Damian Sendler: It is difficult to define acute respiratory distress syndrome (ARDS) as a single clinical entity because of its wide range of symptoms. Lung injury causation, resolution, and healing have evolved significantly during the last several decades. ARDS mortality and morbidity are still high despite the fact that only therapy aimed at reducing ventilation-induced lung damage have shown consistent benefit to yet. Numerous potential treatments that showed promise in preclinical investigations were found to be useless in human trials, most likely as a result of the clinical and biological heterogeneity that affects ARDS patients’ treatment response.
Damian Jacob Sendler: Patients who are most likely to benefit from certain treatments will be identified via the use of precision medicine in clinical trials, which may help account for the variability of ARDS patients’ responses. National Institutes of Health (NIH) hosted an October 2019 session of interdisciplinary specialists to discuss research potential and obstacles for speeding precision medicine in the treatment of ARDS. Preclinical ARDS models play a critical role in the creation and validation of a precision medicine strategy.
Dr. Sendler: Cohort studies are vital for advancing precision medicine, and innovative clinical trial methodologies are needed to support this strategy. It is our hope that this Position Paper will serve as a guide for the advancement of precision medicine in ARDS. Precision therapeutics for ARDS have never been more critical than they are now because a COVID-19 pandemic has made many of the major principles, breakthroughs, and problems presented at this workshop urgently necessary.
Damian Sendler
As much as a quarter of all critically sick patients who need mechanical ventilation develop acute respiratory distress syndrome (ARDS).
In spite of significant progress in avoiding ARDS-induced lung injury,2 ARDS is still linked with a high death rate and long-term morbidity among survivors.
Damian Jacob Markiewicz Sendler: ARDS has yet to be successfully treated with a particular medication. Uncountable preclinical treatments have been shown to be unsuccessful in human trials because of the variability in clinical and biological characteristics of ARDS in humans. 6 In a precision medicine approach, such underlying heterogeneity is supposed to be openly addressed in order to better understand how different individuals with the same illness respond to treatment.
Due to the inability to thoroughly identify possible causes of heterogeneity, precision medicine approaches to ARDS are not feasible. Patients with certain clinical–molecular multivariable phenotypes may respond differently to treatments that have been judged unsuccessful for the general population, according to growing evidence8, 9, 10. This gives rise to renewed optimism for the use of precision medicine in the treatment of ARDS.
As a result of these developments, the NHLBI’s Division of Lung Diseases organized a meeting to identify research possibilities and identify possible hurdles to advancing precision medicine in ARDS treatment. The invited preclinical, human translational, and clinical ARDS trial specialists were joined by experts from outside the area of ARDS in precision medicine and adaptive trial design. Weighing existing research in ARDS and recommending strategic coordination of future research from bench to bedside, this Position Paper summarizes the group’s presentations and debates. The participants of the workshop came up with the following summaries. It’s worth noting that this workshop was held before to the COVID-19 pandemic, which was brought on by the newly discovered coronavirus SARS-CoV2. COVID-19, which has become a prevalent cause of ARDS, demonstrates the wide range of phenotypes that may arise from even a single precipitant of lung damage and the necessity for high-efficiency trials to swiftly assess potential therapeutics. This Position Paper includes a short overview of important elements of the epidemic by workshop participants, many of whom have been actively engaged in clinical research linked to COVID.
Formulation of executive summaries and assertions of viewpoint.
Damien Sendler: The National Institutes of Health (NHLBI) held a workshop in Bethesda, Maryland, from October 22 to 23, 2019, bringing together specialists in ARDS, precision medicine, and adaptive trial design. It was organized by CSC, BTT, and the NRA, and was themed Precision Medicine in ARDS. Through a series of pre-workshop conference calls, with input from the session moderators (including JCM, RMB, MNG, TRM, JAB, TJS, and MM), the workshop chairs organized the meeting into three sessions to discuss thematic questions that broadly defined current and future research directions for advancing precision medicine in ARDS. It was determined that three key questions needed to be addressed in order to design future clinical trials that would help advance ARDS’ precision medicine: (1) the current state of ARDS research; (2) what can be learned from other disease areas that have made precision medicine advances; and (3) pressing considerations. For the presentations, workshop chairmen and moderators divided the group into groups according to competence.
