WNT9A Affects Late-Onset Acute Respiratory Distress Syndrome and 28-Day Survival: Evidence from a Three-Step Multiomics Study.

Late-onset (more than 48 h after ICU admission) acute respiratory distress syndrome (ARDS) is associated with shorter survival time and higher mortality; however, the underlying molecular targets remain unclear. As the WNT gene family is known to drive inflammation, immunity, and tissue fibrosis, all of which are closely related to the pathogenesis and prognosis of ARDS, we aim to investigate the associations of the WNT family with late-onset ARDS and 28-day survival. Genetic (n = 380), epigenetic (n = 185), transcriptional (n = 160), and protein (n = 300) data of patients with ARDS were extracted from the MEARDS (Molecular Epidemiology of ARDS) cohort. We used sure independence screening to identify late onset-related genetic biomarkers and constructed a genetic score on the basis of eight SNPs, which was associated with risk for late-onset ARDS (odds ratio [OR], 2.72; P = 3.81 × 10-14) and survival (hazard ratio [HR], 1.28; P = 0.008). The associations were further externally validated in the iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk) (ORlate onset, 2.49 [P = 0.006]; HRsurvival, 1.87 [P = 0.045]) and MESSI (Molecular Epidemiology of Severe Sepsis in the ICU) (ORlate onset, 4.12 [P = 0.026]; HRsurvival, 1.45 [P = 0.036]) cohorts. Furthermore, we functionally interrogated the six mapped genes of eight SNPs in the multiomics data and noted associations of WNT9A (WNT family member 9A) in epigenetic (ORlate onset, 2.95 [P = 9.91 × 10-4]; HRsurvival, 1.53 [P = 0.011]) and protein (ORlate onset, 1.42 [P = 0.035]; HRsurvival, 1.38 [P = 0.011]) data. The mediation analysis indicated that the effects of WNT9A on ARDS survival were mediated by late onset (HRindirect, 1.12 [P = 0.014] for genetic data; HRindirect, 1.05 [P = 0.030] for protein data). The essential roles of WNT9A in immunity and fibrosis may explain the different trajectories of recovery and dysfunction between early- and late-onset ARDS, providing clues for ARDS treatment.

Management of Lung Cancer in the Patient with Interstitial Lung Disease.

Patients with interstitial lung disease (ILD), especially those with pulmonary fibrosis, are at increased risk of developing lung cancer. Management of lung cancer in patients with ILD is particularly challenging. Diagnosis can be complicated by difficulty differentiating lung nodules from areas of focal fibrosis, and percutaneous biopsy approaches confer an increased risk of complications in those with pulmonary fibrosis. Lung cancer treatment in these patients pose several specific considerations. The degree of lung function impairment may preclude lobectomy or surgical resection of any type. Surgical resection can trigger an acute exacerbation of the underlying ILD. The presence of ILD confers an increased risk of pneumonitis with radiotherapy, and many of the systemic therapies also carry an increased risk of pneumonitis in this population. The safety of immunotherapy in the setting of ILD remains to be fully elucidated and concerns remain as to triggering pneumonitis. The purpose of this review is to summarize the evidence regarding consideration for tissue diagnosis, chemotherapy and immunotherapy, radiotherapy, and surgery, in this patient population and discuss emerging areas of research. We also propose a multidisciplinary approach and practical considerations for monitoring for ILD progression during lung cancer treatment.

Outcomes of Patients With Interstitial Lung Disease Receiving Programmed Cell Death 1 Inhibitors: A Retrospective Case Series.

