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1. Causal inference can lead us to modifiable mechanisms and informative archetypes in sepsis

Author

Baillie, J. Kenneth, Angus, Derek, Burnham, Katie, Calandra, Thierry, Calfee, Carolyn, Gutteridge, Alex, Hacohen, Nir, Khatri, Purvesh, Langley, Raymond, Ma’ayan, Avi, Marshall, John, Maslove, David, Prescott, Hallie C., Rowan, Kathy, Scicluna, Brendon P., Seymour, Christopher, Shankar-Hari, Manu, Shapiro, Nathan, Joost Wiersinga, W., Singer, Mervyn, and Randolph, Adrienne G.

Published
2024
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2. Molecular mimicry in multisystem inflammatory syndrome in children

Author

Bodansky, Aaron, Mettelman, Robert C., Sabatino, Jr, Joseph J., Vazquez, Sara E., Chou, Janet, Novak, Tanya, Moffitt, Kristin L., Miller, Haleigh S., Kung, Andrew F., Rackaityte, Elze, Zamecnik, Colin R., Rajan, Jayant V., Kortbawi, Hannah, Mandel-Brehm, Caleigh, Mitchell, Anthea, Wang, Chung-Yu, Saxena, Aditi, Zorn, Kelsey, Yu, David J. L., Pogorelyy, Mikhail V., Awad, Walid, Kirk, Allison M., Asaki, James, Pluvinage, John V., Wilson, Michael R., Zambrano, Laura D., Campbell, Angela P., Thomas, Paul G., Randolph, Adrienne G., Anderson, Mark S., and DeRisi, Joseph L.

Published
2024
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4. NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2–related complications

Author

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, 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, Investigators, Overcoming COVID-19 Network Study Group, Yates, Masson, Smith, Chelsea, Zinter, MattS, McLaughlin, Gwenn, Randolph, Adrienne G, Newhams, Margaret M, Moon, Hye Kyung, Kobayashi, Takuma, Melo, Jeni, Chen, Sabrina R, Behl, Supriya, Drapeau, Noelle M, McCulloh, Russell J, Nofziger, Ryan A, Staat, Mary Allen, Rohlfs, Chelsea C, Reed, Nelson, Geha, Raif S, DeRisi, Joseph, Campbell, Angela P, and Anderson, Mark

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Lung, Vaccine Related, Infectious Diseases, Rare Diseases, Pneumonia, Clinical Research, Prevention, Emerging Infectious Diseases, Biodefense, Pediatric, Genetics, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Adult, Humans, Child, Adolescent, SARS-CoV-2, COVID-19, Autoantibodies, NF-kappa B, Haploinsufficiency, Leukocytes, Mononuclear, Interferon Type I, NF-kappa B p52 Subunit, Anti-interferon autoantibody, MIS-C, NFKB2, inborn errors of immunity, Overcoming COVID-19 Network Study Group Investigators, Immunology, Allergy
Abstract

BackgroundAutoantibodies 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.ObjectiveWe 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.MethodsCirculating 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.ResultsAmong 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.ConclusionsHigh 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.

Published
2023

6. Author Correction: Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C.

Author

Tang, Juanjie, Novak, Tanya, Hecker, Julian, Grubbs, Gabrielle, Zahra, Fatema Tuz, Bellusci, Lorenza, Pourhashemi, Sara, Chou, Janet, Moffitt, Kristin, Halasa, Natasha B, Schwartz, Stephanie P, Walker, Tracie C, Tarquinio, Keiko M, Zinter, Matt S, Staat, Mary A, Gertz, Shira J, Cvijanovich, Natalie Z, Schuster, Jennifer E, Loftis, Laura L, Coates, Bria M, Mack, Elizabeth H, Irby, Katherine, Fitzgerald, Julie C, Rowan, Courtney M, Kong, Michele, Flori, Heidi R, Maddux, Aline B, Shein, Steven L, Crandall, Hillary, Hume, Janet R, Hobbs, Charlotte V, Tremoulet, Adriana H, Shimizu, Chisato, Burns, Jane C, Chen, Sabrina R, Moon, Hye Kyung, Lange, Christoph, Randolph, Adrienne G, and Khurana, Surender

Subjects
Good Health and Well Being
Published
2022

7. Characteristics and Clinical Outcomes of Vaccine-Eligible US Children Under-5 Years Hospitalized for Acute COVID-19 in a National Network

Author

Zambrano, Laura D., Newhams, Margaret M., Simeone, Regina M., Fleming-Dutra, Katherine E., Halasa, Natasha, Wu, Michael, Orzel-Lockwood, Amber O., Kamidani, Satoshi, Pannaraj, Pia S., Chiotos, Kathleen, Cameron, Melissa A., Maddux, Aline B., Schuster, Jennifer E., Crandall, Hillary, Kong, Michele, Nofziger, Ryan A., Staat, Mary A., Bhumbra, Samina S., Irby, Katherine, Boom, Julie A., Sahni, Leila C., Hume, Janet R., Gertz, Shira J., Maamari, Mia, Bowens, Cindy, Levy, Emily R., Bradford, Tamara T., Walker, Tracie C., Schwartz, Stephanie P., Mack, Elizabeth H., Guzman-Cottrill, Judith A., Hobbs, Charlotte V., Zinter, Matt S., Cvijanovich, Natalie Z., Bline, Katherine E., Hymes, Saul R., Campbell, Angela P., Randolph, Adrienne G., Murdock, Meghan, Kelley, Heather, Sanders, Ronald C., Miron, Laura, Barkely, Hannah, Jumarang, Jaycee, Hakimi, Daniel, Niell, Liria Muriscot, Baig, Natasha, Temte, Elizabeth, Thayer, Imogene, Petruccelli, Lexi, Zorensky, Frances, Sierra, Yamila, Gonzalez, Mark D., Ciric, Caroline R., Choi, Jong-Ha C., Baida, Nadine, Randolph, Adrienne G., Kucukak, Suden, Listerud, Eve, Clark, Maya, Dittrich, Rylie, Johnson, Brandi A., Drapeau, Noelle M., Martin, Lora, Malloch, Lacy, Martin, Maygan, Sanders, Cameron, Patterson, Kayla, Sullivan, Melissa, Pruitt, Shannon, Hymes, Saul, Harwayne-Gidansky, Ilana, Rohlfs, Chelsea C., Wolfe, Amber, Phengchomphet, Kathlyn, Bush, Jenny, Mohammed, Fatima A., Stewart, Laura S., Fernandez, Kailee, Abojaib, Leenah, Kyles, Molly J., and Campbell, Angela P.

Published
2023
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8. High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases

Author

Jia, Xiaoxiao, Crawford, Jeremy Chase, Gebregzabher, Deborah, Monson, Ebony A., Mettelman, Robert C., Wan, Yanmin, Ren, Yanqin, Chou, Janet, Novak, Tanya, McQuilten, Hayley A., Clarke, Michele, Bachem, Annabell, Foo, Isabelle J., Fritzlar, Svenja, Carrera Montoya, Julio, Trenerry, Alice M., Nie, Shuai, Leeming, Michael G., Nguyen, Thi H.O., Kedzierski, Lukasz, Littler, Dene R., Kueh, Andrew, Cardamone, Tina, Wong, Chinn Yi, Hensen, Luca, Cabug, Aira, Laguna, Jaime Gómez, Agrawal, Mona, Flerlage, Tim, Boyd, David F., Van de Velde, Lee-Ann, Habel, Jennifer R., Loh, Liyen, Koay, Hui-Fern, van de Sandt, Carolien E., Konstantinov, Igor E., Berzins, Stuart P., Flanagan, Katie L., Wakim, Linda M., Herold, Marco J., Green, Amanda M., Smallwood, Heather S., Rossjohn, Jamie, Thwaites, Ryan S., Chiu, Christopher, Scott, Nichollas E., Mackenzie, Jason M., Bedoui, Sammy, Reading, Patrick C., Londrigan, Sarah L., Helbig, Karla J., Randolph, Adrienne G., Thomas, Paul G., Xu, Jianqing, Wang, Zhongfang, Chua, Brendon Y., and Kedzierska, Katherine

