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We sought to determine whether hyperinflammatory acute respiratory distress syndrome (ARDS) and hypoinflammatory ARDS, which have been associated with differences in plasma biomarkers and mortality risk, also display differences in bronchoalveolar lavage (BALF) biomarker profiles. We then described the relationship between hyperinflammatory ARDS and hypoinflammatory ARDS to novel subphenotypes derived using BALF biomarkers.Secondary analysis of a randomized control trial testing omega-3 fatty acids for the treatment of ARDS.Five North American intensive care units.Adults (n = 88) on invasive mechanical ventilation within 48 hours of ARDS onset.None.We classified 57 patients as hypoinflammatory and 31 patients as hyperinflammatory using a previously validated logistic regression model. Of 14 BALF biomarkers analyzed, interleukin-6 and granulocyte colony stimulating factor were higher among patients with hyperinflammatory ARDS compared with hypoinflammatory ARDS, though the differences were not robust to multiple hypothesis testing. We then performed a de novo latent class analysis of the 14 BALF biomarkers to identify two classes well separated by alveolar profiles. Class 2 (n = 63) displayed significantly higher interleukin-6, von Willebrand factor, soluble programmed cell death receptor-1, % neutrophils, and other biomarkers of inflammation compared with class 1 (n = 25). These BALF-derived classes had minimal overlap with the plasma-derived hyperinflammatory and hypoinflammatory classes, and the majority of both plasma-derived classes were in BALF-derived class 2 and characterized by high BALF biomarkers. Additionally, the BALF-derived classes were associated with clinical severity of pulmonary disease, with class 2 exhibiting lower Pao2 to Fio2 and distinct ventilatory parameters, unlike the plasma-derived classes, which were only related to nonpulmonary organ dysfunction.Hyperinflammatory and hypoinflammatory ARDS subphenotypes did not display significant differences in alveolar biologic profiles. Identifying ARDS subgroups using BALF measurements is a unique approach that complements information obtained from plasma, with potential to inform enrichment strategies in trials of lung-targeted therapies.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. This has been described in patients with COVID-19 pneumonia, but the underlying mechanisms have not been completely defined. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop radiographic fibrosis.We enrolled COVID-19 patients admitted to the ICU who had hypoxemic respiratory failure, were hospitalized and alive for at least 10 days, and had chest imaging done during hospitalization (n= 119). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected at 24h and 48-96h. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and radiographic evidence of fibrosis using logistic regression adjusting for age, sex, and APACHE score.We identified 39 patients (33%) with features of fibrosis. Within 24h of ICU admission, plasma proteins related to tissue remodeling (MMP-9, Amphiregulin) and monocyte chemotaxis (CCL-2/MCP-1, CCL-13/MCP-4) were associated with the subsequent development of fibrosis whereas markers of inflammation (IL-6, TNF-α) were not. After 1 week, plasma MMP-9 increased in patients without fibrosis. In ETAs, only CCL-2/MCP-1 was associated with fibrosis at the later timepoint.This cohort study identifies proteins of tissue remodeling and monocyte recruitment that may identify early fibrotic remodeling following COVID-19. Measuring changes in these proteins over time may allow for early detection of fibrosis in patients with COVID-19.

ImportanceIt is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies.ObjectiveTo derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies.Design, Setting, and ParticipantsThis was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022.ExposuresTEs identified by K-means clustering of plasma biomarkers collected at hospital arrival.Main Outcomes and MeasuresAn association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS.ResultsA total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001).Conclusions and RelevanceResults of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