BACKGROUND: Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) inhibitors, are used to treat multiple cancers. Limited data exist as to the use of ICIs in patients with coexistent interstitial lung disease (ILD). We conducted a retrospective case series to assess clinical and radiologic outcomes of patients with ILD treated with PD-1 inhibitors. METHODS: Eligible patients were 18 years of age or older, treated with pembrolizumab or nivolumab for oncologic indications, and had evidence of ILD on chest computed tomography scan not attributable to radiotherapy before initiation of ICI therapy. Outcomes of interest included mortality, hospitalizations for respiratory-related causes, development of pneumonitis, and radiologic change in ILD over a 1-year follow-up period. RESULTS: We included 41 patients in the analysis. At 1 year, 17 patients (41.5%) were alive, 23 had died (56.1%), and 1 (2.4%) was lost to follow-up. Of 23 deaths, 16 (69.6%) were due to cancer, 4 (17.4%) to causes excluding cancer and ILD, and 3 (13.0%) to hypoxemic respiratory failure from ILD- or ICI-induced pneumonitis. Three patients (7.3%) required hospitalization owing to ILD, including drug-induced pneumonitis, and 3 (7.3%) developed pneumonitis attributable to anti-PD-1 therapy. On follow-up computed tomography scans, 32 patients (78.0%) had stable or improved ILD and 9 (22.0%) had progression. CONCLUSION: Patients with ILD receiving PD-1 inhibitors more frequently died of cancer-related causes than from ILD. Further research is needed to determine the safety of ICIs in patients with ILD and if ILD subtype may help to refine ICI-associated risks.

Management and Outcomes of Suspected Infectious and Inflammatory Lung Abnormalities Identified on Lung Cancer Screening CT.

BACKGROUND. Incidental findings are frequently encountered during lung cancer screening (LCS). Limited data describe the prevalence of suspected acute infectious and inflammatory lung processes on LCS and how they should be managed. OBJECTIVE. The purpose of this study was to determine the prevalence, radiologic reporting and management, and outcome of suspected infectious and inflammatory lung processes identified incidentally during LCS and to propose a management algorithm. METHODS. This retrospective study included 6314 low-dose CT (LDCT) examinations performed between June 2014 and April 2019 in 3800 patients as part of an established LCS program. Radiology reports were reviewed, and patients with potentially infectious or inflammatory lung abnormalities were identified and analyzed for descriptors of imaging findings, Lung-RADS designation, recommendations, and clinical outcomes. Using the descriptors, outcomes, and a greater than 2% threshold risk of malignancy, a follow-up algorithm was developed to decrease additional imaging without affecting cancer detection. RESULTS. A total of 331/3800 (8.7%) patients (178 men, 153 women; mean age [range], 66 [53-87] years) undergoing LCS had lung findings that were attributed to infection or inflammation. These abnormalities were reported as potentially significant findings using the S modifier in 149/331 (45.0%) and as the dominant nodule used to determine the Lung-RADS category in 96/331 (29.0%). Abnormalities were multiple or multifocal in 260/331 (78.5%). Common descriptors were ground-glass (155/331; 46.8%), tree-in-bud (56/331; 16.9%), consolidation (41/331; 12.4%), and clustered (67/331; 20.2%) opacities. A follow-up chest CT outside of screening was performed within 12 months or less in 264/331 (79.8%) and within 6 months or less in 186/331 (56.2%). A total of 260/331 (78.5%) opacities resolved on follow-up imaging. Two malignancies (2/331; 0.6%) were associated with these abnormalities and both had consolidations. Theoretic adoption of a proposed management algorithm for suspected infectious and inflammatory findings reduced unnecessary follow-up imaging by 82.6% without missing a single malignancy. CONCLUSION. Presumed acute infectious or inflammatory lung abnormalities are frequently encountered in the setting of LCS. These opacities are commonly multifocal and resolve on follow-up. Less than 1% are associated with malignancy. CLINICAL IMPACT. Adoption of a conservative management algorithm can standardize recommendations and reduce unnecessary imaging without increasing the risk of missing a malignancy.

Late-onset moderate to severe acute respiratory distress syndrome is associated with shorter survival and higher mortality: a two-stage association study.