Published
2024
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10. Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C

Author

Tang, Juanjie, Novak, Tanya, Hecker, Julian, Grubbs, Gabrielle, Zahra, Fatema Tuz, Bellusci, Lorenza, Pourhashemi, Sara, Chou, Janet, Moffitt, Kristin, Halasa, Natasha B, Schwartz, Stephanie P, Walker, Tracie C, Tarquinio, Keiko M, Zinter, Matt S, Staat, Mary A, Gertz, Shira J, Cvijanovich, Natalie Z, Schuster, Jennifer E, Loftis, Laura L, Coates, Bria M, Mack, Elizabeth H, Irby, Katherine, Fitzgerald, Julie C, Rowan, Courtney M, Kong, Michele, Flori, Heidi R, Maddux, Aline B, Shein, Steven L, Crandall, Hillary, Hume, Janet R, Hobbs, Charlotte V, Tremoulet, Adriana H, Shimizu, Chisato, Burns, Jane C, Chen, Sabrina R, Moon, Hye Kyung, Lange, Christoph, Randolph, Adrienne G, and Khurana, Surender

Subjects
Pediatric, Pneumonia, Emerging Infectious Diseases, Infectious Diseases, Biodefense, Immunization, Prevention, Vaccine Related, Lung, Clinical Research, Good Health and Well Being, Adolescent, Antibodies, Viral, COVID-19, Child, Child, Preschool, Humans, Membrane Glycoproteins, Neutralization Tests, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Systemic Inflammatory Response Syndrome, Viral Envelope Proteins
Abstract

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.

Published
2022

11. Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children

Author

Podd, Bradley S., Banks, Russell K., Reeder, Ron, Telford, Russell, Holubkov, Richard, Carcillo, Joseph, Berg, Robert A., Wessel, David, Pollack, Murray M., Meert, Kathleen, Hall, Mark, Newth, Christopher, Lin, John C., Doctor, Allan, Shanley, Tom, Cornell, Tim, Harrison, Rick E., Zuppa, Athena F., Sward, Katherine, Dean, J. Michael, and Randolph, Adrienne G.

Published
2023
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12. The Modified Clinical Progression Scale for Pediatric Patients: Evaluation as a Severity Metric and Outcome Measure in Severe Acute Viral Respiratory Illness

Author

Leland, Shannon B., Staffa, Steven J., Newhams, Margaret M., Khemani, Robinder G., Marshall, John C., Young, Cameron C., Maddux, Aline B., Hall, Mark W., Weiss, Scott L., Schwarz, Adam J., Coates, Bria M., Sanders, Ronald C., Jr, Kong, Michele, Thomas, Neal J., Nofziger, Ryan A., Cullimore, Melissa L., Halasa, Natasha B., Loftis, Laura L., Cvijanovich, Natalie Z., Schuster, Jennifer E., Flori, Heidi, Gertz, Shira J., Hume, Janet R., Olson, Samantha M., Patel, Manish M., Zurakowski, David, and Randolph, Adrienne G.

Published
2023
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13. Association of Asthma With Treatments and Outcomes in Children With Critical Influenza

Author

Kong, Michele, Murdock, Meghan, Sanders, Ronald C., Jr., Irby, Katherine, Hefley, Glenda, Maddux, Aline B., Mourani, Peter M., Van, Kevin A., Mansour, Rachel, Miller, Kristen R., Grunwell, Jocelyn R., Coates, Bria M., Shukla, Avani, Chavez, Jairo, Randolph, Adrienne G., Newhams, Margaret M., Chen, Sabrina R., Jung, Emily, Flori, Heidi R., Dahmer, Mary K., Jayachandran, Chaandini, Hume, Janet R., Goertzen, Lexie, Faanes, Brittany, Schuster, Jennifer E., Bledsoe, Megan C., Clark, Shannon E., Cullimore, Melissa L., Wellman, Rachel L., Gertz, Shira J., Nofziger, Ryan A., Twinem, Nicole, Shein, Steven L., Rasal, Rajashri, Hall, Mark W., Flowers, Maggie, Steele, Lisa, Weiss, Scott L., Bush, Jenny L., Burnett, Ryan H., Thomas, Neal J., Spear, Debra, Halasa, Natasha B., Stewart, Laura S., Lynch, Tricia L., Olson, Samantha M., Patel, Manish M., Miller, Kristen, Patel, Manish, Fitzpatrick, Anne M., and Phipatanakul, Wanda

