TABLE 1.

Potential treatable traits in ARDS across aetiology, physiology and morphology, and biology

Domain	Subdomain	Trait	Test	Evidence	Interventions to be tested	Challenges
Aetiology	Causal pathogen	COVID-19	PCR for virus	[16]	Dexamethasone
	ARDS-mimic	Diffuse acute interstitial lung diseases	History Imaging Immunological analysis	[75–77]	Immunosuppression	Relatively rare and requires systematic investigation to identify
		Diffuse pulmonary infections	History Serology Imaging Culture Metabolic products Metagenomics	[78]	Antimicrobials
		Drug-induced diffuse lung disease	History	www.pneumotox.com	Withhold drug
	Amplifiers of lung injury	Fluid overload	History Clinical examination Ultrasound Extravascular lung water	[79]	Diuretics Vasopressors	Diagnosis of fluid overload can be challenging
		Ventilator-induced lung injury	Tidal volume Driving pressure Mechanical power	[80]	Lower tidal volumes	No direct test for the actual development of VILI
	Nonresolving lung injury	Fibroproliferation	Markers of fibroproliferation in bronchoalveolar lavage fluid	[27]	Corticosteroids Antifibrotics	Biomarker test not routinely available
		Secondary infection	Imaging Culture Metagenomics	[81]	Antimicrobials	Identify ventilator-associated pneumonia in patient with ARDS
Physiology	Shunt	PaO2/FIO2	Blood gas	[43, 44]	Prone positioning Adjust PEEP Lung recruitment	Various thresholds proposed in different studies Influence of PEEP on PaO2/FIO2
	Ventilation	Dead space ventilation	Dead space calculation Ventilatory ratio	[82]	Adjust PEEP	Volumetric capnography not widely available
	Drive	High respiratory drive on NIV	Oesophageal pressure	[34]	Analgesia and sedation	Balance between high drive and too low drive
	Mechanics	High mechanical power	Formula based	[49]	Adjust PEEP, tidal volume and/or respiratory rate	Various thresholds proposed and unclear how to adjust settings based on value
		Driving pressure	Ventilator settings Oesophageal pressure	[83]	Adjust PEEP	Various thresholds proposed in different studies
Morphology	Imaging	Focal	Imaging	[53, 84, 85 ]	Prone positioning Low PEEP	Misclassification of morphology common and associated with worse outcome
		Nonfocal	Imaging	[53, 84, 85]	Lung recruitment High PEEP
Biology	Systemic host response	Hyperinflammatory (or Reactive)	IL-8, bicarbonate and protein C IL-6, bicarbonate and TNFRI	[31, 60, 62, 63, 86]	High PEEP Restrictive fluid Simvastatin Immunomodulation	No routine test available Frequently unknown if cause or effect of lung injury
	Epithelial injury	Damaged epithelium	Biomarkers e.g. sRAGE	[87]	Epithelial protection
	Endothelial injury	Vascular permeability and endothelial injury	Biomarkers e.g. angiopoietin 1 and 2	[88]	Endothelial protection Immunomodulation
	Angiopathy	Microthrombosis	Biomarkers e.g. D-dimers, PAI-1 Perfusion imaging	[89, 90]	Anticoagulation Immunomodulation
	Local host response	Pulmonary hyper-inflammation	Biomarkers in bronchoalveolar lavage fluid	[91]	Immunomodulation

There are a wide range of clinical conditions, ARDS severities and mediators in lung injury pathogenesis that may be targetable for treatment. Most interventions listed are speculative and should not yet be applied. The list is also not exhaustive. For all these interventions, we emphasise the need for phenotype-aware randomised controlled trials. COVID-19: coronavirus disease 2019; ARDS: acute respiratory distress syndrome; VILI: ventilator-induced lung injury; PaO₂: arterial oxygen tension; FIO₂: inspiratory oxygen fraction; PEEP: positive end-expiratory pressure; NIV: noninvasive mechanical ventilation; IL: interleukin; TNFRI: tumour necrosis factor receptor 1; sRAGE: soluble receptor for advanced glycation endproducts; PAI-1: plasminogen activator inhibitor-1.