Review

. 2021 Nov 23;25(1):404.

doi: 10.1186/s13054-021-03822-z.

Promises and challenges of personalized medicine to guide ARDS therapy

Katherine D Wick¹, Daniel F McAuley², Joseph E Levitt³, Jeremy R Beitler⁴, Djillali Annane^{5

6}, Elisabeth D Riviello⁷, Carolyn S Calfee^{8

9}, Michael A Matthay^{8

9}

Affiliations

¹ Cardiovascular Research Institute, University of California San Francisco, 513 Parnassus Avenue, HSE 760, San Francisco, CA, 94143, USA. katherine.wick@ucsf.edu.
² Belfast Health and Social Care Trust, Royal Victoria Hospital and Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
³ Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, CA, USA.
⁴ Center for Acute Respiratory Failure and Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University, New York, NY, USA.
⁵ Department of Intensive Care, FHU SEPSIS, and RHU RECORDS, Hôpital Raymond Poincaré (APHP), Garches, France.
⁶ Laboratory of Infection & Inflammation, School of Medicine Simone Veil, INSERM, University Versailles Saint Quentin, University Paris Saclay, Garches, France.
⁷ Harvard Medical School and Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁸ Cardiovascular Research Institute, University of California San Francisco, 513 Parnassus Avenue, HSE 760, San Francisco, CA, 94143, USA.
⁹ Departments of Medicine and Anesthesia, University of California, San Francisco, San Francisco, CA, USA.

PMID: 34814925
PMCID: PMC8609268
DOI: 10.1186/s13054-021-03822-z

Review

Promises and challenges of personalized medicine to guide ARDS therapy

Katherine D Wick et al. Crit Care. 2021.

. 2021 Nov 23;25(1):404.

doi: 10.1186/s13054-021-03822-z.

Authors

Katherine D Wick¹, Daniel F McAuley², Joseph E Levitt³, Jeremy R Beitler⁴, Djillali Annane^{5

6}, Elisabeth D Riviello⁷, Carolyn S Calfee^{8

9}, Michael A Matthay^{8

9}

Affiliations

¹ Cardiovascular Research Institute, University of California San Francisco, 513 Parnassus Avenue, HSE 760, San Francisco, CA, 94143, USA. katherine.wick@ucsf.edu.
² Belfast Health and Social Care Trust, Royal Victoria Hospital and Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
³ Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, CA, USA.
⁴ Center for Acute Respiratory Failure and Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University, New York, NY, USA.
⁵ Department of Intensive Care, FHU SEPSIS, and RHU RECORDS, Hôpital Raymond Poincaré (APHP), Garches, France.
⁶ Laboratory of Infection & Inflammation, School of Medicine Simone Veil, INSERM, University Versailles Saint Quentin, University Paris Saclay, Garches, France.
⁷ Harvard Medical School and Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁸ Cardiovascular Research Institute, University of California San Francisco, 513 Parnassus Avenue, HSE 760, San Francisco, CA, 94143, USA.
⁹ Departments of Medicine and Anesthesia, University of California, San Francisco, San Francisco, CA, USA.

PMID: 34814925
PMCID: PMC8609268
DOI: 10.1186/s13054-021-03822-z

Abstract

Identifying new effective treatments for the acute respiratory distress syndrome (ARDS), including COVID-19 ARDS, remains a challenge. The field of ARDS investigation is moving increasingly toward innovative approaches such as the personalization of therapy to biological and clinical sub-phenotypes. Additionally, there is growing recognition of the importance of the global context to identify effective ARDS treatments. This review highlights emerging opportunities and continued challenges for personalizing therapy for ARDS, from identifying treatable traits to innovative clinical trial design and recognition of patient-level factors as the field of critical care investigation moves forward into the twenty-first century.

Keywords: Acute lung injury; Acute respiratory distress syndrome; COVID-19; Clinical trials; Personalized medicine.

