Cough Capture as a Portal Into the Lung

The lung is a privileged organ; blood does not reflect most lung processes well, if at all. Therefore, for population scale diagnostics, the investigator team is developing non-invasive portals to the lung, for eventual early detection/risk assessment and diagnostic purposes. However, large macromolecules are not likely suspended nor readily detected in the breath. In particular, genomic DNA in the breath condensate (EBC) is very sparse, and where present, generally highly fragmented, not readily amenable to sequencing based assessments of DNA somatic mutation burden or distribution. Because gDNA (and protein) is challenging to obtain non-invasively from EBC, the study team considered alternative surrogate lower airway specimens. Cough capture is rarely done, and the investigator team is in the process of optimizing its collection. Importantly, the team will be evaluating how much of coughed material is from saliva contamination. Additionally, analyzing material that is target captured by capturing deep lung extracellular vesicles (EVs) using immobilized CCSP/SFTPC antibodies targeting EVs from distal bronchiole Club and alveolar type 2 cells could circumvent the mouth contamination problem, leaving a non-invasive portal to the deep lung suitable for large molecules, and in turn suitable for myriad epidemiologic and clinical applications. The investigator team proposes (Aim 1) to pursue optimizing cough collection, and testing the efficacy and practicality of partitioning cough specimen for deep-lung specific extra-cellular vesicles (EVs). This cough specimen will be compared to that from invasively collected deep lung samples BAL/bronchial brushings, and to the potential contaminating mouth rinse, all from the same individuals. (Aim 2) The study team initially proposes to examine these cough specimens for somatic mutations by SMM bulk sequencing for single nucleotide variation, developed in the Vijg/Maslov labs. Finally, the investigator team will (Aim 3) test all airway specimens (cough, mouthwash and BAL) for lung surrogacy of cough, using proteins known to be specific for lung, as opposed to oral cavity/saliva, in the Sidoli/proteomics core. The investigator team envisions that the translational impact of non-invasively obtained DNA or protein markers could allow for more rapid acute clinical diagnoses, and facilitate precision prevention and/or early detection of many acute and chronic respiratory disorders, including lung cancer, asthma and COPD, acute and chronic infectious diseases, and indeed systemic disorders of inflammation and metabolism.

Sex

All

Minimum age

21 Years

Inclusion Criteria:

* Age: minimum age of 21 years
* Gender: Male and Female adults
* Ethnicity: All ethnic groups and races
* Subjects undergoing bronchoscopy for diagnostic purposes or therapy
* Subjects without a known diagnosis of lung cancer who are not scheduled for lung tissue collection procedures
* Subjects with a known or suspected diagnosis of asthma or COPD and are scheduled for a visit at Montefiore Asthma or COPD Center and individual practices, and/or in-hospital with exacerbation

Exclusion Criteria:

* Bleeding diathesis or known coagulopathy precluding clinically indicated biopsy (e.g., INR\>1.3, PTTr\>1.3), thrombocytopenia \<50,000, uremia with serum creatinine \>3.0
* Unstable angina
* Recent myocardial infarction (within 3 months),
* Uncontrolled congestive heart failure or severe pulmonary hypertension (mean PAP\>75 mmHg)

• BACKGROUNDMitchell MI, Ben-Dov IZ, Ye K, Liu C, Shi M, Sadoughi A, Shah C, Siddiqui T, Okorozo A, Gutierrez M, Unawane R, Biamonte L, Parikh K, Spivack S, Loudig O. Exhaled breath condensate contains extracellular vesicles (EVs) that carry miRNA cargos of lung tissue origin that can be selectively purified and analyzed. J Extracell Vesicles. 2024 Apr;13(4):e12440. doi: 10.1002/jev2.12440. PMID 38659349
• BACKGROUNDShi M, Han W, Loudig O, Shah CD, Dobkin JB, Keller S, Sadoughi A, Zhu C, Siegel RE, Fernandez MK, DeLaRosa L, Patel D, Desai A, Siddiqui T, Gombar S, Suh Y, Wang T, Hosgood HD, Pradhan K, Ye K, Spivack SD. Initial development and testing of an exhaled microRNA detection strategy for lung cancer case-control discrimination. Sci Rep. 2023 Apr 24;13(1):6620. doi: 10.1038/s41598-023-33698-8. PMID 37095155
• BACKGROUNDHuang Z, Sun S, Lee M, Maslov AY, Shi M, Waldman S, Marsh A, Siddiqui T, Dong X, Peter Y, Sadoughi A, Shah C, Ye K, Spivack SD, Vijg J. Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nat Genet. 2022 Apr;54(4):492-498. doi: 10.1038/s41588-022-01035-w. Epub 2022 Apr 11. PMID 35410377
• RESULTZefi O, Waldman S, Marsh A, Shi MK, Sonbolian Y, Khulan B, Siddiqui T, Desai A, Patel D, Okorozo A, Khader S, Dobkin J, Sadoughi A, Shah C, Spivack S, Peter Y. Distinctive field effects of smoking and lung cancer case-control status on bronchial basal cell growth and signaling. Respir Res. 2024 Aug 19;25(1):317. doi: 10.1186/s12931-024-02924-w. PMID 39160511
• RESULTKhulan B, Ye K, Shi MK, Waldman S, Marsh A, Siddiqui T, Okorozo A, Desai A, Patel D, Dobkin J, Sadoughi A, Shah C, Gera S, Peter Y, Liao W, Vijg J, Spivack SD. Normal bronchial field basal cells show persistent methylome-wide impact of tobacco smoking, including in known cancer genes. Epigenetics. 2025 Dec;20(1):2466382. doi: 10.1080/15592294.2025.2466382. Epub 2025 Feb 20. PMID 39980243
• RESULTS.D. Spivack, M.W. Azam, A. Okorozo, K. Batbayar, A.Y. Maslov, M. Lee, J. Vijg, and O. Loudig. Development of Cough Access to the Deep Lung for Somatic Mutagenesis Assessment [abstract]. Am J Respir Crit Care Med 2025;211:A4800. https://doi.org/10.1164/ajrccm.2025.211.Abstracts.A4800