Epidemiology of ARDS and ALI

Blank, Ross; Napolitano, Lena M.

doi:10.1016/j.ccc.2011.05.005

Cited by 103 publications

(78 citation statements)

References 120 publications

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“…In humans, surfactant deficiency manifests as respiratory distress syndrome (RDS), which is a major cause of mortality in children less than 1 year old (46). RDS is particularly common among premature infants because surfactant production by ATII cells occurs primarily in the final weeks of gestation.…”

Section: Discussionmentioning

confidence: 99%

Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

Goetzman

Alcorn

Bharathi

et al. 2014

Journal of Biological Chemistry

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Background:The contribution of long-chain acyl-CoA dehydrogenase (LCAD) to human fatty acid oxidation is not understood. Results: LCAD localizes to lung alveolar type II cells, which produce pulmonary surfactant; LCAD-deficient mice have surfactant dysfunction. Conclusion: LCAD is important for lung energy metabolism and lung function. Significance: LCAD may play a role in human lung disease and unexplained sudden infant death.

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Section: Discussionmentioning

confidence: 99%

Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

Goetzman

Alcorn

Bharathi

et al. 2014

Journal of Biological Chemistry

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“…In addition, because the reported protein quantitative trait locus studies were performed exclusively in European populations (53), it remains unknown whether non-European populations manifest the same genetic determinants of circulating IL1RA. ARDS continues to inflict significant morbidity and mortality upon critically ill patients (2,3,21,78). A clearer understanding of genetic risk factors for ARDS susceptibility may help to identify subgroups best suited for participation in clinical trials, and may aid in the development of specific, targeted therapy for molecular subgroups as our understanding of ARDS pathogenesis and ARDS endophenotypes evolves.…”

Section: Discussionmentioning

confidence: 99%

IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

Meyer

Feng

et al. 2013

Am J Respir Crit Care Med

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Rationale: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete. Objectives: To identify genetic risk variants for ARDS using large scale genotyping. Methods: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n ¼ 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P , 5 3 10 24 for replication in stage II, a trauma case-control population (n ¼ 778). SNPs replicating their association in stage II (P , 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n ¼ 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDSassociated genotype and plasma protein levels. Measurements and Main Results: A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P , 0.004) and III (P , 0.02), and was robust to clinical adjustment (combined odds ratio ¼ 0.81; P ¼ 4.2 3 10 25 ). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN. Conclusions: The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.Keywords: functional genetic polymorphism; acute lung injury; acute respiratory distress syndrome; IL-1 receptor antagonist; replication Acute respiratory distress syndrome (ARDS) is a syndrome characterized by acute bilateral alveolar flooding and severe hypoxemia in the absence of clinical heart failure (1, 2). ARDS afflicts an estimated 190,000 people annually in the United States, and carries a mortality of between 30 and 40% (3). The syndrome can emerge after a variety of potential inciting events, such as sepsis, pneumonia, aspiration, and trauma. However, the risk of ARDS after potential at-risk injuries is not uniform; it appears that individual genetic variation contributes to a patient's susceptibility to ARDS (4, 5). The pathophysiology underlying ARDS remains imprecisely understood, but dysregulated inflammation and altered permeability of the alveolocapillary membrane seem Supported by National Institutes of Health (NIH) grants to fund the study populations, Hospital of the University of Pennsylvania (HL060290, HL079063), Harborview (GM066946), and Massachusetts General Hospital (HL060710). Additional NIH grants RC2HL101770, HL081619, HL090021, and HL102254 supported the genetic and molecular investigations described herein. The genetic determinants of acute respiratory distress syndrome (ARDS) susceptibility remain incompletely u...

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“…These syndrome definitions are reliable and timely, with good construct validity, predictive validity, and low measurement burden. These clinical definitions have facilitated earlier recognition and timely treatment of both sepsis (17) and ARDS (18), likely contributing to the observed declines in mortality from these syndromes (18)(19)(20). But, although useful, these consensus definitions do not identify patients with a high likelihood of an explicit disease process, such as dysregulation of a particular immune pathway in sepsis or the presence of diffuse alveolar damage in ARDS.…”

Section: Why Lump?mentioning

confidence: 99%

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

Prescott

Calfee

Thompson

et al. 2016

Am J Respir Crit Care Med

269

237

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Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.

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Epidemiology of ARDS and ALI

Cited by 103 publications

References 120 publications

Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

IL1RNCoding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

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