Background Innate immune dysregulation may contribute to age-related differences in outcomes among critically ill adults. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is an important innate immune marker with prognostic value in sepsis, but age-related differences have not been studied. Methods This was a prospective cohort from a large tertiary care hospital enrolling adults from both medical and trauma-surgical ICUs. Plasma sTREM-1 was measured in participants within 24 hours of ICU admission. We analyzed associations between age (≤50 and >50 years) and sTREM-1 using linear regression. We then examined associations between sTREM-1 and both 28-day mortality and persistent organ dysfunction (defined as need for dialysis, vasopressors, or invasive mechanical ventilation) 7 days following admission using relative risk regression. Results Of 231 critically ill adults, older patients (n = 122) had higher prevalence of chronic disease and sepsis on enrollment than younger patients, but acute illness severity was similar. Age over 50 was associated with 27% higher sTREM-1 concentrations (95% CI 6%-53%), adjusted for sex and Charlson comorbidity index (CCI). Two-fold higher sTREM-1 was associated with 2.42-fold higher risk for mortality (95% CI 1.57, 3.73) and 1.86-fold higher risk for persistent organ dysfunction (95% CI 1.45, 2.39), adjusted for sex, CCI, and age. Conclusions sTREM-1 was elevated among critically ill older adults, and strongly associated with both death and persistent organ dysfunction. Immune responses associated with sTREM-1 may contribute to age-related differences in ICU outcomes, warranting further study as a potential therapeutic target in older adults.

Background Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Our objective was to evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19. Methods We prospectively enrolled 171 ICU patients, including 78 (46%) patients positive and 93 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 h and 3 days after ICU admission. Results In critically ill COVID-19 and non-COVID-19 patients, the most common ICU admission diagnoses were respiratory failure or pneumonia, followed by sepsis and other diagnoses. Similar proportions of patients in both groups received invasive mechanical ventilation at the time of study enrollment. COVID-19 and non-COVID-19 patients had similar rates of acute respiratory distress syndrome, severe acute kidney injury, and in-hospital mortality. While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores. In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (p Conclusions These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction may not be characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics in COVID-19.

Rationale: No direct comparisons of clinical features, laboratory values, and outcomes between critically ill patients with coronavirus disease (COVID-19) and patients with influenza in the United ...

Critically ill patients manifest many of the same immune features seen in coronavirus disease 2019 (COVID-19), including both “cytokine storm” and “immune suppression.” However, direct comparisons of molecular and cellular profiles between contemporaneously enrolled critically ill patients with and without severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited. We sought to identify immune signatures specifically enriched in critically ill patients with COVID-19 compared with patients without COVID-19. We enrolled a multisite prospective cohort of patients admitted under suspicion for COVID-19, who were then determined to be SARS-CoV-2-positive ( n = 204) or -negative ( n = 122). SARS-CoV-2-positive patients had higher plasma levels of CXCL10, sPD-L1, IFN-γ, CCL26, C-reactive protein (CRP), and TNF-α relative to SARS-CoV-2-negative patients adjusting for demographics and severity of illness (Bonferroni P value < 0.05). In contrast, the levels of IL-6, IL-8, IL-10, and IL-17A were not significantly different between the two groups. In SARS-CoV-2-positive patients, higher plasma levels of sPD-L1 and TNF-α were associated with fewer ventilator-free days (VFDs) and higher mortality rates (Bonferroni P value < 0.05). Lymphocyte chemoattractants such as CCL17 were associated with more severe respiratory failure in SARS-CoV-2-positive patients, but less severe respiratory failure in SARS-CoV-2-negative patients ( P value for interaction < 0.01). Circulating T cells and monocytes from SARS-CoV-2-positive subjects were hyporesponsive to in vitro stimulation compared with SARS-CoV-2-negative subjects. Critically ill SARS-CoV-2-positive patients exhibit an immune signature of high interferon-induced lymphocyte chemoattractants (e.g., CXCL10 and CCL17) and immune cell hyporesponsiveness when directly compared with SARS-CoV-2-negative patients. This suggests a specific role for T-cell migration coupled with an immune-checkpoint regulatory response in COVID-19-related critical illness.

