elastase group. Further confirmation of the association of with elevated active neutrophil elastase was found based on standard culture and targeted real-time PCR.

Conclusions: High levels of active neutrophil elastase are associated to low microbiome diversity and specifically to infection.
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http://dx.doi.org/10.1183/13993003.00769-2020DOI Listing
October 2020

Antisense oligonucleotide targeting of thrombopoietin represents a novel platelet depletion method to assess the immunomodulatory role of platelets.

J Thromb Haemost 2020 07 6;18(7):1773-1782. Epub 2020 May 6.

Marc and Ruti Bell Program in Vascular Biology, Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA.

Background: Platelets are effector cells of the innate and adaptive immune system; however, understanding their role during inflammation-driven pathologies can be challenging due to several drawbacks associated with current platelet depletion methods. The generation of antisense oligonucleotides (ASOs) directed to thrombopoietin (Tpo) mRNA represents a novel method to reduce circulating platelet count.

Objective: To understand if Tpo-targeted ASO treatment represents a viable strategy to specifically reduce platelet count in mice.

Methods: Female and male mice were treated with TPO-targeted ASOs and platelet count and function was assessed, in addition to circulating blood cell counts and hematopoietic stem and progenitor cells. The utility of the platelet-depletion strategy was assessed in a murine model of lower airway dysbiosis.

Results And Conclusions: Herein, we describe how in mice, ASO-mediated silencing of hepatic TPO expression reduces platelet, megakaryocyte, and megakaryocyte progenitor count, without altering platelet activity. TPO ASO-mediated platelet depletion can be achieved acutely and sustained chronically in the absence of adverse bleeding. TPO ASO-mediated platelet depletion allows for the reintroduction of new platelets, an advantage over commonly used antibody-mediated depletion strategies. Using a murine model of lung inflammation, we demonstrate that platelet depletion, induced by either TPO ASO or anti-CD42b treatment, reduces the accumulation of inflammatory immune cells, including monocytes and macrophages, in the lung. Altogether, we characterize a new platelet depletion method that can be sustained chronically and allows for the reintroduction of new platelets highlighting the utility of the TPO ASO method to understand the role of platelets during chronic immune-driven pathologies.
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http://dx.doi.org/10.1111/jth.14808DOI Listing
July 2020

Work-related adverse respiratory health outcomes at a machine manufacturing facility with a cluster of bronchiolitis, alveolar ductitis and emphysema (BADE).

Occup Environ Med 2020 06 4;77(6):386-392. Epub 2020 Mar 4.

Respiratory Health Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA

Objectives: Four machine manufacturing facility workers had a novel occupational lung disease of uncertain aetiology characterised by lymphocytic bronchiolitis, alveolar ductitis and emphysema (BADE). We aimed to evaluate current workers' respiratory health in relation to job category and relative exposure to endotoxin, which is aerosolised from in-use metalworking fluid.

Methods: We offered a questionnaire and spirometry at baseline and 3.5 year follow-up. Endotoxin exposures were quantified for 16 production and non-production job groups. Forced expiratory volume in one second (FEV) decline ≥10% was considered excessive. We examined SMRs compared with US adults, adjusted prevalence ratios (aPRs) for health outcomes by endotoxin exposure tertiles and predictors of excessive FEV decline.

Results: Among 388 (89%) baseline participants, SMRs were elevated for wheeze (2.5 (95% CI 2.1 to 3.0)), but not obstruction (0.5 (95% CI 0.3 to 1.1)). Mean endotoxin exposures (range: 0.09-28.4 EU/m) were highest for machine shop jobs. Higher exposure was associated with exertional dyspnea (aPR=2.8 (95% CI 1.4 to 5.7)), but not lung function. Of 250 (64%) follow-up participants, 11 (4%) had excessive FEV decline (range: 403-2074 mL); 10 worked in production. Wheeze (aPR=3.6 (95% CI 1.1 to 12.1)) and medium (1.3-7.5 EU/m) endotoxin exposure (aPR=10.5 (95% CI 1.3 to 83.1)) at baseline were associated with excessive decline. One production worker with excessive decline had BADE on subsequent lung biopsy.

Conclusions: Lung function loss and BADE were associated with production work. Relationships with relative endotoxin exposure indicate work-related adverse respiratory health outcomes beyond the sentinel disease cluster, including an incident BADE case. Until causative factors and effective preventive strategies for BADE are determined, exposure minimisation and medical surveillance of affected workforces are recommended.
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http://dx.doi.org/10.1136/oemed-2019-106296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404615PMC
June 2020

Looking Higher: Is It Prime Time for the Oral-Lung Axis in HIV-related Lung Disease?

