Cecilia Van Cauwenberghe, from TechVision Group, Frost & Sullivan provides a fascinating overview of acute respiratory distress syndrome, including refocusing clinical concerns and disease management, as well as the overall characteristics and health implications
Acute respiratory distress syndrome (ARDS) is an inflammatory disease characterised by a severe dysfunction of the pulmonary epithelial cells and the capillary endothelial cells. According to a recent study published by Yang et al., 2018, the process occurs along with the infiltration of alveolar macrophages and neutrophils in the respiratory track and additional biochemical adverse effects that may lead to cell apoptosis (programmed cell death), necroptosis (programmed form of necrosis or inflammatory cell death), NETosis (cell death characterised by the release of decondensed chromatin and granular contents to the extracellular space),and fibrosis (formation of excess fibrous connective tissue). The authors emphasise that inflammatory cascades also impair the regulation of vascular endothelial barrier and vascular permeability.
In fact, all stages of ARDS involve inflammatory responses, which mean that an in-depth understanding of immune signalling and regulatory pathways in the pulmonary microenvironment plays an essential role in ARDS clinical management with the development of effective therapeutic interventions. This perspective has detonated the interest in associating clinical and basic research with the critical study of the molecular regulation of inflammatory cells and cytokines in the pathogenesis of ARDS.
Statistical framework and economic burden
ARDS is a life-threatening respiratory disease that reports 10.4% of intensive care unit admissions worldwide, corresponding to more than 3 million patients with ARDS annually, according to the epidemiological studies carried out by Bellani et al., 2016. The authors remark that ARDS appears to be generally under-recognised and undertreated, thereby explaining its high mortality rate. In the United States alone, ARDS affects approximately 200,000 patients each year, representing broadly 75,000 deaths annually. According to Frost & Sullivan’s competitive pipeline analysis, Das, 2015, ARDS involves 3.6 million hospital days per year in this country. Furthermore, from patients surviving the disease only 49% can return to work, which implies an average annual loss in earnings of $27,000 per ARDS patient. Moreover, 13% of ARDS patients on average need permanent renal replacement therapy, typically dialysis, that is, an additional annual cost of dialysis $89,000 per ARDS patient. Summarising, the ARDS economic burden in the United States is approximately $1.16 billion per year.
Early recognition guidelines
The Berlin definition proposes three categories of ARDS based on the severity of hypoxemia: mild, with a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) between 200 and 300 millimeters of mercury (mmHg); moderate, with a PaO2/FiO2 between 100 and 200 mmHg and severe, with a PaO2/FiO2 lower than 100 mmHg. These categories are additionally supported by explicit criteria related to the timing of the syndrome’s onset, the origin of oedema and the chest radiograph outcomes for early recognition.
Biochemically, ARDS is typified by three main phases:
1) an exudative phase in which antigen-presenting cells (APCs) trigger immune responses leading to the aforementioned epithelial and endothelial cell damage; 2) a proliferative phase in which the release of vascular endothelial growth factor (VEGF) increases vascular permeability and exudation of protein-rich fluid that may become chronic; and 3) a lung remodelling phase in which lungs change their architecture involving the formation of fibrosis and honeycomb geometries thus impairing gas exchange. Therefore, an effective ARDS clinical management necessarily implies recognising first signs at early stages and once diagnosed, preventing tissue hypoperfusion and adequate gas exchange ratio.
Disease management discussion
Fan et al., 2018, have reviewed the advances in diagnosis and treatment of ARDS over the last five years by critically and systematically assessing MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews dating from 2012 to 2017 and searching for randomised clinical trials, meta-analyses, systematic reviews and clinical practice guidelines for ARDS.
According to the researchers, no effective therapeutic treatments focused on the underlying biology of the disease are exhibited. Gattinoni et al., 2018, have noted that present disease management approaches are based on improved guidelines for lung-protective mechanical ventilation and symptoms relief. The authors also remark the level of uncertainty in many studies, the complexity of the disease, as well as, inappropriate enrollment criteria and imprecise deployment of the interventions, among others. Regarding this approach, Beloncle et al., 2018, have remarked that despite major enhancements in ventilation strategies, hospital mortality and morbidity associated with ARDS remain dramatically high. The authors foresee some potential improvements in the field by paying attention to adjacent measures to limit the risks of inflammation, infection and fluid overload, prevent ventilator-induced lung injury and patient self-inflicted lung injury and advance pharmacological treatments on the base of immune system modulation. However, according to Reiss et al., 2018, inflammation-directed therapies have yet failed to improve the outcome in ARDS patients.
The authors highlight the underestimation of the syndrome’s complexity, including its complex interrelations between inflammatory circuits. Indeed, recent gene expression analyses from patients with ARDS reveal a vast number of distinct expressed genes significantly overlapping immunologic conditions. To address this concern, the researchers propose the combination of model-driven simulations, data-driven modelling and hypothesis-driven experimental studies illustrating regulatory circuits interacting during pulmonary inflammation. Hussein et al., 2018, also claim the crucial need to introduce ‘omics’ approaches to assess suitable therapeutic targets and develop new strategies to reduce heterogeneity and optimise the design of clinical trials.
I would like to thank all contributors from industry involved with the development and delivery of this article and Frost & Sullivan’s staff from the TechVision Group.
Bellani, G., Laffey, J.G., Pham, T., Fan, E., Brochard, L., Esteban, A., Gattinoni, L., Van Haren, F., Larsson, A., McAuley, D.F. and Ranieri, M., 2016.
Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. Jama, 315(8), pp.788-800.
Beloncle, F. and Mercat, A., 2018. Approaches and techniques to avoid development or progression of acute respiratory distress syndrome. Current opinion in critical care, 24(1), pp.10-15.
Das, R., 2015. A Product and Pipeline Analysis of the Human Plasmaderived Therapeutics Market – Launch of Novel Immunoglobulin Products and Increasing Awareness of Therapeutic Options to Drive Double-digit Market Growth. Frost & Sullivan Competitive Pipeline Analysis.
Fan, E., Brodie, D. and Slutsky, A.S., 2018. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA, 319(7), pp.698- 710.
Gattinoni, L., Marini, J.J. and Quintel, M., 2018. Time to Rethink the Approach to Treating Acute Respiratory Distress Syndrome. JAMA, 319(7), pp.664-666.
Hussain, M., Xu, C., Ahmad, M., Majeed, A., Lu, M., Wu, X., Tang, L. and Wu, X., 2018. Acute Respiratory Distress Syndrome: Bench-to-Bedside.
Approaches to Improve Drug Development. Clinical Pharmacology & Therapeutics. Reiss, L.K., Schuppert, A. and Uhlig, S., 2018. Inflammatory processes during acute respiratory distress syndrome: a complex system. Current opinion in critical care, 24(1), pp.1-9.
Yang, C.Y., Chen, C.S., Yiang, G.T., Cheng, Y.L., Yong, S.B., Wu, M.Y. and Li, C.J., 2018. New Insights into the Immune Molecular Regulation of the Pathogenesis of Acute Respiratory Distress Syndrome. International journal of molecular sciences, 19(2), p.588.
Cecilia Van Cauwenberghe, PhD, MSc, BA
Associate fellow and senior industry analyst
TechVision Group, Frost & Sullivan
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