Published
2023
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14. Type I interferon signature and cycling lymphocytes in macrophage activation syndrome

Author

Huang, Zhengping, Brodeur, Kailey E., Chen, Liang, Du, Yan, Wobma, Holly, Hsu, Evan E., Liu, Meng, Chang, Joyce C., Chang, Margaret H., Chou, Janet, Day-Lewis, Megan, Dedeoglu, Fatma, Halyabar, Olha, Lederer, James A., Li, Tianwang, Lo, Mindy S., Lu, Meiping, Meidan, Esra, Newburger, Jane W., Randolph, Adrienne G., Son, Mary Beth, Sundel, Robert P., Taylor, Maria L., Wu, Huaxiang, Zhou, Qing, Canna, Scott W., Wei, Kevin, Henderson, Lauren A., Nigrovic, Peter A., and Lee, Pui Y.

Subjects
Interferon -- Analysis, T cells -- Analysis -- Genetic aspects, RNA sequencing -- Genetic aspects -- Analysis, Genes -- Genetic aspects -- Analysis, Tofacitinib -- Analysis, Biological response modifiers -- Analysis -- Genetic aspects, Killer cells -- Analysis -- Genetic aspects, RNA -- Analysis -- Genetic aspects, Macrophages -- Analysis, Health care industry, Children's Hospital (Boston, Massachusetts)
Abstract

BACKGROUND. Macrophage activation syndrome (MAS) is a life-threatening complication of Still's disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS. METHOD. We profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies. RESULTS. Bulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-[gamma] signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-[gamma] signatures and localized the cell proliferation signature to cycling [CD38.sup.+][HLA-DR.sup.+] cells within [CD4.sup.+] T cell, [CD8.sup.+] T cell, and NK cell populations. [CD38.sup.+][HLA-DR.sup.+] lymphocytes exhibited prominent IFN-[gamma] production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking [CD38.sup.+][HLA- DR.sup.+] lymphocytes with monocytes through IFN-[gamma] signaling. Notably, the expansion of [CD38.sup.+][HLA-DR.sup.+] lymphocytes in MAS was greaterthan in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15--both elevated in MAS patients - synergistically augmented the generation of [CD38.sup.+][HLA- DR.sup.+] lymphocytes, while Janus kinase inhibition mitigated this response. CONCLUSION. MAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate [CD38.sup.+][HLA-DR.sup.+] cycling lymphocytes that produce IFN-[gamma]., Introduction Still's disease (SD) is characterized by recurrent fever, skin rash, arthritis, and systemic inflammation. SD was first recognized in children and is commonly called systemic juvenile idiopathic arthritis (sJIA) [...]

Published
2023
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15. Acute respiratory distress syndrome.

Author

Matthay, Michael A, Zemans, Rachel L, Zimmerman, Guy A, Arabi, Yaseen M, Beitler, Jeremy R, Mercat, Alain, Herridge, Margaret, Randolph, Adrienne G, and Calfee, Carolyn S

Subjects
Humans, Respiratory Distress Syndrome, Adult, Carbon Dioxide, Angiopoietin-2, von Willebrand Factor, Cadherins, Interleukin-8, Vasodilator Agents, Antigens, CD, Glucocorticoids, Radiography, Respiration, Artificial, High-Frequency Ventilation, Positive-Pressure Respiration, Quality of Life, Ventilator-Induced Lung Injury, Biomarkers, Antigens, CD, Respiration, Artificial, Respiratory Distress Syndrome, Adult, Clinical Sciences
Abstract

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30-40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