PubMed Disclaimer

Conflict of interest statement

KDW has received funding from NIH 5T32GM8440-24. DFM: Funding for PHIND trial from Innovate UK; grants/contracts from NIHR, Wellcome Trust, MRC, Northern Ireland HSC R&D division, and Novavax as an investigator for ARDS and Covid-19 trials; patent from Queen’s Belfast University for novel treatment for inflammatory disease (USB962032); consulting fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, and Eli Lilly for the study of ARDS and Covid-19; Speaker fees from GlaxoSmithKline for educational seminars; DSMB member for Vir Biotechnology, Inc. and Faron Pharmaceuticals; Co-director of research for the Intensive Care Society; Director of EME program for MRC/NIHR. Spouse has received consultancy fees from Insmed and the California Institute for Regenerative medicine. JEL has received a grant from the NIH (UH3HL141722) to study inhaled budesonide and formoterol for the treatment of hospitalized patients with pneumonia and hypoxemia for the prevention of acute respiratory failure. JRB: Grant funding from NIH grants K23-HL133489 and R21-HL145506. Consulting fees from Sedana Medical and Biomarck Pharmaceuticals for clinical trial design/planning, and Hamilton Medical for work as a medical monitor. DA has received a public grant through the national program “Programme d’Investissements d’avenir” under the reference ANR-18-RHUS-0004 for investigating corticosteroid therapy in COVID-19 and sepsis. This work is part of Federations Hospitalo-universitaires (FHU) Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis (SEPSIS). EDR declares no competing interests. CSC: Grant funding from the NIH for the investigation of ARDS; grant support from Roche/Genentech, and Bayer for observational studies of ARDS; consultancy fees from Roche/Genentech, Bayer, Gen1e Life Sciences, and Vasomune; fees for serving on the medical board of Prometric and Quark Pharmaceuticals; personal fees from Quantum Leap Healthcare Collaborative. MAM: Grant funding from the NIH for the investigation of ARDS; grant support from Roche/Genentech for observational studies of ARDS; consulting income from Citius Pharmaceuticals, Johnson and Johnson, and Novartis.

Figures

**Fig. 1**
Biologic mechanisms in ARDS that may be targeted by various personalizable therapies. *MSC* mesenchymal stromal cells, *CFH* cell-free hemoglobin, F₂*-IsoP* F₂ isoprostanes, *APAP* acetaminophen. Figure created in BioRender

**Fig. 2**
Estimated incidence of ARDS before and during the COVID-19 pandemic in the USA. ARDS prior to COVID-19 estimated from Rubenfeld et al., NEJM, 2005 (200,000/12 months or 300,000/18 months) [41]. COVID-19 ARDS estimated from 650,000 US deaths between March 2020 and September 2021, assuming 80% with severe pneumonia/ARDS and mortality of 20% from COVID-19 ARDS

**Fig. 3**
Mechanisms of MSC therapy for ARDS. *TNFα* tumor necrosis factor alpha, IL interleukin, *PMN* polymorphonuclear cells (neutrophils), *PGE-2* prostaglandin E2, *TSG-6* TNF stimulated gene 6, *HGF* hepatocyte growth factor, *ROS* reactive oxygen species, *LL37* cathelicidin antimicrobial peptide LL37, *KGF* keratinocyte growth factor, *Ang* angiopoietin, *AFC* alveolar fluid clearance

See this image and copyright information in PMC

References

1. Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Network NA. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2(8):611–620. - PMC - PubMed
1. Sinha P, Delucchi KL, Thompson BT, McAuley DF, Matthay MA, Calfee CS, Network NA. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 2018;44(11):1859–1869. - PMC - PubMed
1. Sinha P, Delucchi KL, Chen Y, Zhuo H, Abbott J, Wang C, Wickersham N, McNeil JB, Jauregui A, Ke S, Vessel K, Gomez A, Hendrickson CM, Kangelaris KN, Sarma A, Leligdowicz A, Liu KD, Matthay MA, Ware LB, Calfee CS. Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study. Thorax. 2021. 10.1136/thoraxjnl-2021-217158. - PMC - PubMed
1. Calfee CS, Delucchi KL, Sinha P, Matthay MA, Hackett J, Shankar-Hari M, McDowell C, Laffey JG, O'Kane CM, McAuley DF, et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. 2018;6(9):691–698. - PMC - PubMed
1. Famous KR, Delucchi K, Ware LB, Kangelaris KN, Liu KD, Thompson BT, Calfee CS, Network A. Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med. 2017;195(3):331–338. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Promises and challenges of personalized medicine to guide ARDS therapy

Affiliations

Promises and challenges of personalized medicine to guide ARDS therapy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources