TABLE 1

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

DomainSubdomainTraitTestEvidenceInterventions to be testedChallenges
AetiologyCausal pathogenCOVID-19PCR for virus[16]Dexamethasone
ARDS-mimicDiffuse acute interstitial lung diseasesHistory
Imaging
Immunological analysis
[75–77]ImmunosuppressionRelatively rare and requires systematic investigation to identify
Diffuse pulmonary infectionsHistory
Serology
Imaging
Culture
Metabolic products
Metagenomics
[78]Antimicrobials
Drug-induced diffuse lung diseaseHistorywww.pneumotox.comWithhold drug
Amplifiers of lung injuryFluid overloadHistory
Clinical examination
Ultrasound
Extravascular lung water
[79]Diuretics
Vasopressors
Diagnosis of fluid overload can be challenging
Ventilator-induced lung injuryTidal volume
Driving pressure
Mechanical power
[80]Lower tidal volumesNo direct test for the actual development of VILI
Nonresolving lung injuryFibroproliferationMarkers of fibroproliferation in bronchoalveolar lavage fluid[27]Corticosteroids
Antifibrotics
Biomarker test not routinely available
Secondary infectionImaging
Culture
Metagenomics
[81]AntimicrobialsIdentify ventilator-associated pneumonia in patient with ARDS
PhysiologyShuntPaO2/FIO2Blood gas[43, 44]Prone positioning
Adjust PEEP
Lung recruitment
Various thresholds proposed in different studies
Influence of PEEP on PaO2/FIO2
VentilationDead space ventilationDead space calculation
Ventilatory ratio
[82]Adjust PEEPVolumetric capnography not widely available
DriveHigh respiratory drive on NIVOesophageal pressure[34]Analgesia and sedationBalance between high drive and too low drive
MechanicsHigh mechanical powerFormula based[49]Adjust PEEP, tidal volume and/or respiratory rateVarious thresholds proposed and unclear how to adjust settings based on value
Driving pressureVentilator settings
Oesophageal pressure
[83]Adjust PEEPVarious thresholds proposed in different studies
MorphologyImagingFocalImaging[53, 84, 85 ]Prone positioning
Low PEEP
Misclassification of morphology common and associated with worse outcome
NonfocalImaging[53, 84, 85]Lung recruitment
High PEEP
BiologySystemic host responseHyperinflammatory (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 injuryDamaged epitheliumBiomarkers e.g. sRAGE[87]Epithelial protection
Endothelial injuryVascular permeability and endothelial injuryBiomarkers e.g. angiopoietin 1 and 2[88]Endothelial protection
Immunomodulation
AngiopathyMicrothrombosisBiomarkers e.g. D-dimers, PAI-1
Perfusion imaging
[89, 90]Anticoagulation
Immunomodulation
Local host responsePulmonary hyper-inflammationBiomarkers 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.