Background Reduced BMI is an absolute contraindication for lung transplantation (LTx) at most centers in the United States. The objective of this study was to quantify post-LTx survival of moderate to severely underweight patients with cystic fibrosis (CF) (BMI Methods Using United Network for Organ Sharing Registry data (undergoing transplant from June 2005-November 2015), Kaplan-Meier estimates of median posttransplant survival were calculated for all patients with CF, COPD, and idiopathic pulmonary fibrosis (IPF), as well as low and normal weight CF subgroups. Cox regression modeling stratified according to transplant center assessed risk of posttransplant mortality in recipients with CF and a BMI Results Median posttransplant survival (95% CI) for CF, COPD, and IPF was 7.9 (7.2-8.6), 5.9 (5.6-6.2), and 5.5 (5.2-5.8) years, respectively. Although an absolute decrease was noted in posttransplant survival for recipients with CF and a BMI Conclusions Transplant recipients with CF and a BMI

Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules amongst diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflect proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants Alpha, Beta, Gamma, Kappa, and Delta exhibit comparable levels of replication in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak.To assess the role of ANGPTL4 in COVID-19-related outcomes.Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University.Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4.Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per logANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

COVID-19 is both a viral illness and a disease of immunopathology. Proximal events within the innate immune system drive the balance between deleterious inflammation and viral clearance. We hypothesize that a divergence between the generation of excessive inflammation through over activation of the TLR associated myeloid differentiation primary response (MyD88) pathway relative to the TIR-domain-containing adaptor-inducing IFN-β (TRIF) pathway plays a key role in COVID-19 severity. Both viral elements and damage associated host molecules act as TLR ligands in this process. In this review, we detail the mechanism for this imbalance in COVID-19 based on available evidence, and we discuss how modulation of critical elements may be important in reducing severity of disease.

Background Acute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies. Defining subphenotypes with distinct prognoses or biologic features can improve therapeutic trials, but prior work has focused on ARDS, which excludes many acute HRF patients. We aimed to characterize persistent and resolving subphenotypes in the broader HRF population. Methods In this secondary analysis of 2 independent prospective ICU cohorts, we included adults with acute HRF, defined by invasive mechanical ventilation and PaO2-to-FIO2 ratio ≤ 300 on cohort enrollment (n = 768 in the discovery cohort and n = 1715 in the validation cohort). We classified patients as persistent HRF if still requiring mechanical ventilation with PaO2-to-FIO2 ratio ≤ 300 on day 3 following ICU admission, or resolving HRF if otherwise. We estimated relative risk of 28-day hospital mortality associated with persistent HRF, compared to resolving HRF, using generalized linear models. We also estimated fold difference in circulating biomarkers of inflammation and endothelial activation on cohort enrollment among persistent HRF compared to resolving HRF. Finally, we stratified our analyses by ARDS to understand whether this was driving differences between persistent and resolving HRF. Results Over 50% developed persistent HRF in both the discovery (n = 386) and validation (n = 1032) cohorts. Persistent HRF was associated with higher risk of death relative to resolving HRF in both the discovery (1.68-fold, 95% CI 1.11, 2.54) and validation cohorts (1.93-fold, 95% CI 1.50, 2.47), after adjustment for age, sex, chronic respiratory illness, and acute illness severity on enrollment (APACHE-III in discovery, APACHE-II in validation). Patients with persistent HRF displayed higher biomarkers of inflammation (interleukin-6, interleukin-8) and endothelial dysfunction (angiopoietin-2) than resolving HRF after adjustment. Only half of persistent HRF patients had ARDS, yet exhibited higher mortality and biomarkers than resolving HRF regardless of whether they qualified for ARDS. Conclusion Patients with persistent HRF are common and have higher mortality and elevated circulating markers of lung injury compared to resolving HRF, and yet only a subset are captured by ARDS definitions. Persistent HRF may represent a clinically important, inclusive target for future therapeutic trials in HRF.

