Andrew Reese Moore

All Publications

• Drivers of prognosis and clinical trajectories differ between COVID and non-COVID acute hypoxic respiratory failure. PloS one Pienkos, S., Moore, A. R., Roque, J., Jensen, A., Pacheco-Navarro, A., Lebold, K. M., Parmer-Chow, C., Sanchez, P. A., Morin, H., O'Donnell, C., Ramaswamy, T., Collins, W., Wilson, J. G., Rogers, A. J., Levitt, J. E. 2025; 20 (12): e0339604

  Abstract

  Examine non-respiratory comorbidities that may affect prognosis in acute hypoxic respiratory failure (AHRF) and respiratory trajectories, comparing those with COVID and non-COVID etiologies of AHRF.This is a retrospective cohort study of patients with AHRF from COVID and non-COVID etiologies treated with high flow oxygen, noninvasive ventilation, or endotracheal intubation in ICUs in two United States hospitals.We compared drivers of prognosis and respiratory trajectories between 241 patients with AHRF from COVID and 99 patients with non-COVID AHRF. Patients with COVID had a lower prevalence of major comorbidities or terminal illness (OR 0.14), neurologic disease (OR 0.19), goals of care limitations (OR 0.54), and shock (OR 0.11). A lower proportion of the COVID group were managed with invasive mechanical ventilation (IMV) early in their AHRF course (OR 0.15); however, fewer COVID patients had improvement in AHRF in the first 7 days (OR 0.49), and a greater proportion of COVID patients required IMV on day 14 (OR 2.57). Additionally, fewer COVID patients died or transitioned to comfort care within 14 days following AHRF onset (OR 0.24), and more COVID patients had severe hypoxemia at end-of-life (OR 2.42).Patients with AHRF from COVID had fewer non-respiratory comorbidities or goals of care limitations, more prolonged respiratory failure and higher risk of mortality related to hypoxemia. These differences could explain why patients with COVID AHRF may experience greater benefit from disease-specific therapies targeting AHRF compared to patients with non-COVID AHRF.

  View details for DOI 10.1371/journal.pone.0339604

  View details for PubMedID 41452892

  View details for PubMedCentralID PMC12742738

• Neutrophil dysregulation differentiates pediatric septic shock biomarker-based mortality-risk strata: insights from weighted gene co-expression network and transcriptomic analyses. Frontiers in immunology Dunwoodie, L., Huang, M., Moore, A. R., Stanski, N. L., Standage, S. W., Kaplan, J. M., Zingarelli, B., Harmon, K., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Schwarz, A. J., Lutfi, R., Thomas, N. J., Haileselassie, B., Jain, P. N., Sweeney, T. E., Kamaleswaran, R., Atreya, M. R., Lautz, A. J. 2025; 16: 1663704

  Abstract

  Pediatric sepsis is a leading cause of global mortality, particularly among children, with limited therapeutic options beyond antibiotics and organ support. The Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) stratifies mortality risk in pediatric septic shock, yet the molecular mechanisms underlying high mortality risk remain incompletely understood.We analyzed whole blood transcriptomes collected from 81 children with septic shock on day 1 of meeting study criteria. Patients were stratified into high- and low-mortality risk groups according to the PERSEVERE-II biomarker risk model. Using weighted gene co-expression network analysis (WGCNA) and differential gene expression analyses, we identified molecular pathways and transcription factors (TFs) associated with mortality risk. Cell type differences were inferred using CIBERSORTx and using a reference single-cell dataset inclusive of neutrophils and their subsets.We identified distinct molecular profiles with high-risk patients displaying significant overexpression of genes related to neutrophil degranulation and innate immunity, alongside suppressed adaptive immune responses. The predominance of developing neutrophils underscored a major role of emergency granulopoiesis. Key TFs identified, including LTF, FOXM1, KLF1, and CEBPB, were linked to high-risk gene expression signatures. Our findings indicate a pathological shift toward a dysregulated neutrophil-driven hyperinflammation and adaptive immune suppressive state, which together are associated with adverse outcomes.Our results suggest that neutrophil dysregulation underpins the high mortality risk conferred by the PERSEVERE-II model. The identified transcriptional regulators may provide potential targets to mitigate neutrophil dysregulation and improve outcomes among high-risk patients.