PURPOSE: To evaluate the association between acute respiratory distress syndrome (ARDS) onset time and prognosis. METHODS: Patients with moderate to severe ARDS (N = 876) were randomly assigned into derivation (N = 520) and validation (N = 356) datasets. Both 28-day and 60-day survival times after ARDS onset were analyzed. A data-driven cutoff point between early- and late-onset ARDS was determined on the basis of mortality risk effects of onset times. We estimated the hazard ratio (HR) and odds ratio (OR) of late-onset ARDS using a multivariate Cox proportional hazards model of survival time and a multivariate logistic regression model of mortality rate, respectively. RESULTS: Late-onset ARDS, defined as onset over 48 h after intensive care unit (ICU) admission (N = 273, 31%), was associated with shorter 28-day survival time: HR = 2.24, 95% CI 1.48-3.39, P = 1.24 × 10-4 (derivation); HR = 2.16, 95% CI 1.33-3.51, P = 1.95 × 10-3 (validation); and HR = 2.00, 95% CI 1.47-2.72, P = 1.10 × 10-5 (combined dataset). Late-onset ARDS was also associated with shorter 60-day survival time: HR = 1.70, 95% CI 1.16-2.48, P = 6.62 × 10-3 (derivation); HR = 1.78, 95% CI 1.15-2.75, P = 9.80 × 10-3 (validation); and HR = 1.59, 95% CI 1.20-2.10, P = 1.22 × 10-3 (combined dataset). Meanwhile, late-onset ARDS was associated with higher 28-day mortality rate (OR = 1.46, 95% CI 1.04-2.06, P = 0.0305) and 60-day mortality rate (OR = 1.44, 95% CI 1.03-2.02, P = 0.0313). CONCLUSIONS: Late-onset moderate to severe ARDS patients had both shorter survival time and higher mortality rate in 28-day and 60-day observations.

Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death.

BACKGROUND: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values. However, these scores are hampered by the need for a reliable baseline SCr value and the absence of a component differentiating transient from persistent rises in SCr. We hypothesized that identification of resolving or nonresolving AKI subphenotypes based on the early trajectory of SCr values in the ICU would better differentiate patients at risk of hospital mortality. METHODS: We performed a secondary analysis of two prospective studies of ICU patients admitted to a trauma ICU (group 1; n = 1914) or general medical-surgical ICUs (group 2; n = 1867). In group 1, we tested definitions for resolving and nonresolving AKI subphenotypes and selected the definitions resulting in subphenotypes with the greatest separation in risk of death relative to non-AKI controls. We applied this definition to group 2 and tested whether the subphenotypes were independently associated with hospital mortality after adjustment for AKI severity. RESULTS: AKI occurred in 46% and 69% of patients in groups 1 and 2, respectively. In group 1, a resolving AKI subphenotype (defined as a decrease in SCr of 0.3 mg/dl or 25% from maximum in the first 72 h of study enrollment) was associated with a low risk of death. A nonresolving AKI subphenotype (defined as all AKI cases not meeting the "resolving" definition) was associated with a high risk of death. In group 2, the resolving AKI subphenotype was not associated with increased mortality (relative risk [RR] 0.86, 95% CI 0.63-1.17), whereas the nonresolving AKI subphenotype was associated with higher mortality (RR 1.68, 95% CI 1.15-2.44) even after adjustment for AKI severity stage. CONCLUSIONS: The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity. These AKI subphenotypes might better define the patients at risk for poor outcomes who might benefit from novel interventions.

Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin.

BACKGROUND: The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been specifically investigated. The aim of this study was to identify genetic variants contributing to ALI/ARDS from pulmonary or extrapulmonary causes. METHODS: We conducted a multistage genetic association study. We first performed a large-scale genotyping (50K ITMAT-Broad_CARe Chip) in 1717 critically ill Caucasian patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p≤0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n=765) and pneumonia/pulmonary sepsis (Population II; n=838), as causes for ALI/ARDS. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n=224, Stage III). RESULTS: In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p<0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p<0.006, Stage II; p<0.05, Stage III). Meta-analysis confirmed these associations. CONCLUSIONS: Different genetic variants may influence ARDS susceptibility depending on direct versus indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI/ARDS, respectively.

Body mass index and acute kidney injury in the acute respiratory distress syndrome.