Am J Respir Crit Care Med 2020 02;201(4):402-403

Department of MedicineNew York University School of MedicineNew York, New York.

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http://dx.doi.org/10.1164/rccm.201911-2170EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049914PMC
February 2020

Interleukin-17 Inhibition in Spondyloarthritis Is Associated With Subclinical Gut Microbiome Perturbations and a Distinctive Interleukin-25-Driven Intestinal Inflammation.

Arthritis Rheumatol 2020 04 12;72(4):645-657. Epub 2020 Mar 12.

New York University School of Medicine, New York, New York.

Objective: To characterize the ecological effects of biologic therapies on the gut bacterial and fungal microbiome in psoriatic arthritis (PsA)/spondyloarthritis (SpA) patients.

Methods: Fecal samples from PsA/SpA patients pre- and posttreatment with tumor necrosis factor inhibitors (TNFi; n = 15) or an anti-interleukin-17A monoclonal antibody inhibitor (IL-17i; n = 14) underwent sequencing (16S ribosomal RNA, internal transcribed spacer and shotgun metagenomics) and computational microbiome analysis. Fecal levels of fatty acid metabolites and cytokines/proteins implicated in PsA/SpA pathogenesis or intestinal inflammation were correlated with sequence data. Additionally, ileal biopsies obtained from SpA patients who developed clinically overt Crohn's disease (CD) after treatment with IL-17i (n = 5) were analyzed for expression of IL-23/Th17-related cytokines, IL-25/IL-17E-producing cells, and type 2 innate lymphoid cells (ILC2s).

Results: There were significant shifts in abundance of specific taxa after treatment with IL-17i compared to TNFi, particularly Clostridiales (P = 0.016) and Candida albicans (P = 0.041). These subclinical alterations correlated with changes in bacterial community co-occurrence, metabolic pathways, IL-23/Th17-related cytokines, and various fatty acids. Ileal biopsies showed that clinically overt CD was associated with expansion of IL-25/IL-17E-producing tuft cells and ILC2s (P < 0.05), compared to pre-IL-17i treatment levels.

Conclusion: In a subgroup of SpA patients, the initiation of IL-17A blockade correlated with features of subclinical gut inflammation and intestinal dysbiosis of certain bacterial and fungal taxa, most notably C albicans. Further, IL-17i-related CD was associated with overexpression of IL-25/IL-17E-producing tuft cells and ILC2s. These results may help to explain the potential link between inhibition of a specific IL-17 pathway and the (sub)clinical gut inflammation observed in SpA.
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http://dx.doi.org/10.1002/art.41169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113119PMC
April 2020

Methods in Lung Microbiome Research.

Am J Respir Cell Mol Biol 2020 03;62(3):283-299

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.

The lung microbiome is associated with host immune response and health outcomes in experimental models and patient cohorts. Lung microbiome research is increasing in volume and scope; however, there are no established guidelines for study design, conduct, and reporting of lung microbiome studies. Standardized approaches to yield reliable and reproducible data that can be synthesized across studies will ultimately improve the scientific rigor and impact of published work and greatly benefit microbiome research. In this review, we identify and address several key elements of microbiome research: conceptual modeling and hypothesis framing; study design; experimental methodology and pitfalls; data analysis; and reporting considerations. Finally, we explore possible future directions and research opportunities. Our goal is to aid investigators who are interested in this burgeoning research area and hopefully provide the foundation for formulating consensus approaches in lung microbiome research.
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http://dx.doi.org/10.1165/rcmb.2019-0273TRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055701PMC
March 2020

Severe lung disease characterized by lymphocytic bronchiolitis, alveolar ductitis, and emphysema (BADE) in industrial machine-manufacturing workers.

Am J Ind Med 2019 11 28;62(11):927-937. Epub 2019 Aug 28.

Respiratory Health Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia.

Background: A cluster of severe lung disease occurred at a manufacturing facility making industrial machines. We aimed to describe disease features and workplace exposures.

Methods: Clinical, functional, radiologic, and histopathologic features were characterized. Airborne concentrations of thoracic aerosol, metalworking fluid, endotoxin, metals, and volatile organic compounds were measured. Facility airflow was assessed using tracer gas. Process fluids were examined using culture, polymerase chain reaction, and 16S ribosomal RNA sequencing.