  View details for DOI 10.3389/fimmu.2025.1663704

  View details for PubMedID 41346599

  View details for PubMedCentralID PMC12672347

• A consensus blood transcriptomic framework for sepsis. Nature medicine Scicluna, B. P., Cano-Gamez, K., Burnham, K. L., Davenport, E. E., Moore, A. R., Khan, S., Hinds, C. J., Cremer, O. L., Khatri, P., Sweeney, T. E., Knight, J. C., van der Poll, T. 2025

  Abstract

  Sepsis is a life-threatening condition driven by a maladaptive host response to infection. To establish a standardized blood transcriptomic subtype model, we aggregated blood transcriptomics data from two major sepsis cohorts: the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) project (n = 678 sampled on intensive care unit admission; ClinicalTrials.gov registration no. NCT01905033 ) and the Genomic Advances in Sepsis (GAinS) study (n = 444 sampled on intensive care unit admission and n = 817 follow-up samples; ClinicalTrials.gov registration no. NCT00131196 ). We demonstrate a strong interconnection across three separate classification methods, resulting in the proposed groupings of three consensus transcriptomic subtypes (CTSs). The distinguishing characteristics of CTS1 included gene activation of typical inflammatory pathways, more pronounced endothelial activation and an overall immature neutrophil theme. CTS2 was characterized by gene activation of a heme metabolism pathway, fibrinolytic disturbances and platelet and eosinophil signatures. CTS3 was associated with genes involved in the activation of allograft rejection, interferon signaling and anticoagulation functions, together with lymphocyte and nonclassical monocyte features. Evaluating CTS classification in independent patient cohorts, specifically the vasopressin vs noradrenaline as initial therapy in septic shock (VANISH) randomized controlled trial (n = 176; ISRCTN registration no. ISRCTN20769191 ) and patients hospitalized with suspected sepsis at a district hospital in Uganda (n = 128), ascertained the robustness of our approach. Notably, post hoc analysis of a pseudo-randomized cohort, along with a reanalysis of the VANISH trial data, unmasked a harmful signal in CTS2-assigned patients treated with corticosteroids. The CTS classification method aligns diverse sepsis transcriptomic subgroupings into a robust, reproducible framework, thereby enabling biological interpretation and potentially assisting aspects of clinical trial design to advance precision medicine in sepsis.

  View details for DOI 10.1038/s41591-025-03964-5

  View details for PubMedID 41028542

  View details for PubMedCentralID 6970225

• A consensus immune dysregulation framework for sepsis and critical illnesses. Nature medicine Moore, A. R., Zheng, H., Ganesan, A., Hasin-Brumshtein, Y., Maddali, M. V., Levitt, J. E., van der Poll, T., Lu, J., Bouma, H. R., Scicluna, B. P., Giamarellos-Bourboulis, E. J., Kotsaki, A., Martin-Loeches, I., Garduno, A., Rothman, R. E., Sevransky, J., Wright, D. W., Atreya, M. R., Moldawer, L. L., Efron, P. A., Kralovcova, M., Karvunidis, T., Giannini, H. M., Meyer, N. J., Sweeney, T. E., Rogers, A. J., Khatri, P. 2025

  Abstract

  Critical care syndromes such as sepsis, acute respiratory distress syndrome (ARDS) and trauma continue to have unacceptably high morbidity and mortality, with progress limited by the inherent heterogeneity within syndromic illnesses. Although numerous immune endotypes have been proposed for sepsis and critical care, the similarities and differences between these endotypes remain unclear, hindering clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine in critical care through the sharing of transcriptomic data. Here, evaluating the overlap of existing immune endotypes in sepsis across >7,074 samples from 37 independent cohorts, we developed cell-type-specific gene expression signatures to quantify dysregulation within immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. Importantly, this dysregulation was also observed in patients with ARDS, trauma and burns, suggesting a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation are associated with differential mortality in patients treated with anakinra in the SAVE-MORE trial (n = 452) and corticosteroids in the VICTAS (n = 89) and VANISH (n = 117) trials, underscoring their prognostic and therapeutic implications. In conclusion, our proposed immunology-based framework for quantifying cellular compartment dysregulation offers a potentially valuable tool for understanding immune dysregulation in critical illness with prognostic and therapeutic significance.

