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1. Vasoactive drugs for the treatment of pulmonary hypertension associated with interstitial lung diseases: a systematic review

Author

Francesco Blasi, Stefano Aliberti, Antonio Voza, Gabriele Bongiovanni, Antonio Tonutti, Anna Stainer, Mattia Nigro, Dean L Kellogg, Anoop Nambiar, Andrea Gramegna, Marco Mantero, and Francesco Amati

Subjects
Medicine, Diseases of the respiratory system, RC705-779
Abstract

Objectives Vasoactive drugs have exhibited clinical efficacy in addressing pulmonary arterial hypertension, manifesting a significant reduction in morbidity and mortality. Pulmonary hypertension may complicate advanced interstitial lung disease (PH-ILD) and is associated with high rates of disability, hospitalisation due to cardiac and respiratory illnesses, and mortality. Prior management hinged on treating the underlying lung disease and comorbidities. However, the INCREASE trial of inhaled treprostinil in PH-ILD has demonstrated that PH-ILD can be effectively treated with vasoactive drugs.Methods This comprehensive systematic review examines the evidence for vasoactive drugs in the management of PH-ILD.Results A total of 1442 pubblications were screened, 11 RCTs were considered for quantitative synthesis. Unfortunately, the salient studies are limited by population heterogeneity, short-term follow-up and the selection of outcomes with uncertain clinical significance.Conclusions This systematic review underscores the necessity of establishing a precision medicine-oriented strategy, directed at uncovering and addressing the intricate cellular and molecular mechanisms that underlie the pathophysiology of PH-ILD.PROSPERO registration number CRD42023457482.

Published
2024
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2. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerabilityResearch in context

Author

Anoop Nambiar, Dean Kellogg, III, Jaime Justice, Martin Goros, Jonathan Gelfond, Rodolfo Pascual, Shahrukh Hashmi, Michal Masternak, Larissa Prata, Nathan LeBrasseur, Andrew Limper, Stephen Kritchevsky, Nicolas Musi, Tamara Tchkonia, and James Kirkland

Subjects
Senescence, Senolytics, Idiopathic pulmonary fibrosis, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, chronic, irreversible fibrotic lung disease. IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed ‘senolytics’. We previously conducted an open-label single-arm pilot study of the senolytic combination of dasatinib and quercetin (D + Q) in patients with IPF but lack of control group limited interpretation and next-stage trial planning. The primary objective of this confirmatory randomized placebo-controlled pilot trial (RCT; NCT02874989) was to report adverse events with D + Q and inform study feasibility for future efficacy trials. Methods: Twelve participants with IPF aged >50 years were blinded and randomized at a 1:1 ratio to either receive three weeks of D + Q (D: 100 mg/d and Q: 1250 mg/d, three consecutive days per week) or matching placebo. Findings: All participants completed the scheduled drug dosing regimen (108/108 doses) and planned assessments (60/60). While the placebo arm reported fewer overall non-serious AEs (65 vs 22), there were no serious adverse events related to D + Q. Most AEs in the D + Q arm are common in IPF patients or anticipated side effects of D. Sleep disturbances and anxiety were disproportionately represented in the D + Q arm (4/6 vs 0/6). Frailty, pulmonary, or physical function were explored before and after intermittent D + Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups. Interpretation: Intermittently-dosed D + Q in patients with IPF is feasible and generally well-tolerated. Further prospective studies, such as a larger RCT, are needed to confirm the safety and efficacy of D + Q in patients with IPF. Funding: This work was supported by National Institutes of Health grants R33AG61456 (JLK, TT), Robert and Arlene Kogod (JLK, TT), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT) San Antonio Claude D. Pepper Older Americans Independence Center’s (OAIC) Pilot/Exploratory Studies Core (PESC) Grant (AMN, NM); NIH K01 AG059837 (JNJ), P30 AG021332 (SBK, JNJ); NIH R37 AG013925 (JLK), the Connor Group (JLK), Glenn/AFAR BIG Award (JLK), Robert J. and Theresa W. Ryan (JLK), and the Noaber and Ted Nash Long Life Foundations (JLK).