The awake prone position (AP) strategy for patients with acute respiratory distress syndrome (ARDS) is a safe, simple, and cost-effective technique used to improve hypoxemia. We aimed to evaluate intubation and mortality risk in patients with coronavirus disease (COVID-19) who underwent AP during hospitalisation. In this retrospective, multicentre observational study conducted between May 1 and June 12, 2020 in 27 hospitals in Mexico and Ecuador, non-intubated patients with COVID-19 managed with AP or supine positioning were included to evaluate intubation and mortality risk through logistic regression models; multivariable and centre adjustment, propensity score analyses, and E-values were calculated to limit confounding. This study was registered at https://clinicaltrials.gov/ct2/show/NCT04407468 827 non-intubated patients with COVID-19 in the AP (n=505) and supine (n=322) groups were included for analysis. Less patients in the AP group required endotracheal intubation (23.6% versus 40.4%) or died (20% versus 37.9%). AP was a protective factor for intubation even after multivariable adjustment (OR=0.39, 95%CI: 0.28–0.56, p, Awake prone positioning in non-intubated hospitalised patients with COVID-19 was associated with a lower risk of intubation and mortality in this multicentre observational study.

Chronic lung allograft dysfunction (CLAD) is the most important long-term complication after lung transplant (LTx), and clinical experience suggests significant variability in its management. We sought to capture azithromycin practices among LTx providers internationally. A survey was distributed via the International Society for Heart and Lung Transplantation and completed by 103 respondents (15 countries). Azithromycin indications, timing, and dosing varied significantly, and 37 (36%) reported inconsistency even within their center. Thirty (29%) reported initiating azithromycin prophylactically (during initial transplant hospitalization). Of 73 others, only 10 (14%) reported waiting until CLAD diagnosis (with persistent ≥20% pulmonary function decline). Most initiated azithromycin after a CLAD risk-factor/event, including 59 (81%) for a persistent ≥10% decrement in FEV 1 , 32 (44%) for lymphocytic bronchiolitis, and 27 (37%) for bronchoalveolar lavage neutrophilia . Azithromycin prescribing patterns appear to vary significantly, and further study is needed to elucidate the optimal timing and indications for its initiation after LTx.

Rationale: Serial measurements of alveolar macrophage (AM) transcriptional changes in patients with acute respiratory distress syndrome (ARDS) could identify cell-specific biological programs that ...

RATIONALE: Several studies have identified host immune signatures that are associated with COVID-19. However, it is unclear whether these immune signatures are specific to COVID-19 or are merely reflective of illness severity. In vitro studies have demonstrated that human T-cell responses to SARS-CoV-2-specific antigens are mediated through interferon-gamma (IFN-γ). Methods: We prospectively enrolled a multi-site cohort of patients admitted to the ICU under suspicion for COVID-19 who were then determined to be SARS-CoV-2-positive (n = 82) or-negative (n = 97) by RT-PCR. We measured multiple molecular and cellular immune profiles from blood and endotracheal aspirates (ETAs) collected on ICU admission. Our primary analysis tested for associations between IFN-γ and interferon-inducible mediators (CXCL10 and soluble PD-L1 (sPD-L1)) in blood or ETAs and SARS-CoV-2 status. We then stratified our cohort into SARS-CoV-2-negative and-positive groups and tested for associations between interferon-inducible mediators and clinical outcomes and SARS-CoV-2-copy-number. We used cytometry time-of-flight (CyTOF) to simultaneously measure 39 cell surface and intracellular markers on peripheral blood mononuclear cells collected from a subset of patients with ARDS. We then compared immune cell signatures in subjects with vs. without SARS-CoV-2. Results: The mean APACHE III score was higher in SARS-CoV-2-negative vs.-positive subjects (80±30 vs. 69±29), but the groups were otherwise well-matched. SARS-CoV-2-positive subjects had higher plasma concentrations of IFN-γ, CXCL10, and sPD-L1 relative to SARSCoV-2-negative patients adjusting for age, sex, and severity of illness (all p ≤ 0.01). The levels of IL-6, TNF-α, IL-8, MCP-1, and IL-17A were not significantly different between the two groups. SARS-CoV-2-positive subjects also had higher CXCL10 concentrations in ETAs than SARS-CoV-2-negative subjects. Higher plasma concentrations of CXCL10 and sPD-L1 were associated with higher mortality (Table 1) and more severe respiratory disease (ventilator-free days (VFDs), ARDS) in SARS-CoV-2-positive, but not-negative, patients. In contrast, higher IL-6 was associated with a lower number of VFDs and ARDS in both groups. IFN-γ and CXCL10 (but not IL-6) were associated with SARS-CoV-2-copy-number. Using CyTOF, we found SARS-CoV-2-positive subjects had a lower proportion of CXCR3+ (CXCL10 receptor) T-cells, a higher proportion of PD-L1+ monocytes, and less T-cell and monocyte intracellular cytokine staining vs. SARS-CoV-2-negative patients. Conclusion: Our findings suggest interferon-inducible mediator responses and immune cell hypofunction are characteristic of critically ill subjects with SARS-CoV-2 compared with similar patients without SARS-CoV-2. Our identification of immune signatures that are associated with SARS-CoV-2 infection but are distinct from other forms of critical illness clarifies COVID-19 pathophysiology.