  View details for DOI 10.1038/s41591-025-03956-5

  View details for PubMedID 41028543

  View details for PubMedCentralID 4057290

• Stewardship of Intravenous Fluids During Shortage and Beyond. The Journal of emergency medicine Moore, A. R., Gordon, A. J., Marvel, J. T., Maddali, M. V., Chen, J. H., Urdaneta, A., Wilson, J. G. 2025; 80: 194-198

  Abstract

  BACKGROUND: Recent supply chain issues caused by Hurricane Helene highlighted opportunities to improve stewardship of intravenous (IV) fluids.OBJECTIVES: To quantify IV fluid bags saved by using "round down" strategies designed to limit use of partial bags of IV fluid in the emergency department (ED), and to estimate the associated environmental impact of this intervention.METHODS: This was a retrospective analysis of all 30 mL/kg IV fluid bolus orders placed in the EDs at Stanford Healthcare for adult patients from 2020 to 2023. We calculated the number of IV fluid bags that would be saved or reduced in size by rounding down to either the nearest 250 mL or the nearest 500 mL. Projected environmental impact was assessed using previously published estimates of CO2 emissions and plastic waste generated by IV fluid use.RESULTS: Across 11,964 30 mL/kg IV fluid orders, rounding down would have saved up to 1567 bags of IV fluid, and reduced the size of IV fluid bag used for up to 3890 boluses. Depending on which "round down" strategy was used, the median reduction in fluid volume was 121 to 244 mL per patient. For each 1000 patients, this reduction was estimated to decrease CO2 emissions by 112.8 kg and eliminate 14 kg of plastic waste.CONCLUSION: Use of a "round down" strategy for IV fluid resuscitation in sepsis could substantially reduce the number of bags of IV fluid used, with associated reductions in CO2 emissions and plastic waste.

  View details for DOI 10.1016/j.jemermed.2025.09.027

  View details for PubMedID 41289786

• Heterogeneity in association of myocardial injury and mortality in sepsis or acute respiratory distress syndrome by subphenotype: a retrospective study. Critical care (London, England) Sanchez, P. A., Obeidalla, S., Kerchberger, V. E., Moore, A. R., Maddali, M. V., Kangelaris, K. N., Hendrickson, C. M., Evrard, B., Liu, K. D., Bastarache, J. A., Matthay, M. A., Rogers, A. J., Calfee, C. S. 2025; 29 (1): 363

  Abstract

  Myocardial injury is common in acute respiratory distress syndrome (ARDS) and sepsis and associated with increased mortality. Two latent class analysis derived subphenotypes are associated with differential risk of mortality in these populations, though the association of troponin-I with mortality within each subphenotype is unknown.The derivation (n = 597 in EARLI) and validation (n = 452 in VALID) cohorts consisted of patients with sepsis or ARDS admitted to the ICU and enrolled in two separate prospective observational studies. Patients with troponin-I measured between hospital presentation and within 24 h of ICU admission were included. A parsimonious classifier model using interleukin-8, soluble tumor necrosis factor receptor-1, and vasopressor use assigned patients to subphenotype. Association between peak troponin-I concentration and 60-day in-hospital mortality within each subphenotype was assessed through logistic regression adjusting for age, admission laboratory values, vasopressor use, invasive ventilation use, and cardiac comorbidities.Median peak troponin-I was significantly higher in the hyperinflammatory vs hypoinflammatory subphenotype in both cohorts (0.07 vs 0.04 ng/mL and 0.17 vs 0.07 ng/mL, both p < 0.05). The association between peak troponin-I and mortality differed between inflammatory subphenotypes (p-interaction 0.004, EARLI). In EARLI, each doubling of peak troponin-I was associated with increased adjusted odds of 60-day mortality (aOR 1.14, 95% CI 1.02-1.28) in the hypoinflammatory subphenotype only. These findings were corroborated in VALID (aOR 1.11, 95% CI 1.03-1.21 in hypoinflammatory).Admission peak troponin-I is significantly associated with 60-day mortality in patients with sepsis or ARDS. This association was distinctly driven by the hypoinflammatory subphenotype.

