ACUTE RESPIRATORY DISTRESS SYNDROME

CHALLENGES FOR TRANSLATIONAL RESEARCH ANDOPPORTUNITIES FOR PRECISION MEDICINE

ARDS: a complex, under-recognized, and life-threatening syndrome

Acute respiratory distress syndrome (ARDS)was first described as a clinical syndrome byDavid Ashbaugh, Thomas Petty, and coauthorsin 1967. The next 20 years of ARDS research focused primarily on pathophysiology andpathogenesis, including both animal and humanstudies. Several refinements of the definition ofARDS were published including the 4-pointacute lung injury score in 1988, the AmericanEuropean Consensus definition in 1994, and thelatest Berlin definition of ARDS in 2012.

ARDS is defined using the clinical criteria of bilateral pulmonary opacities on chest radiograph,arterial hypoxemia [partial pressure of arterialoxygen (PaO2) to fraction of inspired oxygen(FiO2) ratio ≤ 300 with positive end-expiratorypressure (PEEP) ≥ 5 cmH2O] within one week ofa clinical insult or new or worsening respiratorysymptoms, and the exclusion of cardiac failureas the primary cause. ARDS is a syndrome ofpulmonary edema and inflammation that oftenincludes non-pulmonary organ dysfunction. Although ARDS is present in more than 10% ofintensive care unit (ICU) admissions and innearly 25% of ICU patients requiring mechanicalventilation, it is still an under-recognized challenge for clinicians, with a hospital mortalityrate of 35-45%. Beyond such a high mortalityrate, ARDS is associated with greater healthcareutilization, reduced quality of life among survivors and worse long-term physical and cognitive outcomes.

A need for translational research to discoverdisease modifying therapies for ARDS

Fifty years after its first clinical description, anddespite intense research, the identification of aneffective ARDS therapy has failed to date. Majorprogress has been made in reducing mortalityfrom ARDS with “lung-protective” ventilation,using a tidal volume of 6 mL per kg of predictedbody weight and a plateau airway pressure of lessthan 30 cm H2O. In more severely hypoxemicpatients with ARDS, neuromuscular blockadeand prone positioning have further reduced mortality, probably by extending the therapeuticeffects of lung protective ventilation. Fluid-con-servative therapy has also increased ventilator-freedays in patients with ARDS. The lack of successof pharmacological therapies for ARDS, however,presents a continued challenge in the field and many negative trials on pharmacologicalagents, including beta-agonists, corticosteroids,anticoagulants, and surfactant replacement,among others, have now been performed.

In 2003, it was already suggested by a NationalHeart, Lung, and Blood Institute working groupon future directions for research into acute lunginjury that an improved understanding of diseaseheterogeneity, through use of biological approaches to translational models, would providemajor new insight into the pathogenesis and resolution of ARDS. Translation of basic researchfindings to clinical practice remains daunting because of the heterogeneity and complexity ofARDS. Recent basic studies have done well tomirror the multiple-hit hypothesis for ARDS

Acute respiratory distress syndrome:challenges for translational research andopportunities for precision medicine

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pathogenesis, which states that lung injury occursmost readily with concomitant physiological insultsthat prime the immune system for an amplifiedresponse to mechanical lung stress. However,young, typically healthy animals are managedright after ARDS onset for limited time in thesestudies. Future animal models should reproducethe comorbidities, risk factors for multiorganfailure, and prolonged critical illness common inpatients with ARDS.

Many of the treatments tested may simply not beefficacious, and for some others, the side effectsmay outweigh the benefits. However, while benefit has been demonstrated in numerous preclinical studies for many candidate therapies,most have failed to translate to improved outcomes for patients in randomized clinical trials,suggesting that either the experimental modelspoorly represent the clinical syndrome or that theappropriate subset of patients to target with thenovel therapies has not been correctly identified.Because ARDS mortality remains high, currentinitiatives also include primary prevention, witha key challenge being to identify at-risk patients

in whom ARDS is likely to develop and whowould benefit if ARDS were prevented. No preventive pharmacologic strategy has proveneffective to date, and although clinical scores canidentify patients who are more likely to developARDS, biomarkers may improve the predictivevalue of clinical-only scores in select at-risk populations.