Intro: Early innate immune responses are hypothesized to impact inflammation and therefore severity of disease and organ injury in COVID-19. Prior work in sepsis has identified CD14 as a marker of innate immune responses to bacterial infection and emerging evidence has implicated CD14 in COVID-19. CD14 exists in membrane bound and soluble (sCD14) form. A soluble N-terminal fragment of sCD14, sCD14 subtype (sCD14-ST, “Presepsin”) has been shown to have utility in diagnosis of sepsis and prognosis of associated organ failure and death. Goal: To determine the relationship between plasma sCD14 and sCD14-ST levels, COVID-19 status, and COVID-19 related outcomes in a cohort of prospectively enrolled critically ill patients admitted under suspicion for COVID-19. Methods: Critically ill patients under investigation for COVID-19 were prospectively enrolled between April 2020 and November 2020 at three hospitals affiliated with University of Washington. We ascertained COVID-19 status by SARS-CoV-2 RT-PCR upon admission. We measured plasma sCD14 and sCD14-ST levels in samples collected within 24 hours of admission. We tested for associations between biomarker levels and COVID-19 status using logistic regression adjusting for age, sex and APACHE III. In patients with COVID-19, we tested for associations between biomarker levels and disease severity and clinical outcomes using regression analyses adjusting for age, sex and APACHE III. Results: The cohort (n=222) mean age was 55 years, it was predominantly male (66%), in hospital mortality was 26%, and 50% of patients were positive by SARS-CoV-2 RT-PCR. Patients with COVID-19 had lower APACHE III scores (p: 0.013) than non-COVID-19. SCD14-ST levels were inversely associated with risk of SARS-CoV-2 positivity in multivariate regression (OR: 0.70, 95% CI: 0.57-0.84). Among patients with COVID-19, sCD14-ST levels were associated with higher APACHE III scores (beta: 7.3, 95% CI: 4.1-11), lower ventilatorfree days (beta:-1.6, 95% CI:-3.2 to-0.05) and higher risk for AKI (OR: 1.6, 95% CI: 1.0 to 2.7). SCD14-ST levels were not associated with these clinical outcomes in non-COVID-19 controls. In contrast to sCD14-ST levels, sCD14 levels did not differ between COVID-19 and non-COVID-19 patients and were not associated with COVID-19 clinical outcomes. Conclusions: In critically ill patients, sCD14-ST levels are inversely associated with risk of COVID-19 and positively associated with severity of disease and clinical outcomes among patients with COVID-19 while sCD14 levels were not associated with COVID-19 status or related outcomes. Early measurements of sCD14-ST levels could have prognostic utility in COVID-19.

Rationale: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Objective: To evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19Methods: We prospectively enrolled 169 ICU patients with suspicion of COVID-19 infection, including 78 (46%) patients positive and 91 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 hours and 3 days after ICU admission. Measurement and Main Results: ICU patients with and without COVID-19 had similar rates of severe acute kidney injury, shock, thromboembolism and in-hospital mortality. Rates of ARDS were higher in COVID-19 (aRR = 5.9, 95% CI: 3.2-11.0). While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores (Figure 1). In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (Bonferroni corrected p