  View details for DOI 10.1186/s13054-025-05613-2

  View details for PubMedID 40826103

  View details for PubMedCentralID PMC12363128

• Plasma-Based Endotypes in Acute Respiratory Distress Syndrome Identify High-Risk Patients With Extrapulmonary Disease: Why Looking Outside the Lung Compartment Enriches for Nonpulmonary Morbidity and Mortality. Critical care medicine Moore, A. R., Bhatraju, P. K., Rogers, A. J. 2025

  View details for DOI 10.1097/CCM.0000000000006753

  View details for PubMedID 40558603

• A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response. Immunity Ganesan, A., Moore, A. R., Zheng, H., Toh, J., Freedman, M., Magis, A. T., Heath, J. R., Khatri, P. 2025

  Abstract

  Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with an increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single-cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature was associated with each of these risk factors prior to infection. Furthermore, this conserved immune signature was modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted the individuals with sepsis who would be harmed by hydrocortisone treatment and individuals with asthma who would not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of the baseline immune state and response to chronic, subacute, and acute illnesses.

  View details for DOI 10.1016/j.immuni.2025.05.020

  View details for PubMedID 40532705

• Oxygenation trajectories following inhaled nitric oxide in non-intubated and mechanically ventilated COVID-19 patients CHEST Critical Care Ramaswamy , T. S., et al 2025

  View details for DOI 10.1016/j.chstcc.2025.100200

• Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes. Critical care (London, England) Atreya, M. R., Huang, M., Moore, A. R., Zheng, H., Hasin-Brumshtein, Y., Fitzgerald, J. C., Weiss, S. L., Cvijanovich, N. Z., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Nowak, J., Thomas, N. J., Quasney, M., Dahmer, M. K., Baines, T., Haileselassie, B., Lautz, A. J., Stanski, N. L., Standage, S. W., Kaplan, J. M., Zingarelli, B., Sahay, R., Zhang, B., Sweeney, T. E., Khatri, P., Sanchez-Pinto, L. N., Kamaleswaran, R. 2024; 28 (1): 246

  Abstract

  Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches.We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme.Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes.Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

  View details for DOI 10.1186/s13054-024-05020-z

  View details for PubMedID 39014377

  View details for PubMedCentralID 6970225

• Molecular Endotypes of Idiopathic Pulmonary Fibrosis: A Latent Class Analysis of Two Multicenter Observational Cohorts. American journal of respiratory and critical care medicine Maddali, M. V., Moore, A. R., Sinha, P., Newton, C. A., Kim, J. S., Adegunsoye, A., Ma, S. F., Strek, M. E., Chen, C. H., Linderholm, A. L., Zemans, R. L., Moore, B. B., Wolters, P. J., Martinez, F. J., Rogers, A. J., Raj, R., Noth, I., Oldham, J. M. 2024

  Abstract

  Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. While antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objective: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n=875) and validation (n=347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naïve to antifibrotic therapy at time of biomarker measurement (n=555). Results: LCA independently identified two latent classes in both cohorts (p<0.0001). WAP four-disulfide core domain protein 2 (WFDC2) was the most important determinant of class membership across cohorts. Membership in Class 2 was characterized by higher biomarker concentrations and higher risk of death or transplantation (discovery: HR 2.02 [95% CI 1.64-2.48]; p<0.001; validation: HR 1.95 [1.34-2.82]; p<0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (pinteraction=0.030), with a favorable antifibrotic response in Class 2 (HR 0.64 [0.45-0.93]; p=0.018) but not in Class 1 (HR 1.19 [0.77-1.84]; p=0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and response to antifibrotics. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials.