Published
2023
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3. Cough-Specific Quality of Life Predicts Disease Progression Among Patients With Interstitial Lung Disease

Author

Janet Lee, Emily White, Elizabeth Freiheit, Mary Beth Scholand, Mary E. Strek, Anna J. Podolanczuk, Nina M. Patel, Rebecca Bascom, Elizabeth Belloli, Nitin Bhatt, Sangeeta Bhorade, Amy Case, Richard Castriotta, Gerard Criner, Sonye Danoff, Joao De Andrade, Alpa Desai, Marilyn Glassberg, Craig Glazer, Mridu Gulati, Nishant Gupta, Mark Hamblin, Tristan Huie, Robert Kaner, Daniel Kass, Hyun Kim, Maryl Kreider, Lisa Lancaster, Joseph Lasky, Andrew Limper, Sydney Montesi, Joshua Mooney, Lake Morrison, Anoop Nambiar, Steven Nathan, Bhupinder Natt, Tessy Paul, Rafael Perez, Anna Podolanczuk, Ganesh Raghu, Adrian Shifren, Mary Strek, Nevins Todd, Rajat Walia, Stephen Weight, Timothy Whelan, and Paul Wolters

Subjects
Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published
2022

4. Essential Features of an Interstitial Lung Disease Multidisciplinary Meeting An International Delphi Survey

Author

Alan K. Y. Teoh, Anne E. Holland, Julie Morisset, Kevin R. Flaherty, Athol U. Wells, Simon L. F. Walsh, Ian Glaspole, Wim A. Wuyts, Tamera J. Corte, Huzaifa Adamali, J. Shirine Allam, Sofia Antillon, Katherina M. Antoniou, Rodrigo Athanazio, Sergey Avdeev, Alexander Averyanov, Arata Azuma, Bruno Baldi, Elisabetta Balestro, Rebecca Bascom, Shalini Bastiampillai, Lutz Beckert, Jü¨ergen Behr, Paul Beirne, David Bennett, Raphael Borie, Demosthenes Bouros, Ben Brockway, Kevin Brown, Francisco Javier Callejas González, Diego Castillo, Ronald Chacon Chaves, Daniel Chambers, Sally Chapman, Nazia Chaudhuri, Harold Collard, Vincent Cottin, Bruno Crestani, Jesper Rømhild Davidsen, Devesh J. Dhasmana, Sahajal Dhooria, Juan Ignacio Enghelmayer, Alexandre Todorovic Fabro, Puneet Garcha, Nicole Goh, Alejandro Gomez, Christopher Grainge, Tomohiro Handa, Tristan Huie, Gary Hunninghake, Yoshikazu Inoue, Helen Jo, Kerri Johannson, Rene Jonkers, Eoin Judge, Yasemin Kabasakal, Leticia Kawano Dourado, Gregory Keir, Nasreen Khalil, Yet Hong Khor, Melissa King Biggs, Maria Kokosi, Yasuhiro Kondoh, Vasillis Kouranos, Michael Kreuter, David Lederer, Su Ying Low, Joachim Mü¨ller Quernheim, Toby Maher, Eliane Mancuzo, George Margaritopoulos, Carol Mason, Mariano Mazeini, Nesrin Mogulkoc, Maria Molina, Yuben Moodley, António Morais, Anoop Nambiar, Imre Noth, Hilario Nunes, Takashi Ogura, Oguzhan Okutan, Nina Patel, Carlos Pereira, Wojciech Piotrowski, Venerino Poletti, Silvia Quadrelli, Elzbieta Radzikowska, Pilar Rivera Ortega, Christopher J. Ryerson, Mauricio Salinas, Rafaela Sanchez, Recep Savas, Moises Selman, Adrian Shifren, Maria Raquel Soares, Eman Sobh, Jin Woo Song, Paolo Spagnolo, Martina Sterclova, Irina Strambu, Mary E. Strek, Takafumi Suda, Gabriela Tabaj, Jasna Tekavec Trkanjec, Fatma Tokgoz Akyil, Claudia Toma, Rade Tomic, Hiromi Tomioka, Daniel Traila, Lauren Troy, Sergio Trukillo, Argyrios Tzouvelekis, Carlo Vancheri, Brenda Elena Varela, Francesco Varone, Martina Vasakova, Elizabeth Veitch, Vanesa Vicens Zygmunt, Thomas Wessendorf, Glen Westall, Marlies Wijsenbeek, Margaret L. Wilsher, Jeremy Wrobel, Cesar Yoshito Fukuda, Chris Zappala, Pulmonary Medicine, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, AII - Amsterdam institute for Infection and Immunity, Pulmonology, and AII - Inflammatory diseases

