Browsing by Author "Dahmer, Mary K."

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    Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort
    (Research Square, 2023-12-06) Atreya, Mihir R.; Huang, Min; Moore, Andrew R.; Zheng, Hong; Hasin-Brumshtein, Yehudit; Fitzgerald, Julie C.; Weiss, Scott L.; Cvijanovich, Natalie Z.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Thomas, Neal J.; Quasney, Michael; Dahmer, Mary K.; Baines, Torrey; Haileselassie, Bereketeab; Lautz, Andrew J.; Stanski, Natalja L.; Standage, Stephen W.; Kaplan, Jennifer M.; Zingarelli, Basilia; Sweeney, Timothy E.; Khatri, Purvesh; Sanchez-Pinto, L. Nelson; Kamaleswaran, Rishikesan; Pediatrics, School of Medicine
    Background: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions. Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme. Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes. Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative 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.
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    Early Use of Adjunctive Therapies for Pediatric Acute Respiratory Distress Syndrome: A PARDIE Study
    (American Thoracic Society, 2020-06) Rowan, Courtney M.; Klein, Margaret J.; Hsing, Deyin Doreen; Dahmer, Mary K.; Spinella, Philip C.; Emeriaud, Guillaume; Hassinger, Amanda B.; Piñeres-Olave, Byron E.; Flori, Heidi R.; Haileselassie, Bereketeab; Lopez-Fernandez, Yolanda M.; Chima, Ranjit S.; Shein, Steven L.; Maddux, Aline B.; Lillie, Jon; Izquierdo, Ledys; Kneyber, Martin C.J.; Smith, Lincoln S.; Khemani, Robinder G.; Thomas, Neal J.; Yehya, Nadir; Pediatrics, School of Medicine
    Rationale: Few data exist to guide early adjunctive therapy use in pediatric acute respiratory distress syndrome (PARDS).Objectives: To describe contemporary use of adjunctive therapies for early PARDS as a framework for future investigations.Methods: This was a preplanned substudy of a prospective, international, cross-sectional observational study of children with PARDS from 100 centers over 10 study weeks.Measurements and Main Results: We investigated six adjunctive therapies for PARDS: continuous neuromuscular blockade, corticosteroids, inhaled nitric oxide (iNO), prone positioning, high-frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation. Almost half (45%) of children with PARDS received at least one therapy. Variability was noted in the median starting oxygenation index of each therapy; corticosteroids started at the lowest oxygenation index (13.0; interquartile range, 7.6-22.0) and HFOV at the highest (25.7; interquartile range, 16.7-37.3). Continuous neuromuscular blockade was the most common, used in 31%, followed by iNO (13%), corticosteroids (10%), prone positioning (10%), HFOV (9%), and extracorporeal membrane oxygenation (3%). Steroids, iNO, and HFOV were associated with comorbidities. Prone positioning and HFOV were more common in middle-income countries and less frequently used in North America. The use of multiple ancillary therapies increased over the first 3 days of PARDS, but there was not an easily identifiable pattern of combination or order of use.Conclusions: The contemporary description of prevalence, combinations of therapies, and oxygenation threshold for which the therapies are applied is important for design of future studies. Region of the world, income, and comorbidities influence adjunctive therapy use and are important variables to include in PARDS investigations.
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    Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2)
    (Wolters Kluwer, 2023) Emeriaud, Guillaume; López-Fernández, Yolanda M.; Iyer, Narayan Prabhu; Bembea, Melania M.; Agulnik, Asya; Barbaro, Ryan P.; Baudin, Florent; Bhalla, Anoopindar; de Carvalho, Werther Brunow; Carroll, Christopher L.; Cheifetz, Ira M.; Chisti, Mohammod J.; Cruces, Pablo; Curley, Martha A. Q.; Dahmer, Mary K.; Dalton, Heidi J.; Erickson, Simon J.; Essouri, Sandrine; Fernández, Analía; Flori, Heidi R.; Grunwell, Jocelyn R.; Jouvet, Philippe; Killien, Elizabeth Y.; Kneyber, Martin C. J.; Kudchadkar, Sapna R.; Korang, Steven Kwasi; Lee, Jan Hau; Macrae, Duncan J.; Maddux, Aline; Alapont, Vicent Modesto I.; Morrow, Brenda M.; Nadkarni, Vinay M.; Napolitano, Natalie; Newth, Christopher J. L.; Pons-Odena, Martí; Quasney, Michael W.; Rajapreyar, Prakadeshwari; Rambaud, Jerome; Randolph, Adrienne G.; Rimensberger, Peter; Rowan, Courtney M.; Sanchez-Pinto, L. Nelson; Sapru, Anil; Sauthier, Michael; Shein, Steve L.; Smith, Lincoln S.; Steffen, Katerine; Takeuchi, Muneyuki; Thomas, Neal J.; Tse, Sze Man; Valentine, Stacey; Ward, Shan; Watson, R. Scott; Yehya, Nadir; Zimmerman, Jerry J.; Khemani, Robinder G.; Pediatrics, School of Medicine
    Objectives: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. Design: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. Setting: Not applicable. Patients: Patients with or at risk for PARDS. Interventions: None. Measurements and main results: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. Conclusions: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.