  View details for DOI 10.1164/rccm.202402-0339OC

  View details for PubMedID 38913573

• Association between emergency department disposition and mortality in patients with COVID-19 acute respiratory distress syndrome. Journal of the American College of Emergency Physicians open Lebold, K. M., Moore, A. R., Sanchez, P. A., Pacheco-Navarro, A. E., O'Donnell, C., Roque, J., Parmer, C., Pienkos, S., Levitt, J., Collins, W. J., Rogers, A. J., Wilson, J. G. 2024; 5 (3): e13192

  Abstract

  Patients hospitalized for COVID-19 frequently develop hypoxemia and acute respiratory distress syndrome (ARDS) after admission. In non-COVID-19 ARDS studies, admission to hospital wards with subsequent transfer to intensive care unit (ICU) is associated with worse outcomes. We hypothesized that initial admission to the ward may affect outcomes in patient with COVID-19 ARDS.This was a retrospective study of consecutive adults admitted for COVID-19 ARDS between March 2020 and March 2021 at Stanford Health Care. Mortality scores at hospital admission (Coronavirus Clinical Characterization Consortium Mortality Score [4C score]) and ICU admission (Simplified Acute Physiology Score III [SAPS-III]) were calculated, as well as ROX index for patients on high flow nasal oxygen. Patients were classified by emergency department (ED) disposition (ward-first vs. ICU-direct), and 28- and 60-day mortality and highest level of respiratory support within 1 day of ICU admission were compared. A second cohort (April 2021‒July 2022, n = 129) was phenotyped to validate mortality outcome.A total of 157 patients were included, 48% of whom were first admitted to the ward (n = 75). Ward-first patients had more comorbidities, including lung disease. Ward-first patients had lower 4C and similar SAPS-III score, yet increased mortality at 28 days (32% vs. 17%, hazard ratio [HR] 2.0, 95% confidence interval [95% CI] 1.0‒3.7, p = 0.039) and 60 days (39% vs. 23%, HR 1.83, 95% CI 1.04‒3.22, p = 0.037) compared to ICU-direct patients. More ward-first patients escalated to mechanical ventilation on day 1 of ICU admission (36% vs. 14%, p = 0.002) despite similar ROX index. Ward-first patients who upgraded to ICU within 48 h of ED presentation had the highest mortality. Mortality findings were replicated in a sensitivity analysis.Despite similar baseline risk scores, ward-first patients with COVID-19 ARDS had increased mortality and escalation to mechanical ventilation compared to ICU-direct patients. Ward-first patients requiring ICU upgrade within 48 h were at highest risk, highlighting a need for improved identification of this group at ED admission.

  View details for DOI 10.1002/emp2.13192

  View details for PubMedID 38887225

  View details for PubMedCentralID PMC11180691

• 42-gene Severe-or-Mild (SOM) gene expression signature is conserved across viral and bacterial infections and originates from developing neutrophils Moore, A., Freedman, M., Zheng, H., Ganesan, A., Rogers, A., Khatri, P. AMER ASSOC IMMUNOLOGISTS. 2024

  View details for DOI 10.4049/jimmunol.212.supp.0635.5089

  View details for Web of Science ID 001368989500047

• Elevated Plasma Interleukin-18 Identifies High-Risk Acute Respiratory Distress Syndrome Patients not Distinguished by Prior Latent Class Analyses Using Traditional Inflammatory Cytokines: A Retrospective Analysis of Two Randomized Clinical Trials. Critical care medicine Moore, A. R., Pienkos, S. M., Sinha, P., Guan, J., O'Kane, C. M., Levitt, J. E., Wilson, J. G., Shankar-Hari, M., Matthay, M. A., Calfee, C. S., Baron, R. M., McAuley, D. F., Rogers, A. J. 2023

  Abstract

  Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications.Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup.Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients.Six hundred eighty-three patients in SAILS and 511 patients in HARP-2.None.We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009).Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.

