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Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome

Sulaiman, Imran; Chung, Matthew; Angel, Luis; Tsay, Jun-Chieh J; Wu, Benjamin G; Yeung, Stephen T; Krolikowski, Kelsey; Li, Yonghua; Duerr, Ralf; Schluger, Rosemary; Thannickal, Sara A; Koide, Akiko; Rafeq, Samaan; Barnett, Clea; Postelnicu, Radu; Wang, Chang; Banakis, Stephanie; Pérez-Pérez, Lizzette; Shen, Guomiao; Jour, George; Meyn, Peter; Carpenito, Joseph; Liu, Xiuxiu; Ji, Kun; Collazo, Destiny; Labarbiera, Anthony; Amoroso, Nancy; Brosnahan, Shari; Mukherjee, Vikramjit; Kaufman, David; Bakker, Jan; Lubinsky, Anthony; Pradhan, Deepak; Sterman, Daniel H; Weiden, Michael; Heguy, Adriana; Evans, Laura; Uyeki, Timothy M; Clemente, Jose C; de Wit, Emmie; Schmidt, Ann Marie; Shopsin, Bo; Desvignes, Ludovic; Wang, Chan; Li, Huilin; Zhang, Bin; Forst, Christian V; Koide, Shohei; Stapleford, Kenneth A; Khanna, Kamal M; Ghedin, Elodie; Segal, Leopoldo N
Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.
PMID: 34465900
ISSN: 2058-5276
CID: 4998422

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Brosnahan, Shari B; Chen, Xian Jie Cindy; Chung, Juri; Altshuler, Diana; Islam, Shahidul; Thomas, Sarun V; Winner, Megan D; Greco, Allison A; Divers, Jasmin; Spiegler, Peter; Sterman, Daniel H; Parnia, Sam
BACKGROUND:Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES/OBJECTIVE:The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS:A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS:= 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE/UNASSIGNED:Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.
PMID: 34180274
ISSN: 1542-6270
CID: 4926192

Lung cancer characteristics in male and female community members exposed to the dust and fumes from the world trade center towers [Meeting Abstract]

Durmus, N; Pehlivan, S; Zhang, Y; Shao, Y; Arslan, A; Corona, R; Henderson, I; Sterman, D H; Reibman, J
Rationale: World Trade Center (WTC) towers destruction on 9/11/2001 resulted in acute and chronic exposures of local workers, residents and those passing by (community members) to dust and fumes. Nearly half of this population are women, providing an opportunity to examine gender differences in cancers in this underexamined, environmentally exposed group. This study aimed to characterize lung cancer cases in the WTC Environmental Health Center (WTC EHC) focusing on gender.
Method(s): Patients in WTC EHC undergo a questionnaire for exposure information, demographics, and tobacco use. Pathologic and histologic characteristics of tumors and cancer-related biomarkers are recorded. We examined lung cancer characteristics according to gender and smoking history.
Result(s): As of December 31, 2019, 248 WTC EHC patients had a diagnosis of lung cancer. More patients with lung cancer in the WTC EHC were women (n = 142, 57%) compared to men (n = 106, 43%). Many (47% women, 51% men) reported acute dust cloud exposure. Thirtyseven percent (n=76) of lung cancer cases with available smoking history were never smokers and 42% had a <= 5 p-y history. More women compared to men had a <= 5 p-y history of tobacco use (54 vs 26%). The median age of cancer diagnosis in never smoking women was 61 compared to men (66 years). Most lung cancers had histologic type of adenocarcinoma (68%). Few (10%) were squamous cell carcinoma, with 6% carcinoid tumors. Adenocarcinoma was more common in Never smokers compared to Ever smokers (72% vs. 65%, respectively). Adenocarcinoma was most common cancer histologic type in both women and men (70% and 65% respectively) although differences in carcinoid tumors (9% and 3%, respectively), and squamous cell carcinoma (6% and 17%, respectively, p=0.001) The median tumor size at diagnosis was smaller in women (1.7 cm) compared to men (2 cm) (p=0.03) with T1 in 39% of women and 47% of men (p= 0.006). There were no significant differences by stage at diagnosis. Preliminary examination of biomarkers suggested significant differences in p40 (p=0.005), EGFR (p=0.002), and KRAS (p=0.002) between never and ever smokers.
Conclusion(s): Our data suggest that among never smokers, lung cancers is diagnosed at an earlier age among women compared with men. Men had higher percentage of smoking and higher rate of squamous cell carcinoma in ever smokers. Information about lung cancer characteristics in the WTC EHC in both genders accounting for smoking history may provide clues to environmentally-related cancer development and behavior
EMBASE:635308025
ISSN: 1535-4970
CID: 4915642