Subjects
Pulmonary and Respiratory Medicine, PNEUMONIA, medicine.medical_specialty, Respiratory System, Delphi method, NDAS, Interstitial lung disease, THORACIC SOCIETY, R Medicine (General), DIAGNOSIS, behavioral disciplines and activities, Delphi, 03 medical and health sciences, 0302 clinical medicine, Lung diseases, interstitial/diagnosis, Multidisciplinary approach, Delphi technique, Medicine, Humans, CRITERIA, Medical physics, 030212 general & internal medicine, Pulmonologists, Essential features, Science & Technology, business.industry, STATEMENT, respiratory system, medicine.disease, R1, respiratory tract diseases, body regions, surgical procedures, operative, 030228 respiratory system, AGREEMENT, Multidisciplinary meeting, business, Surveys and questionnaires, CONSENSUS, Life Sciences & Biomedicine
Abstract

Supported by the National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis (GNT1116371), and by foundation partner, Boehringer Ingelheim, and program partners, Roche and Galapagos. Rationale : The interstitial lung disease (ILD) multidisciplinary meetings (MDM), composed of pulmonologists, radiologists, and pathologists, is integral to the rendering of an accurate ILD diagnosis. However, there is significant heterogeneity in the conduct of ILD MDMs, and questions regarding their best practices remain unanswered. Objectives : To achieve consensus among ILD experts on essential components of an ILD MDM. Methods : Using a Delphi methodology, semi-structured interviews with ILD experts were used to identify key themes and features of ILD MDMs. These items informed two subsequent rounds of online questionnaires that were used to achieve consensus among a broader, international panel of ILD experts. Experts were asked to rate their level of agreement on a five-point Likert scale. An a priori threshold for consensus was set at a median score 4 or 5 with an interquartile range of 0. Results : We interviewed 15 ILD experts, and 102 ILD experts participated in the online questionnaires. Five items and two exploratory statements achieved consensus on being essential for an ILD MDM following two questionnaire rounds. There was consensus that the presence of at least one radiologist, a quiet setting with a visual projection system, a high-quality chest high-resolution computed tomography, and a standardized template summarizing collated patient data are essential components of an ILD MDM. Experts also agreed that it would be useful for ILD MDMs to undergo an annual benchmarking process and a validation process by fulfilling a minimum number of cases annually. Twenty-seven additional features were considered to be either highly desirable or desirable features based on the degree of consensus. Although our findings on desirable features are similar to the current literature, several of these remain controversial and warrant further research. The study also showed an agreement among participants on several future concepts to improve the ILD MDM, such as performing regular self-assessments and conducting research into shared practices to develop an international expert guideline statement on ILD MDMs. Conclusions : This Delphi study showed consensus among international ILD experts on essential and desirable features of an ILD MDM. Our data represent an important step toward potential collaborative research into future standardization of ILD MDMs. Postprint