Published
2019

16. Evaluation of Mannose Binding Lectin Gene Variants in Pediatric Influenza Virus-Related Critical Illness

Author

Levy, Emily R, Yip, Wai-Ki, Super, Michael, Ferdinands, Jill M, Mistry, Anushay J, Newhams, Margaret M, Zhang, Yu, Su, Helen C, McLaughlin, Gwenn E, Sapru, Anil, Loftis, Laura L, Weiss, Scott L, Hall, Mark W, Cvijanovich, Natalie, Schwarz, Adam, Tarquinio, Keiko M, Mourani, Peter M, Investigators, PALISI PICFLU, and Randolph, Adrienne G

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Biodefense, Infectious Diseases, Lung, Prevention, Pediatric, Sepsis, Emerging Infectious Diseases, Vaccine Related, Influenza, Hematology, Clinical Research, Pneumonia & Influenza, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Infection, Good Health and Well Being, Adolescent, Amino Acid Substitution, Child, Child, Preschool, Coinfection, Critical Illness, Female, Genetic Predisposition to Disease, Humans, Infant, Influenza A virus, Influenza, Human, Male, Mannose-Binding Lectin, Methicillin-Resistant Staphylococcus aureus, Mutation, Missense, Staphylococcal Infections, MBL, influenza, pediatric, methicillin-resistant Staphylococcus aureus, critical illness, sepsis, mortality, PALISI PICFLU Investigators, Immunology, Biochemistry and cell biology
Abstract

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2_Gly54Asp("B") mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections. Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 "low-producer" variants rs11003125("H/L"), rs7096206("Y/X"), rs1800450Gly54Asp("B"), rs1800451Gly57Glu("C"), rs5030737Arg52Cys("D") in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes ("B/B," "C/C") to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity. Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (n = 33, 8% overall) was associated with death (p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002). Conclusions: MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.

Published
2019

17. Risk Factors for Multisystem Inflammatory Syndrome in Children: A Case-control Investigation

Author

Zambrano, Laura D., Wu, Michael J., Martin, Lora, Malloch, Lacy, Chen, Sabrina, Newhams, Margaret M., Kucukak, Suden, Son, Mary Beth, Sanders, Cameron, Patterson, Kayla, Halasa, Natasha, Fitzgerald, Julie C., Leroue, Matthew K., Hall, Mark, Irby, Katherine, Rowan, Courtney M., Wellnitz, Kari, Sahni, Leila C., Loftis, Laura, Bradford, Tamara T., Staat, Mary, Babbitt, Christopher, Carroll, Christopher L., Pannaraj, Pia S., Kong, Michele, Schuster, Jennifer E., Chou, Janet, Patel, Manish M., Randolph, Adrienne G., Campbell, Angela P., and Hobbs, Charlotte V.

Published
2023
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18. Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2)

Author

Emeriaud, Guillaume, López-Fernández, Yolanda M., Iyer, Narayan Prabhu, Bembea, Melania M., Agulnik, Asya, Barbaro, Ryan P., Baudin, Florent, Bhalla, Anoopindar, Brunow de Carvalho, Werther, 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, Modesto i Alapont, Vicent, 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., Emeriaud, Guillaume, López-Fernández, Yolanda M., Khemani, Robinder G., Iyer, Narayan Prabhu, Bembea, Melania, Korang, Steven Kwasi, Steffen, Katherine M., Yehya, Nadir, Smith, Lincoln, Thomas, Neal J., Zimmerman, Jerry J., Erickson, Simon J., Shein, Steven L., Grunwell, Jocelyn R., Dahmer, Mary K., Sapru, Anil, Quasney, Michael W., Flori, Heidi R., Fernandez, Analia, Alapont, Vicent Modesto i, Rimensberger, Peter, Cheifetz, Ira, Rowan, Courtney, Randolph, Adrienne G., Kneyber, Martin, Valentine, Stacey, Kudchadkar, Sapna, Ward, Shan, Nadkarni, Vinay, Curley, Martha A.Q., Bhalla, Anoopindar, Baudin, Florent, Takeuchi, Muneyuki, Cruces, Pablo, Carroll, Christopher L., Napolitano, Natalie, Pons-Odena, Marti, Essouri, Sandrine, Rambaud, Jérome, Barbaro, Ryan, Macrae, Duncan, Dalton, Heidi, Killien, Elizabeth, Maddux, Aline, Tse, Sze Man, Watson, Scott, Sanchez-Pinto, L. Nelson, Sauthier, Michaël, Rajapreyar, Prakadeshwari, Jouvet, Philippe, Newth, Christopher, Morrow, Brenda, Agulnik, Asya, de Carvalho, Werther Brunow, Chisti, Mohamod, Lee, Jan Hau, Lobner, Katie, Kysh, Lynn, Pincivy, Alix, and Dodin, Philippe