Derived Neutrophil-to-Lymphocyte Ratio as a Potential Biomarker for Lung Cancer Survival [Meeting Abstract]

Imperato, A E; Li, Y; Smith, R L; Sauthoff, H; Felner, K; Segal, L N; Sterman, D H; Tsay, J J
RATIONALE: Derived neutrophil-to-lymphocyte ratio (dNLR) of peripheral blood, a marker of host inflammation and cytokine activation, may be a surrogate for more aggressive disease. It is a biomarker that has been associated with survival and response to immunotherapy in non-small cell lung cancer (NSCLC), although an optimal threshold value has not been established. We had previously found in a NSCLC cohort that a dNLR cutoff of 2 was an optimal cutoff to predict survival at 6 months in patients with NSCLC; median survival was significantly shorter in patients with a >=2 dNLR (7.0 months) versus those with a <2 dNLR (64.5 months; p = 0.004). Here we present an interim analysis aiming to validate the use of this biomarker in a second cohort.
METHOD(S): A veteran cohort (n=42) from the VA New York Harbor Healthcare System, who underwent diagnostic bronchoscopy and found to have NSCLC, was used as a validation cohort. Peripheral blood was obtained pre-treatment and at or near the time of diagnosis. The dNLR was calculated as ANC/(W
EMBASE:635310166
ISSN: 1535-4970
CID: 4915442

Characterization of Immune Microenvironment in Primary Tumor and Tumor Draining Lymph Nodes from Patients with Malignant Pleural Mesothelioma Using Digital Spatial Profiling [Meeting Abstract]

Henderson, I J; Mangalick, K; Mezzano, V; Loomis, C; Moreira, A; Pass, H; Sterman, D H
Rationale:Malignant pleural mesothelioma(MPM) has a poor prognosis with median survival of 12-24 months. We are not aware of prior studies examining the immune microenvironment in tumor draining lymph nodes (TDLN) in MPM. Our aim is to compare the tumor microenvironment(TME) and the microenvironment of TDLN. We hypothesize that the TME will display an immunosuppressive phenotype reflected in the TDLN.
Method(s):We performed digital spatial profiling(DSP) using the GeoMx (NanoString) platform on stored primary tumor and nodal biopsy specimens from 3 patients from our tumor bank. Samples from both primary tumor and lymph nodes were sectioned and labeled with pancytokeratin (CK). Tissue was then classified as "tumor" or "nontumor" using semi-automated segmentation based on pan-Cytokeratin (panK) labeling. The slides were then labeled with antibodies to 58 selected markers, with each unique antibody attached to a respective oligonucleotide. The tissue was exposed to UV light separately for tumor and non-tumor regions, cleaving the oligonucleotides from the attached antibodies. The oligonucleotides from the separate tumor and non-tumor regions were quantified using nCounter (NanoString).
Result(s):The non-neoplastic regions of the primary tumor contained higher expression of proteins associated with inflammatory cells including helper T-cells, cytotoxic T-cells, B-cells, macrophages, neutrophils, natural killer cells(Table 1). Furthermore, there was greater expression of immune checkpoint proteins, PD-L1 and CTLA-4, and CD163 and CD14, proteins associated with immunosuppressive macrophages, in the non-neoplastic region compared to the neoplastic region of the tumoe(Table 1). TDLNs contained similar levels of expression of lymphocyte markers, including those delineating cytotoxic T-cells and helper T-cells, as the primary tumor(Table 1). Despite this, TME expressed higher levels of T-cell exhaustion and immunsupression markers (FOXP3, LAG3, PD-1, CTLA-4) than TDLN(Table 1).
Conclusion(s):DSP is feasible in Formalin-fixed paraffin embedded (FFPE) mesothelioma specimens, providing a method for using quantitative immunopathology to study corresponding immune microenvironments. In our study, the non-tumor region of the primary tumor contained macrophages, lymphocytes, natural killer cells, and cancer-associated fibroblasts consistent with prior descriptions of the mesothelioma TME. Increased expression of immune checkpoint molecules in the non-tumor region suggests an immunosuppressive TME. TDLNs demonstrated similar lymphocyte markers, but without corresponding immune checkpoint expression of t suggesting the immunosuppressive phenotype of the TME may not be reflected in TDLNs. This pilot study is the first to use DSP to preliminarily characterize TDLNs in mesothelioma. We plan to apply this approach to stored additional MPM and NSCLC specimens to gain an in-depth understanding of the relationship between TME and TDLN
EMBASE:635309327
ISSN: 1535-4970
CID: 4915482