  View details for DOI 10.1097/CCM.0000000000006028

  View details for PubMedID 37695136

• Right Ventricular Dysfunction Patterns Among Patients with COVID-19 in the Intensive Care Unit - a Retrospective Cohort Analysis. Annals of the American Thoracic Society Sanchez, P. A., O'Donnell, C. T., Francisco, N., Santana, E. J., Moore, A. R., Pacheco-Navarro, A., Roque, J., Lebold, K. M., Parmer, C. M., Pienkos, S. M., Celestin, B. E., Levitt, J. E., Collins, W. J., Lanspa, M. J., Ashley, E. A., Wilson, J. G., Haddad, F., Rogers, A. J. 2023

  Abstract

  Right ventricular (RV) dysfunction is common among patients hospitalized with COVID-19; however, its epidemiology may depend on the echocardiographic parameters used to define it.To evaluate the prevalence of abnormalities in three common echocardiographic parameters of RV function among COVID-19 patients admitted to the intensive care unit, as well as the effect of RV dilatation on differential parameter abnormality and the association of RV dysfunction with 60-day mortality.Retrospective cohort study of COVID-19 ICU patients between March 4th,2020 to March 4th, 2021, who received a transthoracic echocardiogram within 48 hours before to at most 7 days after ICU admission. RV dysfunction and dilatation respectively defined by guideline thresholds for tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RVFAC), RV free wall longitudinal strain (RVFWS), and RV basal dimension or RV end-diastolic area. Association of RV dysfunction with 60-day mortality assessed through logistic regression adjusting for age, prior history of congestive heart failure, invasive ventilation at time of TTE and APACHE II score.116 patients were included, of which 69% had RV dysfunction by > 1 parameter and 36.3% of these had RV dilatation. The three most common patterns of RV dysfunction included: Presence of 3 abnormalities, the combination of abnormal RVFWS and TAPSE, and isolated TAPSE abnormality. Patients with RV dilatation had worse RVFAC (24% vs 36%, p = 0.001), worse RVFWS (16.3% vs 19.1%, p = 0.005), higher RVSP (45mmHg vs 31mmHg, p = 0.001) but similar TAPSE (13mm vs 13mm, p = 0.30) compared to those with normal RV size. After multivariable adjustment, 60-day mortality was significantly associated with RV dysfunction (OR 2.91, 95% CI 1.01 - 9.44), as was the presence of at least 2 parameter abnormalities.ICU patients with COVID-19 had significant heterogeneity in RV function abnormalities present with different patterns associated with RV dilatation. RV dysfunction by any parameter was associated with increased mortality. Therefore, a multiparameter evaluation may be critical in recognizing RV dysfunction in COVID-19.

  View details for DOI 10.1513/AnnalsATS.202303-235OC

  View details for PubMedID 37478340

• Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials. Critical care (London, England) Pienkos, S. M., Moore, A. R., Guan, J., Levitt, J. E., Matthay, M. A., Baron, R. M., Conlon, J., McAuley, D. F., O'Kane, C. M., Rogers, A. J. 2023; 27 (1): 126

  Abstract

  Two acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins.Secondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile (< 69 mg/dL in SAILS, < 44 mg/dL in HARP-2) versus all other quartiles for association with 60-day mortality and medication effect. Fisher's exact test, logistic regression, and Cox Proportional Hazards were used to assess mortality.There were 678 subjects with cholesterol measured in SAILS and 509 subjects in HARP-2, of whom 384 had sepsis. Median cholesterol at enrollment was 97 mg/dL in both SAILS and HARP-2. Low cholesterol was associated with higher APACHE III and shock prevalence in SAILS, and higher Sequential Organ Failure Assessment score and vasopressor use in HARP-2. Importantly, the effect of statins differed in these trials. In SAILS, patients with low cholesterol who received rosuvastatin were more likely to die (odds ratio (OR) 2.23, 95% confidence interval (95% CI) 1.06-4.77, p = 0.02; interaction p = 0.02). In contrast, in HARP-2, low cholesterol patients had lower mortality if randomized to simvastatin, though this did not reach statistical significance in the smaller cohort (OR 0.44, 95% CI 0.17-1.07, p = 0.06; interaction p = 0.22).Cholesterol levels are low in two cohorts with sepsis-related ARDS, and those in the lowest cholesterol quartile are sicker. Despite the very low levels of cholesterol, simvastatin therapy seems safe and may reduce mortality in this group, though rosuvastatin was associated with harm.