Published
2023
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21. Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis

Author

Yonker, Lael M., Swank, Zoe, Bartsch, Yannic C., Burns, Madeleine D., Kane, Abigail, Boribong, Brittany P., Davis, Jameson P., Loiselle, Maggie, Novak, Tanya, Senussi, Yasmeen, Cheng, Chi-An, Burgess, Eleanor, Edlow, Andrea G., Chou, Janet, Dionne, Audrey, Balaguru, Duraisamy, Lahoud-Rahme, Manuella, Arditi, Moshe, Julg, Boris, Randolph, Adrienne G., Alter, Galit, Fasano, Alessio, and Walt, David R.

Published
2023
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22. Consequences beyond acute SARS-CoV-2 infection in children.

Author

Saydah, Sharon H., Campbell, Angela P., and Randolph, Adrienne G.

Subjects
MULTISYSTEM inflammatory syndrome in children, POST-acute COVID-19 syndrome, SARS-CoV-2, SYMPTOMS, DIAGNOSIS
Abstract

Although most children are spared from developing complications from SARS-CoV-2 infection, some may suffer consequences including Long Covid and multisystem inflammatory syndrome in children (MIS-C). Although the occurrence of these conditions has decreased over time, they can still occur, and recognition of symptoms and prompt diagnosis is imperative for early intervention. [ABSTRACT FROM AUTHOR]

Published
2024
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24. From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations For Developing Precision Medicine in ICU

Author

Gordon, Anthony C., primary, Alipanah-Lechner, Narges, additional, Bos, Lieuwe D., additional, Dianti, Jose, additional, Diaz, Janet Victoria, additional, Finfer, Simon, additional, Fujii, Tomoko, additional, Giamarellos-Bourboulis, Evangelos J., additional, Goligher, Ewan C., additional, Gong, Michelle Ng, additional, Karakike, Eleni, additional, Liu, Vincent, additional, Lumlertgul, Nuttha, additional, Marshall, John C., additional, Menon, David K., additional, Meyer, Nuala J, additional, Munroe, Elizabeth S., additional, Myatra, Sheila N., additional, Ostermann, Marlies, additional, Prescott, Hallie C, additional, Randolph, Adrienne G., additional, Schenck, Edward J., additional, Seymour, Christopher W, additional, Shankar-Hari, Manu, additional, Singer, Mervyn, additional, Smit, Marry R., additional, Tanaka, Aiko, additional, Taccone, Fabio Silvio, additional, Thompson, B. Taylor, additional, Torres, Lisa K, additional, Van der Poll, Tom, additional, Vincent, Jean-Louis, additional, and Calfee, Carolyn S, additional

Published
2024
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25. Data-driven clustering identifies features distinguishing multisystem inflammatory syndrome from acute COVID-19 in children and adolescents