The recognition of ARDS phenotypes andendotypes

There has only been recent recognition of theclinical and biological heterogeneity within ARDS,which reflects an incomplete understanding ofARDS biology. Although it was previously subdivided on the basis of clinical risk factors orby a direct versus indirect cause of lung injury,consensus does not currently exist on the mostappropriate approach to reduce ARDS hetero-geneity. In ARDS, recent evidence suggest distinctphenotypes (on the basis of clinical/biochemicalvariables, natural history, disease manifestation,

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“Although ARDS is present in morethan 10% of intensive care unit(ICU) admissions and in nearly 25% of ICU patients requiringmechanical ventilation, it is still anunder-recognized challenge forclinicians, with a hospital mortalityrate of 35-45%.”

and/or response to treatment without any impli-cation about mechanism) and endotypes (definedby a distinct functional or pathobiological mechanism) for ARDS. Phenotypes that have beenreported to date may be classified by severity, biology (e.g. hyperinflammatory versus hypo -inflammatory phenotypes), etiology, timing,lung morphology, or lung physiological or mechanical properties.

For example, a working hypothesis has been thatelevated plasma sRAGE (soluble receptor foradvanced glycation end-products) could reflectthe severity of alveolar epithelial injury in thelungs from patients with ARDS. This theory issupported by recent studies, including evidence inthe ex vivo human lung. It has been demonstratedin ARDS that alveolar fluid clearance (AFC, i.e.

the resolution of alveolar edema) is impairedwhen sRAGE is elevated in the alveolar fluid orplasma. Interestingly, a phenotype of nonfocallung morphology (or nonfocal morphotype) isassociated with an endotype of more severelyimpaired AFC, thus providing the first evidenceof distinct functional patterns between focal andnonfocal ARDS. As RAGE pathway may play amajor role in the mechanisms leading to AFCand its regulation (even though its precise rolesare still under investigation), a growing body ofevidence now supports an association betweenRAGE pathway, impaired AFC and ARDS morphotypes. This may fill a gap in the fullrecognition of a phenotype of lung morphologythat could be linked to an endotype of impairedAFC and an activated RAGE pathway. Of note,such a hypothesis on endotypes could be of

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particular importance because both impairedAFC and higher plasma levels of sRAGE havebeen associated with outcome, because the biological plausibility is high, and it is inherentin the process of ARDS evolution.

Indeed, the current definition of ARDS, based onclinical and radiographic data, has probably hindered the identification of targeted therapiesused to manipulate select biological mechanismsunderlying ARDS. Although we have long beenable to identify subtypes within ARDS (i.e., subsets of patients that do not necessarily implydifferences in function, biology, or observablecharacteristics) that confer different prognoses,the novelty is that we are now able to identifyphenotypes and endotypes that may confer different response to therapy.

Opportunities for precision medicine in ARDS

Precision (or personalized) medicine, i.e. theconcept that everyone has a unique response todisease susceptibility and drug metabolism, is farfrom being a revolutionary concept. More than2,000 years ago, Hippocrates emphasized theimportance of a personalized approach tomedicine: “It is far more important to know whatperson the disease has than what disease theperson has” (Hippocrates (460 BC-370 BC)).Because a growing body of literature now supports the identification of various forms ofARDS with potential differences regarding theirmanagement, response to therapeutic interventionsor prognosis, the next step will be to implementand evaluate the concept of precision medicineto inform therapeutic approach and tailor treatmentand prevention strategies to individual patientswith ARDS.