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
Introduction: Isolated abnormalities in small airways may be demonstrable at rest in symptomatic subjects with normal spirometry; however, the relationship of small airway dysfunction to exertional symptoms remains uncertain. While standard cardiopulmonary exercise testing is frequently ordered in patients with exertional dyspnea, the routine protocol may be limited to respiratory pattern without specific assessment of airway function. In this study, potential mechanisms for exertional dyspnea were assessed by augmenting cardiopulmonary exercise testing protocols to include airway function both during and following exercise.
Method(s): 28 subjects: 16 with exertional dyspnea not attributable to cardiac or pulmonary disease and 12 asymptomatic controls. Baseline pulmonary function testing was conducted with respiratory oscillometry to assess small airway function. An incremental exercise protocol was performed including 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) evaluation of airway reactivity using spirometry and oscillometry post-exercise. Baseline: All subjects demonstrated normal spirometry by ATS criteria. Mean values for R5, R20, R5-20 and AX tended to be higher in the symptomatic as compared with the asymptomatic cohorts (R5: 4.18+/-1.24 vs. 3.66+/-1.06; R20: 3.18+/-0.99 vs. 2.98+/-0.68; R5-20: 1.00+/-0.43 vs. 0.70+/-0.53; AX: 8.62+/-4.40 vs. 5.48+/-5.21). Analysis of individual subjects demonstrated small airway dysfunction in 12/16 symptomatic subjects vs. 4/12 controls. Exercise: Dyspnea was reproduced during exercise in the symptomatic subjects (Borg scale 1 at rest, 6 at peak exercise, p<0.05) but was not present in controls (Borg scale 0 at rest, 1.5 at peak exercise). Tidal airflow vs. volume curves uncovered a mechanism for dyspnea during exercise in symptomatic subjects that was not present in the asymptomatic group (dynamic hyperinflation in 2 vs. 0; expiratory flow limitation in 12 vs. 0, p<0.05). Post exercise: Exercise-induced airway hyper-reactivity (>10% drop in FEV1) was present in 4 symptomatic subjects versus 1 control. Reduction in FEV1 was predominantly attributable to drop in VC rather than reduction in FEV1/VC, consistent with small airway dysfunction. An additional 3 subjects demonstrated small airway hyper-reactivity on post-exercise oscillometry.
Conclusion(s): Exertional dyspnea in patients with normal spirometry was predominantly attributable to small airway dysfunction during exercise and/or small airway hyper-reactivity following exercise. Thus, these data demonstrate that mechanisms for unexplained dyspnea can be unmasked by augmenting standard CPET to include specific assessment of airway function
EMBASE:635309918
ISSN: 1535-4970
CID: 4915452

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

Sulaiman, Imran; Chung, Matthew; Angel, Luis; Koralov, Sergei; Wu, Benjamin; Yeung, Stephen; Krolikowski, Kelsey; Li, Yonghua; Duerr, Ralf; Schluger, Rosemary; Thannickal, Sara; Koide, Akiko; Rafeq, Samaan; Barnett, Clea; Postelnicu, Radu; Wang, Chang; Banakis, Stephanie; Perez-Perez, Lizzette; Jour, George; Shen, Guomiao; Meyn, Peter; Carpenito, Joseph; Liu, Xiuxiu; Ji, Kun; Collazo, Destiny; Labarbiera, Anthony; Amoroso, Nancy; Brosnahan, Shari; Mukherjee, Vikramjit; Kaufman, David; Bakker, Jan; Lubinsky, Anthony; Pradhan, Deepak; Sterman, Daniel; Heguy, Adriana; Uyeki, Timothy; Clemente, Jose; de Wit, Emmie; Schmidt, Ann Marie; Shopsin, Bo; Desvignes, Ludovic; Wang, Chan; Li, Huilin; Zhang, Bin; Forst, Christian; Koide, Shohei; Stapleford, Kenneth; Khanna, Kamal; Ghedin, Elodie; Weiden, Michael; Segal, Leopoldo
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 ( Mycoplasma salivarium ), 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.
PMCID:8010736
PMID: 33791687
ISSN: n/a
CID: 4830952

Lung Cancer Characteristics in the World Trade Center Environmental Health Center