  View details for DOI 10.1186/s13054-023-04387-9

  View details for PubMedID 36978134

  View details for PubMedCentralID 6201750

• Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness. JCI insight Feng, A., Yang, E. Y., Moore, A. R., Dhingra, S., Chang, S. E., Yin, X., Pi, R., Mack, E. K., Völkel, S., Geßner, R., Gündisch, M., Neubauer, A., Renz, H., Tsiodras, S., Fragkou, P. C., Asuni, A. A., Levitt, J. E., Wilson, J. G., Leong, M., Lumb, J. H., Mao, R., Pinedo, K., Roque, J., Richards, C. M., Stabile, M., Swaminathan, G., Salagianni, M. L., Triantafyllia, V., Bertrams, W., Blish, C. A., Carette, J. E., Frankovich, J., Meffre, E., Nadeau, K. C., Singh, U., Wang, T. T., Luning Prak, E. T., Herold, S., Andreakos, E., Schmeck, B., Skevaki, C., Rogers, A. J., Utz, P. J. 2023; 8 (3)

  Abstract

  The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

  View details for DOI 10.1172/jci.insight.163150

  View details for PubMedID 36752204

• Prospective validation of an 11-gene mRNA host response score for mortality risk stratification in the intensive care unit. Scientific reports Moore, A. R., Roque, J., Shaller, B. T., Asuni, T., Remmel, M., Rawling, D., Liesenfeld, O., Khatri, P., Wilson, J. G., Levitt, J. E., Sweeney, T. E., Rogers, A. J. 2021; 11 (1): 13062

  Abstract

  Several clinical calculators predict intensive care unit (ICU) mortality, however these are cumbersome and often require 24h of data to calculate. Retrospective studies have demonstrated the utility of whole blood transcriptomic analysis in predicting mortality. In this study, we tested prospective validation of an 11-gene messenger RNA (mRNA) score in an ICU population. Whole blood mRNA from 70 subjects in the Stanford ICU Biobank with samples collected within 24h of Emergency Department presentation were used to calculate an 11-gene mRNA score. We found that the 11-gene score was highly associated with 60-day mortality, with an area under the receiver operating characteristic curve of 0.68 in all patients, 0.77 in shock patients, and 0.98 in patients whose primary determinant of prognosis was acute illness. Subjects with the highest quartile of mRNA scores were more likely to die in hospital (40% vs 7%, p<0.01) and within 60days (40% vs 15%, p=0.06). The 11-gene score improved prognostication with a categorical Net Reclassification Improvement index of 0.37 (p=0.03) and an Integrated Discrimination Improvement index of 0.07 (p=0.02) when combined with Simplified Acute Physiology Score 3 or Acute Physiology and Chronic Health Evaluation II score. The test performed poorly in the 95 independent samples collected>24h after emergency department presentation. Tests will target a 30-min turnaround time, allowing for rapid results early in admission. Moving forward, this test may provide valuable real-time prognostic information to improve triage decisions and allow for enrichment of clinical trials.

  View details for DOI 10.1038/s41598-021-91201-7

  View details for PubMedID 34158514

• A generalizable 29-mRNA neural-network classifier for acute bacterial and viral infections. Nature communications Mayhew, M. B., Buturovic, L., Luethy, R., Midic, U., Moore, A. R., Roque, J. A., Shaller, B. D., Asuni, T., Rawling, D., Remmel, M., Choi, K., Wacker, J., Khatri, P., Rogers, A. J., Sweeney, T. E. 2020; 11 (1): 1177