Published
2022

6. Immunologic resilience and COVID-19 survival advantage

Author

Grace C. Lee, Marcos I. Restrepo, Nathan Harper, Muthu Saravanan Manoharan, Alisha M. Smith, Justin A. Meunier, Sandra Sanchez-Reilly, Aamir Ehsan, Anne P. Branum, Caitlyn Winter, Lauryn Winter, Fabio Jimenez, Lavanya Pandranki, Andrew Carrillo, Graciela L. Perez, Antonio Anzueto, Hanh Trinh, Monica Lee, Joan M. Hecht, Celida Martinez-Vargas, Raj T. Sehgal, Jose Cadena, Elizabeth A. Walter, Kimberly Oakman, Raymond Benavides, Jacqueline A. Pugh, Scott Letendre, Maristella Steri, Valeria Orrù, Edoardo Fiorillo, Francesco Cucca, Alvaro G. Moreira, Nu Zhang, Elizabeth Leadbetter, Brian K. Agan, Douglas D. Richman, Weijing He, Robert A. Clark, Jason F. Okulicz, Sunil K. Ahuja, Mohamed I. Abdalla, Sandra G. Adams, Joseph Agnew, Saleem Ali, Jennifer Barker, Angela Birdwell, Stephen Bradford, Heather Briggs, Judith Marin Corral, Jennifer J. Dacus, Patrick J. Danaher, Scott A. DePaul, Jill Dickerson, Jollynn Doanne, Samantha Elbel, Corina Escamilla, Robert Farrar, David Feldman, Julianne Flynn, Delvina Ford, Joanna D. Foy, Megan Freeman, Samantha Galley, Maritza Garza, Sherraine Gilman, Jennifer Gomez, Varun K. Goyal, Sally Grassmuck, Joshua Hanson, Brande Harris, Gabrielyd Hastings, Audrey Haywood, Cecilia Hinojosa, Tony T. Ho, Teri Hopkins, Pamela Jewell, Thomas B. Johnson, Vasiliki Kotogiannes, Austin C. Lawler, Chadwick S. Lester, Stephanie M. Levine, Haidee V. Lewis, Angel Louder, Charmaine Mainor, Rachel Maldonado, Yvette Martinez, Neil McElligott, Laura Medlin, Myra Mireles, Kathleen Morneau, Samuel B. Munro, Anoop Nambiar, Daniel Nassery, Robert Nathanson, Jane O’Rorke, Cheryl Padgett, Sergi Pascual-Guardia, Marisa Patterson, Rogelio Perez, Robert E. Phillips, Patrick B. Polk, Michael A. Pomager, Kristy J. Preston, Kevin C. Proud, Michelle Rangel, Temple A. Ratcliffe, Renee L. Reichelderfer, Evan M. Renz, Jeanette Ross, Teresa Rudd, Maria E. Sanchez, Tammy Sanders, Kevin C. Schindler, David Schmit, Claudio Solorzano, Nilam Soni, Win S. Tam, Edward J. Tovar, Anna R. Tyler, Anjuli Vasquez, Maria C. Veloso, Steven G. Venticinque, Jorge A. Villalpando, Melissa Villanueva, Lauren Villegas, Andrew Wallace, Emily Wang, Andreia Williamson, Sadie A. Trammell Velasquez, Andrea Yunes, and Katharine H. Zentner

Subjects
Oncology, medicine.medical_specialty, business.industry, Immunology, Hazard ratio, Odds ratio, medicine.disease, Rate ratio, Framingham Heart Study, Acquired immunodeficiency syndrome (AIDS), Interquartile range, Internal medicine, Cohort, medicine, Immunology and Allergy, Immunocompetence, business
Abstract

Background The risk of severe COVID-19 varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). Objective To examine whether deficits in IR that antedate or are induced by SARS-CoV-2 infection independently predict COVID-19 mortality. Methods IR levels were quantified with two novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n=522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n=13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to clinical outcomes. Results IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection associated with underrepresentation of IHG-I (21%) vs. overrepresentation (77%) of IHG-II or IHG-IV, especially in males vs. females (P Conclusion Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19. Clinical implications Biomarkers tracking immunologic resilience may have broad prognostic utility, as they associated with longevity, as well as resistance to a progressive disease course during SARS-CoV-2, influenza, or HIV infection.

Published
2021

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