Damian Jacob Sendler
Participants created summaries of the information to be given in advance of the workshop, and the chairs were provided with slides for comments. A series of short presentations and group discussions followed, with the goal of distilling important points for each topic. Final consensus statements were drafted by JRB and forwarded to all participants for modification following the workshop, which was done through electronic communication after the meeting to arrive at the final summary statements shown below (Panel 1, Panel 2 ). From the presentations and discussions that took place during the workshop, this Position Paper was crafted with input from all authors and represents the opinions of the interdisciplinary group of writers.
in ARDS, precision medication is a must.
Physicians attempt to provide treatment that is personalized to each patient’s unique needs, maximizing possible benefit and minimizing risk. Precision medicine captures this goal. The practicality of this method may be contingent on the capacity to classify patients in advance based on their likelihood of responding to therapy. In other fields, such as melanoma, BRAF inhibitors or targeting of receptors for oestrogen, progesterone, or human epidermal growth factor receptor 2 in breast cancer11, 12 or subphenotyping of severe asthma13, examples of the value of identifying and targeting treatment-responsive subgroups are provided by rigorous cohort characterisation. ARDS is, by definition, a clinical illness that may manifest itself in a variety of ways. Sub-phenotyping patients with ARDS based on molecular causes that are clinically accessible and actionable is expected to speed up therapeutic development.
Despite this, it is rare to find techniques for measuring alveolar inflammation or barrier function that have been well verified and made freely accessible. When it comes to ARDS diagnosis, there are no strict syndromic criteria and the diagnosis is based on clinical judgment, which introduces inter-clinician variability and, as a consequence, phenotypic variation across doctors. 3 A more exact definition, on the other hand, would not eradicate ARDS’s significant clinical overt heterogeneity.
Patients with ARDS are commonly subtyped using respiratory physiology, but with inconsistent outcomes. The lower the PaO2/FiO2 ratio, the more likely it is that diffuse alveolar damage will be seen on autopsy,14 although the ratio is altered significantly by ventilator settings15 and does not reliably discriminate therapy response. It’s unclear if patients with greater PaO2/FiO2 ratios would benefit from the same therapies as those who have lower PaO2/FiO2 ratios, however stratification of ARDS based on these ratios has shown some effectiveness in clinical trials.
Treatment responsiveness may be affected by treatment-induced lung damage, however it is difficult to evaluate the difference between ventilator techniques on lung injury at the bedside.
Global respiratory mechanics and ventilator support are utilized to identify individuals with ARDS on a regular basis. 19, 18 Focal or diffuse radiographic ARDS classification of lung injury indicates regional mechanical heterogeneity, correlates with biomarkers of alveolar epithelial injury, and has prognostic value, but it is unclear whether it has value in predicting treatment response and is not consistently characterised in practice.
For example, pneumonia, aspiration, and other risk factors for ARDS have been classified as direct (pulmonary) or indirect (extrapulmonary) based on whether the damaging risk factor originated in the lungs or somewhere else (eg, abdominal sepsis, pancreatitis, transfusion-related). It has been shown that indirect ARDS has a lower probability of development to fibrosis and more alveolar epithelial damage than direct ARDS. Numbers 23 and 24 Direct and indirect ARDS may have different clinical predictors of death. 25 However, pinpointing the exact cause of a lung damage is difficult due to the wide range of possible explanations. Direct and indirect injuries can occur simultaneously in patients with no known risk factors.26 1 The categorization of harmful stimuli by direct or indirect precipitant does not take into account whether the stimulus is temporary (e.g., transfusion, trauma, aspiration) or prolonged (e.g., days) (eg, infection, pancreatitis).
ARDS may be influenced by other clinically overt variables, which might affect the disease’s progression and the efficacy of treatment. Additional clinical variability, such as the use of various hydration management and sedation strategies, might have an impact on patient outcomes and the responsiveness of treatment. Twenty-seven and a half blockers and agonists, statins, and inhaled and systemic corticosteroids8, 29, 30 may have a direct impact on the host response to lung damage when administered to treat underlying illnesses. Smoking, drinking alcohol, and poor air quality all have the potential to alter the body’s response to pulmonary assaults. 32, 33, and 32 A variety of pathogen species and strains may cause lung damage in patients with infection-associated ARDS via various virulence mechanisms and pathogen–host interactions. 34 Ventilation-induced lung damage may be targeted with treatments that take advantage of the variation in respiratory mechanics, while medicines aimed at other routes of ARDS etiology have had less success using clinically evident heterogeneity.
Dr. Damian Jacob Sendler and his media team provided the content for this article.