Author

Geva, Alon, Patel, Manish M., Newhams, Margaret M., Young, Cameron C., Son, Mary Beth F., Kong, Michele, Maddux, Aline B., Hall, Mark W., Riggs, Becky J., Singh, Aalok R., Giuliano, John S., Hobbs, Charlotte V., Loftis, Laura L., McLaughlin, Gwenn E., Schwartz, Stephanie P., Schuster, Jennifer E., Babbitt, Christopher J., Halasa, Natasha B., Gertz, Shira J., Doymaz, Sule, Hume, Janet R., Bradford, Tamara T., Irby, Katherine, Carroll, Christopher L., McGuire, John K., Tarquinio, Keiko M., Rowan, Courtney M., Mack, Elizabeth H., Cvijanovich, Natalie Z., Fitzgerald, Julie C., Spinella, Philip C., Staat, Mary A., Clouser, Katharine N., Soma, Vijaya L., Dapul, Heda, Maamari, Mia, Bowens, Cindy, Havlin, Kevin M., Mourani, Peter M., Heidemann, Sabrina M., Horwitz, Steven M., Feldstein, Leora R., Tenforde, Mark W., Newburger, Jane W., Mandl, Kenneth D., and Randolph, Adrienne G.

Published
2021
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26. Maternal Vaccination and Risk of Hospitalization for Covid-19 Among Infants

Author

Halasa, Natasha B., Olson, Samantha M., Staat, Mary A., Newhams, Margaret M., Price, Ashley M., Pannaraj, Pia S., Boom, Julie A., Sahni, Leila C., Chiotos, Kathleen, Cameron, Melissa A., Bline, Katherine E., Hobbs, Charlotte V., Maddux, Aline B., Coates, Bria M., Michelson, Kelly N., Heidemann, Sabrina M., Irby, Katherine, Nofziger, Ryan A., Mack, Elizabeth H., Smallcomb, Laura, Schwartz, Stephanie P., Walker, Tracie C., Gertz, Shira J., Schuster, Jennifer E., Kamidani, Satoshi, Tarquinio, Keiko M., Bhumbra, Samina S., Maamari, Mia, Hume, Janet R., Crandall, Hillary, Levy, Emily R., Zinter, Matt S., Bradford, Tamara T., Flori, Heidi R., Cullimore, Melissa L., Kong, Michele, Cvijanovich, Natalie Z., Gilboa, Suzanne M., Polen, Kara N., Campbell, Angela P., Randolph, Adrienne G., and Patel, Manish M.

Published
2023
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28. The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children

Author

Benamar, Mehdi, Chen, Qian, Chou, Janet, Jule, Amelie M., Boudra, Rafik, Contini, Paola, Crestani, Elena, Lai, Peggy S., Wang, Muyun, Fong, Jason, Rockwitz, Shira, Lee, Pui, Chan, Tsz Man Fion, Altun, Ekin Zeynep, Kepenekli, Eda, Karakoc-Aydiner, Elif, Ozen, Ahmet, Boran, Perran, Aygun, Fatih, Onal, Pinar, Sakalli, Ayse Ayzit Kilinc, Cokugras, Haluk, Gelmez, Metin Yusuf, Oktelik, Fatma Betul, Cetin, Esin Aktas, Zhong, Yuelin, Taylor, Maria Lucia, Irby, Katherine, Halasa, Natasha B., Mack, Elizabeth H., Signa, Sara, Prigione, Ignazia, Gattorno, Marco, Cotugno, Nicola, Amodio, Donato, Geha, Raif S., Son, Mary Beth, Newburger, Jane, Agrawal, Pankaj B., Volpi, Stefano, Palma, Paolo, Kiykim, Ayca, Randolph, Adrienne G., Deniz, Gunnur, Baris, Safa, De Palma, Raffaele, Schmitz-Abe, Klaus, Charbonnier, Louis-Marie, Henderson, Lauren A., and Chatila, Talal A.

Subjects
Suppressor cells -- Health aspects -- Physiological aspects, Cellular signal transduction -- Research, Pediatric research, Health care industry
Abstract

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection., Introduction COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in massive morbidity and mortality worldwide (1, 2). Acute infection is associated in some individuals with [...]