OBJECTIVES: Obesity is increasingly encountered in intensive care units but the relationship between obesity and acute kidney injury is unclear. We aimed to evaluate whether body mass index was associated with acute kidney injury in the acute respiratory distress syndrome and to examine the association between acute kidney injury and mortality in patients with and without obesity. DESIGN: Retrospective study. SETTING: Massachusetts General Hospital and Beth Israel Deaconess Medical Center. PATIENTS: Seven hundred fifty-one patients with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute kidney injury was defined as meeting the "Risk" category according to modified Risk, Injury, Failure, Loss, End-stage criteria based on creatinine and glomerular filtration rate because urine output was only available on the day of intensive care unit admission. Body mass index was calculated from height and weight at intensive care unit admission. The prevalence of acute kidney injury increased significantly with increasing weight (p = .01). The odds of acute kidney injury were twice in obese and severely obese patients compared to patients with normal body mass index, after adjusting for predictors of acute kidney injury (age, diabetes, Acute Physiology and Chronic Health Evaluation III, aspiration, vasopressor use, and thrombocytopenia [platelets ≤ 80,000/mm]). After adjusting for the same predictors, body mass index was significantly associated with acute kidney injury (odds ratio(adj) 1.20 per 5 kg/m increase in body mass index, 95% confidence interval 1.07-1.33). On multivariate analysis, acute kidney injury was associated with increased acute respiratory distress syndrome mortality (odds ratio(adj) 2.76, 95% confidence interval 1.72-4.42) whereas body mass index was associated with decreased mortality (odds ratio(adj) 0.81 per 5 kg/m increase in body mass index, 95% confidence interval 0.71-0.93) after adjusting for mortality predictors. CONCLUSIONS: In acute respiratory distress syndrome patients, obesity is associated with increased development of acute kidney injury, which is not completely explained by severity of illness or shock. Although increased body mass index is associated with decreased mortality, acute kidney injury remained associated with higher mortality even after adjusting for body mass index.

BCL2 genetic variants are associated with acute kidney injury in septic shock*.

OBJECTIVE: Acute kidney injury frequently complicates septic shock and independently predicts mortality in this population. Clinical factors alone do not entirely account for differences in risk of acute kidney injury between patients. Genetic variants are likely to explain this differential susceptibility. To identify genetic variants linked to acute kidney injury susceptibility, we conducted a high-density genotyping association study in a large population of patients with septic shock. DESIGN: Retrospective study. SETTING: Tertiary academic medical center. PATIENTS: One thousand two hundred and sixty-four patients with septic shock were analyzed to elucidate clinical risk factors associated with the development of acute kidney injury. Among them, 887 Caucasian patients were randomly split into discovery and validation cohorts and genotyped using the Illumina Human-CVD BeadChip (Illumina, San Diego, CA). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six hundred and twenty-seven of the 1,264 patients with septic shock and 441 of the 887 patients with genotyping data developed acute kidney injury within the first 72 hrs of intensive care unit admission. Five single nucleotide polymorphisms were associated with acute kidney injury in both the discovery and validation cohorts. Two of these were in the BCL2 gene and both were associated with a decreased risk of acute kidney injury (rs8094315: odds ratio 0.61, p = .0002; rs12457893: odds ratio 0.67, p = .0002, both for combined data). Bcl-2 is involved in the apoptosis pathway, which has previously been implicated in acute kidney injury. Another single nucleotide polymorphism was in the SERPINA4 gene, whose protein product, kallistatin, has been linked to apoptosis in the kidney. CONCLUSIONS: Large-scale genotyping reveals two single nucleotide polymorphisms in the BCL2 gene and a single nucleotide polymorphism in the SERPINA4 gene associated with a decreased risk of developing acute kidney injury, supporting the putative role of apoptosis in the pathogenesis of acute kidney injury.

Pharmacological treatments for acute respiratory distress syndrome.

PURPOSE OF REVIEW: Studies of the pharmacologic management of acute respiratory distress syndrome (ARDS) have yielded conflicting results. The purpose of this review is to discuss recent pharmacologic trials in ARDS, using the conceptual framework of ARDS as a heterogeneous disease. RECENT FINDINGS: Whereas most drug trials in ARDS have been negative, some studies suggest that targeting therapies at subgroups of patients may be successful. Proposed subgroups include early versus late-phase ARDS, direct versus indirect lung injury, and patients with altered coagulation. Corticosteroids have beneficial short-term effects when given at low or moderate doses sooner than 2 weeks but appear to be harmful if initiated later and are of unclear benefit if lung protective ventilation is also used. Surfactant may be helpful in patients with direct lung injury. Anticoagulants and vasodilators may have a greater chance for success in the subset of patients with vascular disease and a high dead-space fraction may identify such a population. SUMMARY: ARDS is a heterogeneous syndrome. Failure to target subgroups more likely to benefit from specific therapies may be one explanation for largely disappointing trial results so far.