Results: Five previously healthy male never-smokers, ages 27 to 50, developed chest symptoms from 1995 to 2012 while working in the facility's production areas. Patients had an insidious onset of cough, wheeze, and exertional dyspnea; airflow obstruction (mean FEV  = 44% predicted) and reduced diffusing capacity (mean = 53% predicted); and radiologic centrilobular emphysema. Lung tissue demonstrated a unique pattern of bronchiolitis and alveolar ductitis with B-cell follicles lacking germinal centers, and significant emphysema for never-smokers. All had chronic dyspnea, three had a progressive functional decline, and one underwent lung transplantation. Patients reported no unusual nonoccupational exposures. No cases were identified among nonproduction workers or in the community. Endotoxin concentrations were elevated in two air samples; otherwise, exposures were below occupational limits. Air flowed from areas where machining occurred to other production areas. Metalworking fluid primarily grew Pseudomonas pseudoalcaligenes and lacked mycobacterial DNA, but 16S analysis revealed more complex bacterial communities.

Conclusion: This cluster indicates a previously unrecognized occupational lung disease of yet uncertain etiology that should be considered in manufacturing workers (particularly never-smokers) with airflow obstruction and centrilobular emphysema. Investigation of additional cases in other settings could clarify the cause and guide prevention.
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http://dx.doi.org/10.1002/ajim.23038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561037PMC
November 2019

The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda.

Lancet Respir Med 2019 10 22;7(10):892-906. Epub 2019 Mar 22.

Department of Science and Technology-National Research Foundation (DST-NRF) Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council Centre for Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; African Microbiome Institute, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

The diverse microbial communities within our bodies produce metabolites that modulate host immune responses. Even the microbiome at distal sites has an important function in respiratory health. However, the clinical importance of the microbiome in tuberculosis, the biggest infectious cause of death worldwide, is only starting to be understood. Here, we critically review research on the microbiome's association with pulmonary tuberculosis. The research indicates five main points: (1) susceptibility to infection and progression to active tuberculosis is altered by gut Helicobacter co-infection, (2) aerosol Mycobacterium tuberculosis infection changes the gut microbiota, (3) oral anaerobes in the lung make metabolites that decrease pulmonary immunity and predict progression, (4) the increased susceptibility to reinfection of patients who have previously been treated for tuberculosis is likely due to the depletion of T-cell epitopes on commensal gut non-tuberculosis mycobacteria, and (5) the prolonged antibiotic treatment required for cure of tuberculosis has long-term detrimental effects on the microbiome. We highlight knowledge gaps, considerations for addressing these knowledge gaps, and describe potential targets for modifying the microbiome to control tuberculosis.
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http://dx.doi.org/10.1016/S2213-2600(18)30501-0DOI Listing
October 2019

The Challenging Road of Moving from Association to Causation for Microbiome Research in Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 May;199(9):1054-1056

3 Interstitial Lung Disease Unit Royal Brompton Hospital London, United Kingdom and.

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http://dx.doi.org/10.1164/rccm.201902-0318EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515869PMC
May 2019

Could the Sputum Microbiota Be a Biomarker That Predicts Mortality after Acute Exacerbations of Chronic Obstructive Pulmonary Disease?

Am J Respir Crit Care Med 2019 May;199(10):1175-1176

1 Division of Pulmonary and Critical Care Medicine New York University School of Medicine New York, New York.

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http://dx.doi.org/10.1164/rccm.201811-2138EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519852PMC
May 2019

The Lung Microbiome and Its Role in Pneumonia.

Clin Chest Med 2018 12;39(4):677-689

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, NYU Human Microbiome Program, New York University School of Medicine, New York, NY 10028, USA. Electronic address:

The use of next-generation sequencing and multiomic analysis reveals new insights on the identity of microbes in the lower airways blurring the lines between commensals and pathogens. Microbes are not found in isolation; rather they form complex metacommunities where microbe-host and microbe-microbe interactions play important roles on the host susceptibility to pathogens. In addition, the lower airway microbiota exert significant effects on host immune tone. Thus, this review highlights the roles that microbes in the respiratory tract play in the development of pneumonia.
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http://dx.doi.org/10.1016/j.ccm.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221463PMC
December 2018

Airway and esophageal eosinophils in children with severe uncontrolled asthma.

Pediatr Pulmonol 2018 12 23;53(12):1598-1603. Epub 2018 Oct 23.

Aerodigestive Center, Hassenfeld Children's Hospital, NYU Langone Health, New York.