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    Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes
    (Springer Nature, 2024-07-17) Atreya, Mihir R.; Huang, Min; Moore, Andrew R.; Zheng, Hong; Hasin-Brumshtein, Yehudit; Fitzgerald, Julie C.; Weiss, Scott L.; Cvijanovich, Natalie Z.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Thomas, Neal J.; Quasney, Michael; Dahmer, Mary K.; Baines, Torrey; Haileselassie, Bereketeab; Lautz, Andrew J.; Stanski, Natalja L.; Standage, Stephen W.; Kaplan, Jennifer M.; Zingarelli, Basilia; Sahay, Rashmi; Zhang, Bin; Sweeney, Timothy E.; Khatri, Purvesh; Sanchez-Pinto, L. Nelson; Kamaleswaran, Rishikesan; Pediatrics, School of Medicine
    Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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    NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications
    (Elsevier, 2023) Bodansky, Aaron; Vazquez, Sara E.; Chou, Janet; Novak, Tanya; Al-Musa, Amer; Young, Cameron; Newhams, Margaret; Kucukak, Suden; Zambrano, Laura D.; Mitchell, Anthea; Wang, Chung-Yu; Moffitt, Kristin; Halasa, Natasha B.; Loftis, Laura L.; Schwartz, Stephanie P.; Walker, Tracie C.; Mack, Elizabeth H.; Fitzgerald, Julie C.; Gertz, Shira J.; Rowan, Courtney M.; Irby, Katherine; Sanders, Ronald C., Jr.; Kong, Michele; Schuster, Jennifer E.; Staat, Mary A.; Zinter, Matt S.; Cvijanovich, Natalie Z.; Tarquinio, Keiko M.; Coates, Bria M.; Flori, Heidi R.; Dahmer, Mary K.; Crandall, Hillary; Cullimore, Melissa L.; Levy, Emily R.; Chatani, Brandon; Nofziger, Ryan; Overcoming COVID-19 Network Study Group Investigators; Geha, Raif S.; DeRisi, Joseph; Campbell, Angela P.; Anderson, Mark; Randolph, Adrienne G.; Pediatrics, School of Medicine
    Background: Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. Objective: We quantified anti-type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections. Methods: Circulating anti-IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFN-α2 autoantibodies exceeding the assay's positive control. Results: Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti-IFN-α2 antibodies. Anti-IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa-light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient's peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. Conclusions: High levels of anti-IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.
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    NFKB2 haploinsufficiency identified via screening for IFNα2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications
    (Elsevier, 2023-04) Bodansky, Aaron; Vazquez, Sara E.; Chou, Janet; Novak, Tanya; Al-Musa, Amer; Young, Cameron; Newhams, Margaret; Kocukak, Suden; Zambrano, Laura D.; Mitchell, Anthea; Wang, Chung-Yu; Moffitt, Kristin; Halasa, Natasha B.; Loftis, Laura L.; Schwartz, Stephanie P.; Walker, Tracie C.; Mack, Elizabeth H.; Fitzgerald, Julie C.; Gertz, Shira J.; Rowan, Courtney M.; Irby, Katherine; Sanders, Ronald C., Jr.; Kong, Michele; Schuster, Jennifer E.; Staat, Mary A.; Zinter, Matt S.; Cvijanovich, Natalie Z.; Tarquinio, Keiko M.; Coates, Bria M.; Flori, Heidi R.; Dahmer, Mary K.; Crandall, Hillary; Cullimore, Melissa L.; Levy, Emily R.; Chatani, Brandon; Nofziger, Ryan; Overcoming COVID-19 Network Study Group Investigators; Geha, Raif S.; DeRisi, Joseph; Campbell, Angela P.; Anderson, Mark; Randolph, Adrienne G.; Pediatrics, School of Medicine
    Background Autoantibodies against type I interferons (IFNs) occur in approximately 10% of adults with life-threatening COVID-19. The frequency of anti-IFN autoantibodies in children with severe sequelae of SARS-CoV-2 infection is unknown. Objective To quantify anti-Type I IFN autoantibodies in a multi-center cohort of children with severe COVID-19, Multisystem Inflammatory Syndrome in Children (MIS-C), and mild SARS-CoV-2 infections. Methods Circulating anti-IFNa2 antibodies were measured by a radioligand binding assay. Whole exome sequencing (WES), RNA-sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFNα2 autoantibodies exceeding the assay’s positive control. Results Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only one had high levels of anti-IFNα2 antibodies. Anti-IFNα2 autoantibodies were not detected in patients treated with intravenous immunoglobulin prior to sample collection. WES identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of NF-kB essential for non-canonical NF-kB signaling. Her peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. Conclusions High levels of anti-IFNα2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare, but can occur in patients with inborn errors of immunity. Clinical implications Anti-IFNα2 autoantibodies should prompt diagnostic evaluation for inborn errors of immunity if identified in children or adolescents.