Lung transplantation can be lifesaving in end-stage cystic fibrosis (CF), but long-term survival is limited by chronic lung allograft dysfunction (CLAD). Persistent upper airway Pseudomonas aeruginosa (PsA) colonization can seed the allograft. While de novo PsA infection is associated with CLAD in non-CF recipients, this association is less clear for CF recipients experiencing PsA recolonization. Here, we evaluate host and pathogen contributions to this phenomenon. In the context of PsA infection, brushings from the airways of CF recipients demonstrate type 1 interferon gene suppression. Airway epithelial cell (AEC) cultures demonstrate similar findings in the absence of pathogens or immune cells, contrasting with the pre-transplant CF AEC phenotype. Type 1 interferon promoters are relatively hypermethylated in CF AECs. CF subjects in this cohort have more mucoid PsA, while non-CF PsA subjects have decreased microbiome α diversity. Peri-transplant protocols may benefit from consideration of this host and microbiome equilibrium.

Background Identifying effective therapies in heterogeneous conditions like acute hypoxemic respiratory failure (AHRF) depends on defining sub-phenotypes with distinct prognosis or therapeutic response. Prior efforts have focused on acute respiratory distress syndrome (ARDS), although ARDS is a minority of all AHRF patients, has limited reliability in research, and is similarly heterogeneous. We propose a novel AHRF sub-phenotype called persistent hypoxemic respiratory failure (PHRF), defined by PaO2:FiO2 ratio ≤ 300 in individuals still requiring mechanical ventilation on day 3 following intubation. We hypothesized individuals with PHRF (+ PHRF) have greater mortality than individuals without PHRF (-PHRF), irrespective of ARDS (+/-ARDS). Methods We included mechanically ventilated AHRF patients (n = 768) from a single-center prospective cohort of medical and surgical ICU patients. We estimated the relative risk of 28-day inpatient mortality associated with + PHRF compared to -PHRF using generalized linear models. We also compared mortality and baseline log-transformed plasma biomarkers of inflammation and endothelial activation/dysfunction in + PHRF/-ARDS, -PHRF/+ARDS, and + PHRF/+ARDS compared to -PHRF/-ARDS. Results Cumulative incidence of + PHRF was 53% (n = 408), of whom 51% were + ARDS by ICU day 3 (n = 209). +PHRF was associated with a 1.55-fold higher risk of death (95% CI: 1.02, 2.34) compared to -PHRF, adjusting for demographics, chronic respiratory disease, and APACHE-III. Absolute mortality was higher in + PHRF/+ARDS (23%) and + PHRF/+ARDS (15%) patients than -PHRF/+ARDS (12%) and -PHRF/-ARDS (7%) patients. Interleukin-6 was 2.36-fold (95% CI: 1.47, 3.80) and 2.62-fold (1.63, 4.20) higher in + PHRF/-ARDS and + PHRF/+ARDS compared to -PHRF/-ARDS; granulocyte-colony stimulating factor was 1.96-fold (95% CI: 1.28, 3.01) and 1.82-fold (95% CI: 1.16, 2.85) higher; angiopoeitin-2 was 1.32-fold (95% CI: 1.01, 1.73) and 1.59-fold (95% CI: 1.21, 2.09) higher. In contrast, -PHRF/+ARDS patients did not have significantly different mortality or plasma biomarkers from -PHRF/-ARDS patients in adjusted models. Conclusions PHRF represents a common sub-phenotype of patients with AHRF, characterized by higher mortality and higher biomarkers of inflammation and endothelial dysfunction than -PHRF. PHRF captures many high-risk patients not included in current ARDS definition who may share biologic features with ARDS. Identifying patients with PHRF can support clinical prognostication and targeted trial enrollment for investigational therapies in the broad AHRF population.