Aim: Children with severe uncontrolled asthma (SUA) have a high burden of symptoms and increased frequency of asthma exacerbations. Reflux esophagitis and eosinophilic esophagitis are important co-morbid factors for SUA. Both are associated with the presence of eosinophils in esophageal mucosa. We hypothesized that esophageal eosinophils are frequently present and correlate with the presence of airway eosinophils in children with SUA.

Method: We performed a retrospective analysis of a prospective database of children who underwent "triple endoscopy" (sleep laryngoscopy, bronchoscopy with bronchoalveolar lavage [BAL] and endobronchial biopsy [EBB], and esophagogastroduodenoscopy with esophageal biopsy [EsB]) at our Aerodigestive Center for evaluation of SUA. Children with known cystic fibrosis, primary ciliary dyskinesia, and aspiration-related lung disease were excluded.

Result: Twenty-four children (21 males) ages 2-16 years were studied. Elevated BAL eosinophils were found in 10 (42%) patients, endobronchial eosinophils in 16 (67%); 7 (29%) had endobronchial eosinophils without elevated BAL eosinophils. Esophageal eosinophils were found in 11 (46%) patients. There was a correlation between the amount of eosinophils in BAL and EBB (R = 0.43, P = 0.05) airway eosinophils, defined as elevated BAL and/or EBB eosinophils, correlated with esophageal eosinophils (R = 0.41, P = 0.047).

Conclusion: We concluded that airway and esophageal eosinophils are frequently present in children with SUA.
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http://dx.doi.org/10.1002/ppul.24180DOI Listing
December 2018

Smoking is associated with quantifiable differences in the human lung DNA virome and metabolome.

Respir Res 2018 Sep 12;19(1):174. Epub 2018 Sep 12.

Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University College of Medicine, 201 Davis Heart & Lung Research Institute, 473 West 12th Avenue, Columbus, OH, 43210, USA.

Background: The role of commensal viruses in humans is poorly understood, and the impact of the virome on lung health and smoking-related disease is particularly understudied.

Methods: Genetic material from acellular bronchoalveolar lavage fluid was sequenced to identify and quantify viral members of the lower respiratory tract which were compared against concurrent bronchoalveolar lavage bacterial, metabolite, cytokine and cellular profiles, and clinical data. Twenty smoker and 10 nonsmoker participants with no significant comorbidities were studied.

Results: Viruses that infect bacteria (phages) represented the vast majority of viruses in the lung. Though bacterial communities were statistically indistinguishable across smokers and nonsmokers as observed in previous studies, lung viromes and metabolic profiles were significantly different between groups. Statistical analyses revealed that changes in viral communities correlate most with changes in levels of arachidonic acid and IL-8, both potentially relevant for chronic obstructive pulmonary disease (COPD) pathogenesis based on prior studies.

Conclusions: Our assessment of human lung DNA viral communities reveals that commensal viruses are present in the lower respiratory tract and differ between smokers and nonsmokers. The associations between viral populations and local immune and metabolic tone suggest a significant role for virome-host interaction in smoking related lung disease.
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http://dx.doi.org/10.1186/s12931-018-0878-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136173PMC
September 2018

Evaluation of the airway microbiome in nontuberculous mycobacteria disease.

Eur Respir J 2018 10 25;52(4). Epub 2018 Oct 25.

Division of Pulmonary, Critical Care, and Sleep Medicine, New York University School of Medicine, New York, NY, USA.

Aspiration is associated with nontuberculous mycobacterial (NTM) pulmonary disease and airway dysbiosis is associated with increased inflammation. We examined whether NTM disease was associated with a distinct airway microbiota and immune profile.297 oral wash and induced sputum samples were collected from 106 participants with respiratory symptoms and imaging abnormalities compatible with NTM. Lower airway samples were obtained in 20 participants undergoing bronchoscopy. 16S rRNA gene and nested mycobacteriome sequencing approaches characterised microbiota composition. In addition, inflammatory profiles of lower airway samples were examined.The prevalence of NTM cultures was 58%. Few changes were noted in microbiota characteristics or composition in oral wash and sputum samples among groups. Among NTM samples, 27% of the lower airway samples were enriched with A mycobacteriome approach identified in a greater percentage of samples, including some nonpathogenic strains. In NTM lower airway samples, taxa identified as oral commensals were associated with increased inflammatory biomarkers.The 16S rRNA gene sequencing approach is not sensitive in identifying NTM among airway samples that are culture-positive. However, associations between lower airway inflammation and microbiota signatures suggest a potential role for these microbes in the inflammatory process in NTM disease.
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http://dx.doi.org/10.1183/13993003.00810-2018DOI Listing
October 2018

Aerodigestive dysbiosis in children with chronic cough.

