Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• New Biomarkers for Acute Respiratory Distress Syndrome

  Acute respiratory distress syndrome (ARDS) remains a serious form of acute lung injury, marked by inflammatory damage, leaky pulmonary vessels and impaired oxygen exchange. Its clinical presentation can change rapidly, while patients with apparently similar oxygenation levels may have very different biological drivers and risks.

  Biomarker research aims to identify those differences earlier and more accurately. For respiratory clinicians, researchers and critical care teams in Australia, the most useful developments will be those that complement bedside assessment, support safer treatment decisions and work across metropolitan and regional health services.

  Why ARDS Needs Better Biological Signals

  ARDS is currently diagnosed through clinical criteria, including timing, chest imaging, oxygenation and the exclusion of hydrostatic pulmonary oedema. These measures are essential, but they do not fully describe the underlying biology. Two patients may meet the same diagnostic threshold while one has predominantly epithelial injury and another has severe endothelial activation or infection-driven inflammation.

  A useful biomarker could help identify disease before full criteria are met, divide patients into biologically meaningful subgroups and estimate likely outcomes. It could also reveal whether a treatment is affecting the intended pathway. This matters in Australian intensive care units, where demand, staffing and access to advanced testing differ between centres in Sydney, Melbourne, Brisbane, Perth and smaller regional hospitals.

  Biomarker group	What it may reflect	Potential clinical value
  Angiopoietin-2 and von Willebrand factor	Endothelial injury and vascular leak	Risk assessment and phenotype recognition
  Soluble RAGE	Alveolar epithelial damage	Identification of severe epithelial injury
  IL-6, IL-8 and TNF-related signals	Systemic and pulmonary inflammation	Prognosis and treatment stratification
  Protein C and thrombomodulin	Coagulation and endothelial dysfunction	Recognition of vascular complications
  Cell-free DNA and microRNAs	Tissue injury and gene regulation	Early detection and research phenotyping

  Endothelial And Epithelial Injury Markers

  The pulmonary endothelium controls movement of fluid and proteins from blood vessels into lung tissue. In ARDS, endothelial activation and disruption contribute to oedema, impaired microcirculation and poor oxygen delivery. Angiopoietin-2, von Willebrand factor, soluble thrombomodulin and related markers have therefore attracted interest as indicators of vascular injury.

  The alveolar epithelium is equally important. Type I and type II cells maintain the air–blood barrier and help clear fluid from the alveolar space. Soluble receptor for advanced glycation end products, or sRAGE, is associated with type I cell injury, while surfactant proteins may indicate epithelial stress. These markers may be especially informative when combined rather than interpreted in isolation.

  Inflammation And Immune Dysregulation

  Cytokines such as interleukin-6 and interleukin-8 can reflect an intense inflammatory response and have been associated with worse outcomes in selected ARDS cohorts. Other candidates include tumour necrosis factor pathways, pentraxin-3, ferritin and markers of neutrophil activation. Their value lies less in producing a single diagnostic number than in showing how strongly the immune system is engaged.

  Inflammatory markers must be interpreted carefully. Infection, trauma, pancreatitis and major surgery can all alter cytokine levels without producing identical lung pathology. Australian clinicians also manage patients with diverse infectious exposures and varying time to hospital presentation, so a result collected in a tertiary ICU should not automatically be treated as a universal threshold.

  Biomarkers And ARDS Phenotypes

  One promising direction is the recognition of hyperinflammatory and hypoinflammatory phenotypes. These groupings may combine clinical variables with plasma biomarkers to identify patients with different mortality risks and potentially different responses to ventilation strategies, fluid management or drug therapy.

  Phenotyping is still evolving. A biomarker panel that performs well in a research cohort may lose accuracy in a mixed ICU population. Age, chronic lung disease, kidney function, immunosuppression and the timing of blood collection can all affect results. Longitudinal sampling may therefore be more useful than a single measurement taken at admission.

  Genomics, Proteomics And Breath Analysis

  Genomic and transcriptomic methods can examine patterns of gene activity rather than one molecule at a time. Proteomics may identify combinations of proteins linked to barrier failure, coagulation or immune signalling, while metabolomics can reveal changes in cellular energy use. MicroRNAs and cell-free DNA are also being studied as indicators of tissue injury and altered regulation.

  Exhaled breath analysis offers a less invasive possibility. Volatile organic compounds may reflect oxidative stress, infection or altered metabolism, although devices and sampling protocols still require standardisation. For Australia, a portable test could eventually have value in outer-metropolitan and regional hospitals, where rapid transport to a specialist centre may be difficult.

  Using Biomarkers With Imaging And Physiology

  Biomarkers should strengthen, rather than replace, established clinical assessment. Oxygenation indices, ventilator mechanics, compliance, ultrasound and computed tomography each provide different information about lung function. Combining these data with biological signals could improve recognition of recruitability, fluid-related deterioration or progressive epithelial damage.

  Research on childhood lung trajectories also reinforces the importance of viewing respiratory health across the life course. Pre-existing airway disease, smoking exposure and earlier impairment may influence how an adult responds to acute lung injury. In practice, a biomarker result needs to be interpreted alongside the patient’s baseline respiratory reserve.

  From Research Assay To Hospital Test

  Clinical translation requires more than statistical association. A candidate marker must have a reliable assay, a clear reference range, acceptable turnaround time and evidence that its use changes management. It should also perform consistently across laboratories and patient groups, including people with sepsis, chronic kidney disease or cardiac failure.

  Australian implementation must account for regulation and procurement. Diagnostic products may require assessment under the Therapeutic Goods Administration framework, while hospital laboratories must meet quality, privacy and governance requirements. Cost also matters: a complex multiplex panel may be unsuitable for routine use if a smaller combination provides similar clinical information.

  Building Practical Biomarker Pathways

  The strongest future pathway is likely to combine a small biomarker panel with electronic clinical data and repeated measurements. A first sample could support early risk classification, while later samples might show whether inflammation or endothelial injury is resolving. Such a system could assist decisions about referral, monitoring and trial enrolment without creating another disconnected test result.

  Research should include public and private hospitals, intensive care networks and regional services rather than relying only on large academic centres. Samples need consistent collection, storage and reporting, with attention to Indigenous health research principles and equitable access. Biomarkers will be most valuable when they clarify a patient’s biological state and lead to a safer, timely action.

  The key point to remember is that ARDS biomarkers are moving towards biological precision, but their real value depends on validated panels, clinical context and practical delivery at the bedside.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)