Background. The triggering receptor expressed on myeloid cells-1 (TREM-1) mediates fatal septic shock in murine models, but studies linking the soluble form of TREM-1 (sTREM-1) to mortality in clinical sepsis are inconclusive, and few have examined its relationship to organ dysfunction. We sought to identify associations between circulating sTREM-1 and both mortality and organ dysfunction among a broad cohort of critically ill medical, post-surgical and trauma patients. Methods. We enrolled a prospective cohort of patients who met two or more criteria for the systemic inflammatory response syndrome (SIRS) within 24 hours of intensive care unit (ICU) admission at a large academic medical center. sTREM-1 concentrations were measured at study enrollment. We used relative risk regression, adjusted for age, sex, and Charlson comorbidity index, to determine associations between sTREM-1 and the primary outcome of 28-day mortality. We also examined secondary outcomes of prevalent organ dysfunction on enrollment, and composites of persistent organ dysfunction or death at day 7. Results. Among 231 critically ill patients, non-survivors (n=19, 8%) had a higher proportion of pre-existing comorbidities, mechanical ventilation (79% vs. 44%) and shock (58% vs. 28%) compared to survivors. At study enrollment, increasing sTREM-1 was associated with a higher risk of severe acute kidney injury (AKI), shock, and acute hypoxemic respiratory failure requiring mechanical ventilation. sTREM-1 was higher among non-survivors than survivors (885 vs 336 pg/mL); each doubling of sTREM-1 concentration was associated with a 2.41-fold higher risk of 28-day mortality (95% CI 1.57, 3.72). Among 92 patients with shock on enrollment, doubling of sTREM-1 was associated with a 3.89-fold higher risk of persistent shock or death by day 7 (95% CI 1.85, 8.17). Higher sTREM-1 was also associated with a higher risk of both persistent AKI and persistent hypoxemic respiratory failure or death. Conclusions. Elevated plasma sTREM-1 is highly associated with 28-day mortality and organ dysfunction across a diverse critically ill population. These data support that early activation of the innate immune system plays a role in the development of organ dysfunction and death. Further studies should address whether modulation of the TREM-1 pathway might be beneficial in critically ill patients.

Background We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes. Methods We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR Results A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31–0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects. Conclusion Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.

SARS-CoV-2, the virus causing COVID-19, has infected millions and has caused hundreds of thousands of fatalities. Risk factors for critical illness from SARS-CoV-2 infection include male gender, obesity, diabetes, and age >65. The mechanisms underlying the susceptibility to critical illness are poorly understood. Of interest, these comorbidities have previously been associated with increased signaling of Th17 cells. Th17 cells secrete IL-17A and are important for clearing extracellular pathogens, but inappropriate signaling has been linked to acute respiratory distress syndrome. Currently there are few treatment options for SARS-CoV-2 infections. This review describes evidence linking risk factors for critical illness in COVID-19 with increased Th17 cell activation and IL-17 signaling that may lead to increased likelihood for lung injury and respiratory failure. These findings provide a basis for testing the potential use of therapies directed at modulation of Th17 cells and IL-17A signaling in the treatment of COVID-19.

Alveolar macrophages (AM) play a central role in initiation and resolution of lung inflammation, but the integration of these opposing core functions is poorly understood. AM expression of cholesterol 25-hydroxylase (CH25H), the primary biosynthetic enzyme for 25-hydroxycholesterol (25HC), far exceeds the expression of macrophages in other tissues, but no role for CH25H has been defined in lung biology. As 25HC is an agonist for the antiinflammatory nuclear receptor, liver X receptor (LXR), we speculated that CH25H might regulate inflammatory homeostasis in the lung. Here, we show that, of natural oxysterols or sterols, 25HC is induced in the inflamed lung of mice and humans. Ch25h(–/–) mice fail to induce 25HC and LXR target genes in the lung after LPS inhalation and exhibit delayed resolution of airway neutrophilia, which can be rescued by systemic treatment with either 25HC or synthetic LXR agonists. LXR-null mice also display delayed resolution, suggesting that native oxysterols promote resolution. During resolution, Ch25h is induced in macrophages upon their encounter with apoptotic cells and is required for LXR-dependent prevention of AM lipid overload, induction of Mertk, efferocytic resolution of airway neutrophilia, and induction of TGF-β. CH25H/25HC/LXR is, thus, an inducible metabolic axis that programs AMs for efferocytic resolution of inflammation.