Pediatr Pulmonol 2018 09 8;53(9):1288-1298. Epub 2018 Jul 8.

Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York.

In pediatric patients with chronic cough, respiratory culture techniques commonly yield negative results. Studies using culture-independent methods have found a high relative abundance of oral microbes in the lower airways, suggesting that the topographical continuity, and dynamics of the intraluminal contents of the aerodigestive system likely influence the lower airway microbiota. We hypothesize that in subjects with chronic cough, clinical diagnosis will correlate with distinct microbial signatures detected using culture-independent methods.

Study Design And Methods: We enrolled 36 pediatric subjects with chronic cough in a cross-sectional study. Subjects were categorized into four clinical groups: asthma, bacterial bronchitis, neurologically impaired-orally fed, and neurologically impaired enterally fed. Samples from the aerodigestive tract were obtained through bronchoscopy and upper endoscopy. 16S rRNA gene sequencing compared the microbiota from bronchoalveolar lavage (BAL), tracheal, supraglottic, esophageal, gastric, and duodenal samples.

Results: We observed that the lower airway microbiota of asthma subjects had higher α diversity as compared with the other groups. β diversity analysis of BAL samples revealed significant differences between the groups. Among the taxonomic differences found, most differentially enriched taxa were upper airway organisms such as Rothia, Gemellaceae (u.g. or uncharacterized genus), and Granulicatella in asthma, Prevotella in bacterial bronchitis, and Veillonella in neurologically impaired orally fed subjects. Greater dissimilarity between the upper airway and lower airway microbiota was associated with increased neutrophilic airway inflammation.

Conclusions: Distinct dysbiotic signatures can be identified in the lower airway microbiota of pediatric subjects with chronic cough that relates to the degree and type of inflammation.
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http://dx.doi.org/10.1002/ppul.24115DOI Listing
September 2018

Severe Obstructive Sleep Apnea Is Associated with Alterations in the Nasal Microbiome and an Increase in Inflammation.

Am J Respir Crit Care Med 2019 01;199(1):99-109

1 Division of Pulmonary, Critical Care, and Sleep Medicine, New York University School of Medicine, New York, New York.

Rationale: Obstructive sleep apnea (OSA) is associated with recurrent obstruction, subepithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome.

Objectives: To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers.

Methods: Two large cohorts were used: 1) a discovery cohort of 472 subjects from the WTCSNORE (Seated, Supine and Post-Decongestion Nasal Resistance in World Trade Center Rescue and Recovery Workers) cohort, and 2) a validation cohort of 93 subjects rom the Zaragoza Sleep cohort. Sleep apnea was diagnosed using home sleep tests. Nasal lavages were obtained from cohort subjects to measure: 1) microbiome composition (based on 16S rRNA gene sequencing), and 2) biomarkers for inflammation (inflammatory cells, IL-8, and IL-6). Longitudinal 3-month samples were obtained in the validation cohort, including after continuous positive airway pressure treatment when indicated.

Measurements And Main Results: In both cohorts, we identified that: 1) severity of OSA correlated with differences in microbiome diversity and composition; 2) the nasal microbiome of subjects with severe OSA were enriched with Streptococcus, Prevotella, and Veillonella; and 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of cooccurring microbes that defined communities. Several common oral commensals (e.g., Streptococcus, Rothia, Veillonella, and Fusobacterium) correlated with apnea-hypopnea index. Three months of treatment with continuous positive airway pressure did not change the composition of the nasal microbiota.

Conclusions: We demonstrate that the presence of an altered microbiome in severe OSA is associated with inflammatory markers. Further experimental approaches to explore causal links are needed.
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http://dx.doi.org/10.1164/rccm.201801-0119OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353011PMC
January 2019

The Road to Precision Medicine in Chronic Obstructive Pulmonary Disease: Squeezing More Out of Chest Computed Tomography Scans.

Ann Am Thorac Soc 2018 04;15(4):428-429

Division of Pulmonary, Critical Care, and Sleep Medicine, New York University School of Medicine, New York City, New York.

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http://dx.doi.org/10.1513/AnnalsATS.201712-945EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879144PMC
April 2018

Chronic obstructive pulmonary disease subpopulations and phenotyping.