Durmus, Nedim; Pehlivan, Sultan; Zhang, Yian; Shao, Yongzhao; Arslan, Alan A; Corona, Rachel; Henderson, Ian; Sterman, Daniel H; Reibman, Joan
The destruction of the World Trade Center (WTC) towers on 11 September 2001 resulted in acute and chronic dust and fume exposures to community members, including local workers and residents, with well-described aerodigestive adverse health effects. This study aimed to characterize lung cancer in the WTC Environmental Health Center (WTC EHC) focusing on gender and smoking history. WTC EHC patients undergo an initial evaluation that includes WTC exposure information, demographics, and tobacco use. Detailed cancer characteristics are recorded from pathology reports. As of 31 December 2019, 248 WTC EHC patients had a diagnosis of lung cancer. More patients with lung cancer were women (57%) compared to men (43%). Many cases (47% women, 51% men) reported acute dust cloud exposure. Thirty-seven percent of lung cancer cases with available smoking history were never-smokers (≤1 pack-years) and 42% had a ≤5 pack-year history. The median age of cancer diagnosis in never-smoking women was 61 years compared to 66 years in men. Adenocarcinoma was more common in never-smokers compared to ever-smokers (72% vs. 65%) and in women compared to men (70% vs. 65%). We provide an initial description of lung cancers in local community members with documented exposure to the WTC dust and fumes.
PMCID:7967411
PMID: 33800009
ISSN: 1660-4601
CID: 4838572

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

Sulaiman, Imran; Chung, Matthew; Angel, Luis; Tsay, Jun-Chieh J; Wu, Benjamin G; Yeung, Stephen T; Krolikowski, Kelsey; Li, Yonghua; Duerr, Ralf; Schluger, Rosemary; Thannickal, Sara A; Koide, Akiko; Rafeq, Samaan; Barnett, Clea; Postelnicu, Radu; Wang, Chang; Banakis, Stephanie; Perez-Perez, Lizzette; Jour, George; Shen, Guomiao; Meyn, Peter; Carpenito, Joseph; Liu, Xiuxiu; Ji, Kun; Collazo, Destiny; Labarbiera, Anthony; Amoroso, Nancy; Brosnahan, Shari; Mukherjee, Vikramjit; Kaufman, David; Bakker, Jan; Lubinsky, Anthony; Pradhan, Deepak; Sterman, Daniel H; Weiden, Michael; Hegu, Adriana; Evans, Laura; Uyeki, Timothy M; Clemente, Jose C; De Wit, Emmie; Schmidt, Ann Marie; Shopsin, Bo; Desvignes, Ludovic; Wang, Chan; Li, Huilin; Zhang, Bin; Forst, Christian V; Koide, Shohei; Stapleford, Kenneth A; Khanna, Kamal M; Ghedin, Elodie; Segal, Leopoldo N
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 ( Mycoplasma salivarium ), 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.
PMCID:7924286
PMID: 33655261
ISSN: n/a
CID: 4801472

Lower airway dysbiosis affects lung cancer progression

Tsay, Jun-Chieh J; Wu, Benjamin G; Sulaiman, Imran; Gershner, Katherine; Schluger, Rosemary; Li, Yonghua; Yie, Ting-An; Meyn, Peter; Olsen, Evan; Perez, Luisannay; Franca, Brendan; Carpenito, Joseph; Iizumi, Tadasu; El-Ashmawy, Mariam; Badri, Michelle; Morton, James T; Shen, Nan; He, Linchen; Michaud, Gaetane; Rafeq, Samaan; Bessich, Jamie L; Smith, Robert L; Sauthoff, Harald; Felner, Kevin; Pillai, Ray; Zavitsanou, Anastasia-Maria; Koralov, Sergei B; Mezzano, Valeria; Loomis, Cynthia A; Moreira, Andre L; Moore, William; Tsirigos, Aristotelis; Heguy, Adriana; Rom, William N; Sterman, Daniel H; Pass, Harvey I; Clemente, Jose C; Li, Huilin; Bonneau, Richard; Wong, Kwok-Kin; Papagiannakopoulos, Thales; Segal, Leopoldo N
In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs and ex vivo 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 group IIIB-IV TNM stage lung cancer 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 IIIB-IV stage disease. In addition, this lower airway microbiota signature was associated with upregulation of IL-17, PI3K, MAPK and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL-17 inflammatory phenotype and activation of checkpoint inhibitor markers.
PMID: 33177060
ISSN: 2159-8290
CID: 4663012