  Abstract

  Improved identification of bacterial and viral infections would reduce morbidity from sepsis, reduce antibiotic overuse, and lower healthcare costs. Here, we develop a generalizable host-gene-expression-based classifier for acute bacterial and viral infections. We use training data (N=1069) from 18 retrospective transcriptomic studies. Using only 29 preselected host mRNAs, we train a neural-network classifier with a bacterial-vs-other area under the receiver-operating characteristic curve (AUROC) 0.92 (95% CI 0.90-0.93) and a viral-vs-other AUROC 0.92 (95% CI 0.90-0.93). We then apply this classifier, inflammatix-bacterial-viral-noninfected-version 1(IMX-BVN-1), without retraining, to an independent cohort (N=163). In this cohort, IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.86 (95% CI 0.77-0.93), and viral-vs.-other 0.85 (95% CI 0.76-0.93). In patients enrolled within 36h of hospital admission (N=70), IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.92 (95% CI 0.83-0.99), and viral-vs.-other 0.91 (95% CI 0.82-0.98). With further study, IMX-BVN-1 could provide a tool for assessing patients with suspected infection and sepsis at hospital admission.

  View details for DOI 10.1038/s41467-020-14975-w

  View details for PubMedID 32132525

• Cat scratch disease: U.S. clinicians' experience and knowledge. Zoonoses and public health Nelson, C. A., Moore, A. R., Perea, A. E., Mead, P. S. 2018; 65 (1): 67-73

  Abstract

  Cat scratch disease (CSD) is a zoonotic infection caused primarily by the bacterium Bartonella henselae. An estimated 12,000 outpatients and 500 inpatients are diagnosed with CSD annually, yet little is known regarding clinician experience with and treatment of CSD in the United States. Questions assessing clinical burden, treatment and prevention of CSD were posed to 3,011 primary care providers (family practitioners, internists, paediatricians and nurse practitioners) during 2014-2015 as part of the annual nationwide DocStyles survey. Among the clinicians surveyed, 37.2% indicated that they had diagnosed at least one patient with CSD in the prior year. Clinicians in the Pacific and Southern regions were more likely to have diagnosed CSD, as were clinicians who saw paediatric patients, regardless of specialty. When presented with a question regarding treatment of uncomplicated CSD, only 12.5% of clinicians chose the recommended treatment option of analgesics and monitoring, while 71.4% selected antibiotics and 13.4% selected lymph node aspiration. In a scenario concerning CSD prevention in immunosuppressed patients, 80.6% of clinicians chose some form of precaution, but less than one-third chose the recommended option of counseling patients to treat their cats for fleas and avoid rough play with their cats. Results from this study indicate that a substantial proportion of U.S. clinicians have diagnosed CSD within the past year. Although published guidelines exist for treatment and prevention of CSD, these findings suggest that knowledge gaps remain. Therefore, targeted educational efforts about CSD may benefit primary care providers.

  View details for DOI 10.1111/zph.12368

  View details for PubMedID 28707827

• Current Guidelines, Common Clinical Pitfalls, and Future Directions for. Laboratory Diagnosis of Lyme Disease, United States EMERGING INFECTIOUS DISEASES Moore, A., Nelson, C., Molins, C., Mead, P., Schriefer, M. 2016; 22 (7): 1169–77

  Abstract

  In the United States, Lyme disease is caused by Borrelia burgdorferi and transmitted to humans by blacklegged ticks. Patients with an erythema migrans lesion and epidemiologic risk can receive a diagnosis without laboratory testing. For all other patients, laboratory testing is necessary to confirm the diagnosis, but proper interpretation depends on symptoms and timing of illness. The recommended laboratory test in the United States is 2-tiered serologic analysis consisting of an enzyme-linked immunoassay or immunofluorescence assay, followed by reflexive immunoblotting. Sensitivity of 2-tiered testing is low (30%-40%) during early infection while the antibody response is developing (window period). For disseminated Lyme disease, sensitivity is 70%-100%. Specificity is high (>95%) during all stages of disease. Use of other diagnostic tests for Lyme disease is limited. We review the rationale behind current US testing guidelines, appropriate use and interpretation of tests, and recent developments in Lyme disease diagnostics.

  View details for DOI 10.3201/eid2207.151694

  View details for Web of Science ID 000378563900004

  View details for PubMedID 27314832

  View details for PubMedCentralID PMC4918152