However, most pieces of evidence supportingsuch phenotypes or endotypes have been generatedby retrospective, small-sized and/or unreplicatedstudies, and more work is needed from us to refine and validate known phenotypes/endotypes,as well as to discover new ones. In addition, thequestion of clinical impact remains open formost proposed ARDS phenotypes/endotypes andfuture studies are warranted to confirm the fullpotential of precision medicine for ARDS, i.e. thepromise to deliver the right (targeted) treatmentat the right time and to the right person.

Main challenges that hamper the implementationof precision medicine in critical care include insufficient evidence generation, infrastructurechallenges, and how to efficiently handle and analyze high throughput data. Although random-ized clinical trials are still the gold standard forevidence generation, an emerging approach is tocollect data as part of ongoing clinical care inorder to generate evidence for patient and economic outcomes. Some of the most important

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“However, most pieces of evidencesupporting such phenotypes orendotypes have been generated byretrospective, small-sized and/orunreplicated studies, and more workis needed from us to refine andvalidate known phenotypes/endotypes,as well as to discover new ones.”

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benefits of precision medicine may involve identifying healthy individuals at elevated riskof disease, to facilitate the implementation of targeted preventive therapies. Depending on thedisease, a precision medicine innovation that accurately identifies at-risk patients and is coupledto an intervention which reduces disease incidenceby 10% could generate hundreds of billions ofdollars in value. However, diagnostic tests havenot flourished as rapidly as expected, due, inpart, to a challenging economic environment forinnovators. To realize the promise of precisionmedicine, it is now crucial to develop evidenceof its benefit, accelerate clinical data integrationand assessment, and promote the integration ofmolecular guidance into care. Advanced studydesigns need to be applied to precision medicinefor ARDS. Firstly, the translation of basic research findings into clinical practice should beimproved using experimentation that is most capable of optimally modeling the heterogeneityand complexity of ARDS. Therefore, ideally,specific endotypes described in patients with ARDSshould be reproduced in future experimentalmodels. There are several other hurdles to effectiveclinical trial designs for ARDS, including cost. The need for large-scale trials with manyparticipating sites poses logistical challenges and requires adequate research infrastructure investment. Therefore, mechanistic physiologicaland biological data should be collected duringthe trials, whenever possible, to evaluate not justwhether a treatment is beneficial, but why andfor whom.

What steps are needed to move precisionmedicine for ARDS closer to reality? First, adeeper understanding of the clinical and biologicalheterogeneity within the syndrome is needed.Large, international, multicenter well-character-ized patient cohorts, with thoughtfully planneddata collection and biosample repositories, are

required to further refine and validate knownphenotypes/endotypes and to identify novel patient subgroups that may not necessarily correspond to our presuppositions about ARDSheterogeneity. Such studies are needed to testprospectively the logistics of incorporating clinical, imaging, and biologic measurements thatbest identifies subgroups for trial enrichment,balancing needs for feasibility and generalizability.Second, the translation of basic research findingsinto clinical practice should be improved usingexperimentation that is most capable of optimallymodeling the heterogeneity and complexity ofARDS. Therefore, ideally, specific endotypesdescribed in patients should be reproduced in future experimental models, and targeted therapiesshould be tested in experimental studies that aremost likely to model specific disrupted functionor biology. Finally, investment in the developmentof point-of-care tests is needed with the objectiveof being able to rapidly assess endotypes at thebedside and the goals of testing more personalizedapproaches to managing patients with ARDS andto ultimately improve clinical outcome.

Matthieu JabaudonAssociate Professor of Medicine,Anesthesiology, and Critical Care

CHU Clermont-Ferrand, Université Clermont Auvergne,CNRS UMR 6293, INSERM U1103, GReDTel: +33 473 750 476mjabaudon@chu-clermontferrand.fr www.taura-project.comwww.gred-clermont.fr @TAURA_project @mj0b

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“In ARDS, recent evidence suggest distinctphenotypes (on the basis of clinical/biochemicalvariables, natural history, disease manifestation,and/or response to treatment without anyimplication about mechanism) and endotypes(defined by a distinct functional or pathobiologicalmechanism) for ARDS.”

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