J Allergy Clin Immunol 2018 06;141(6):1961-1971

Division of Pulmonary and Critical Care Medicine, Cornell University, Joan and Sanford I Weill Medical College, Ithaca, NY.

The diagnosis and treatment of chronic obstructive pulmonary disease (COPD) has been based largely on a one-size-fits-all approach. Diagnosis of COPD is based on meeting the physiologic criteria of fixed obstruction in forced expiratory flows and treatment focus on symptomatic relief, with limited effect on overall prognosis. However, patients with COPD have distinct features that determine very different evolutions of the disease. In this review we highlight distinct subgroups of COPD characterized by unique pathophysiologic derangements, response to treatment, and disease progression. It is likely that identification of subgroups of COPD will lead to discovery of much needed disease-modifying therapeutic approaches. We argue that a precision approach that integrates multiple dimensions (clinical, physiologic, imaging, and endotyping) is needed to move the field forward in the treatment of this disease.
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http://dx.doi.org/10.1016/j.jaci.2018.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996762PMC
June 2018

Airway Microbiota Is Associated with Upregulation of the PI3K Pathway in Lung Cancer.

Am J Respir Crit Care Med 2018 11;198(9):1188-1198

1 Division of Pulmonary and Critical Care Medicine.

Rationale: In lung cancer, upregulation of the PI3K (phosphoinositide 3-kinase) pathway is an early event that contributes to cell proliferation, survival, and tissue invasion. Upregulation of this pathway was recently described as associated with enrichment of the lower airways with bacteria identified as oral commensals.

Objectives: We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways.

Methods: Airway brushings were collected prospectively from subjects with lung nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung cancer diagnoses and 36 subjects with noncancer diagnoses. In addition, samples from 10 healthy control subjects were included. 16S ribosomal RNA gene amplicon sequencing and paired transcriptome sequencing were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed.

Measurements And Main Results: The composition of the lower airway transcriptome in the patients with cancer was significantly different from the control subjects, which included up-regulation of ERK (extracellular signal-regulated kinase) and PI3K signaling pathways. The lower airways of patients with lung cancer were enriched for oral taxa (Streptococcus and Veillonella), which was associated with up-regulation of the ERK and PI3K signaling pathways. In vitro exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus led to upregulation of these same signaling pathways.

Conclusions: The data presented here show that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.
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http://dx.doi.org/10.1164/rccm.201710-2118OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221574PMC
November 2018

Gut Microbiota Perturbations in Reactive Arthritis and Postinfectious Spondyloarthritis.

Arthritis Rheumatol 2018 02 3;70(2):242-254. Epub 2018 Jan 3.

New York University School of Medicine and Hospital for Joint Diseases, New York, New York.

Objective: Reactive arthritis (ReA) is an inflammatory disorder occurring several weeks after gastrointestinal or genitourinary tract infections. HLA-B27 positivity is considered a risk factor, although it is not necessarily predictive of disease incidence. Among nongenetic factors, the intestinal microbiome may play a role in disease susceptibility. The objective of this study was to characterize the gut microbiota and host gene interactions in ReA and postinfectious spondyloarthritis.

Methods: Adult subjects with peripheral spondyloarthritis and control subjects with preceding infections who did not develop arthritis were prospectively recruited from a geographic region with a high prevalence of ReA. Clinical variables, HLA status, and 16S ribosomal RNA gene sequencing of intestinal microbiota were analyzed.

Results: Subjects with ReA showed no significant differences from controls in gut bacterial richness or diversity. However, there was a significantly higher abundance of Erwinia and Pseudomonas and an increased prevalence of typical enteropathogens associated with ReA. Subjects with ultrasound evidence of enthesitis were enriched in Campylobacter, while subjects with uveitis and radiographic sacroiliitis were enriched in Erwinia and unclassified Ruminococcaceae, respectively; both were enriched in Dialister. Host genetics, particularly HLA-A24, were associated with differences in gut microbiota diversity irrespective of disease status. We identified several co-occurring taxa that were also predictive of HLA-A24 status.

Conclusion: This is the first culture-independent study characterizing the gut microbial community in postinfectious arthritis. Although bacterial factors correlated with disease presence and clinical features of ReA, host genetics also appeared to be a major independent driver of intestinal community composition. Understanding of these gut microbiota-host genetic relationships may further clarify the pathogenesis of postinfectious spondyloarthritides.
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http://dx.doi.org/10.1002/art.40359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788722PMC
February 2018