Published
2023
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29. RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness

Author

Sanders, Ronald C., Jr., Irby, Olivia K., Hefley, Glenda, Tellez, David, Typpo, Katri, Markovitz, Barry, Flori, Heidi, Cvijanovich, Natalie, Anas, Nick, Schwarz, Adam, Vargas-Shiraishi, Ofelia, Sapru, Anil, McQuillen, Patrick, Czaja, Angela, Mourani, Peter, Paden, Matthew, Tarquinio, Keiko, Stone, Cheryl L., Wardenburg, Juliane Bubeck, Pinto, Neethi, Montgomery, Vicki, Sullivan, Janice E., Randolph, Adrienne G., Agan, Anna A., Ash, Stephanie, Mistry, Anushay, Newhams, Margaret, Kurachek, Stephen C., Doctor, Allan, Hartman, Mary, Truemper, Edward, Mahapatra, Sidharth, Dawson, Machelle, Ackerman, Kate, Daugherty, L. Eugene, Nofziger, Ryan, Shein, Steve, Hall, Mark W., Steele, Lisa, Hanson-Huber, Lisa, Thomas, Neal J., Spear, Debra, Fitzgerald, Julie, Weiss, Scott, Bush, Jenny L., Graham, Kathryn, Higgerson, Renee, Christie, LeeAnn, Loftis, Laura L., Jaimon, Nancy, Gedeit, Rainer, Murkowski, Kathy, Novak, Tanya, McDonald, Douglas R., Newhams, Margaret M., Mistry, Anushay J., Panoskaltsis-Mortari, Angela, Mourani, Peter M., Weiss, Scott L., Tarquinio, Keiko M., Hartman, Mary E., and Junger, Wolfgang G.

Published
2020
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30. Candidacy for Extracorporeal Life Support in Children After Hematopoietic Cell Transplantation: A Position Paper From the Pediatric Acute Lung Injury and Sepsis Investigators Network’s Hematopoietic Cell Transplant and Cancer Immunotherapy Subgroup

Author

Zinter, Matt S., McArthur, Jennifer, Duncan, Christine, Adams, Roberta, Kreml, Erin, Dalton, Heidi, Abdel-Azim, Hisham, Rowan, Courtney M., Gertz, Shira J., Mahadeo, Kris M., Randolph, Adrienne G., Rajapreyar, Prakadeshwari, Steiner, Marie E., and Lehmann, Leslie

Published
2021
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32. Exuberant fibroblast activity compromises lung function via ADAMTS4

Author

Boyd, David F., Allen, E. Kaitlynn, Randolph, Adrienne G., Guo, Xi-zhi J., Weng, Yunceng, Sanders, Catherine J., and Bajracharya, Resha

Subjects
Proteases -- Analysis, Fibroblasts -- Mechanical properties, Extracellular matrix -- Models, Pulmonary function tests -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS).sup.1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS.sup.1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes--in particular the ECM protease ADAMTS4--and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections. Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function., Author(s): David F. Boyd [sup.1] , E. Kaitlynn Allen [sup.1] , Adrienne G. Randolph [sup.2] [sup.3] , Xi-zhi J. Guo [sup.1] , Yunceng Weng [sup.4] , Catherine J. Sanders [sup.1] [...]

Published
2020
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33. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children

Author

Weiss, Scott L., Peters, Mark J., Alhazzani, Waleed, Agus, Michael S. D., Flori, Heidi R., Inwald, David P., Nadel, Simon, Schlapbach, Luregn J., Tasker, Robert C., Argent, Andrew C., Brierley, Joe, Carcillo, Joseph, Carrol, Enitan D., Carroll, Christopher L., Cheifetz, Ira M., Choong, Karen, Cies, Jeffry J., Cruz, Andrea T., De Luca, Daniele, Deep, Akash, Faust, Saul N., De Oliveira, Claudio Flauzino, Hall, Mark W., Ishimine, Paul, Javouhey, Etienne, Joosten, Koen F. M., Joshi, Poonam, Karam, Oliver, Kneyber, Martin C. J., Lemson, Joris, MacLaren, Graeme, Mehta, Nilesh M., Møller, Morten Hylander, Newth, Christopher J. L., Nguyen, Trung C., Nishisaki, Akira, Nunnally, Mark E., Parker, Margaret M., Paul, Raina M., Randolph, Adrienne G., Ranjit, Suchitra, Romer, Lewis H., Scott, Halden F., Tume, Lyvonne N., Verger, Judy T., Williams, Eric A., Wolf, Joshua, Wong, Hector R., Zimmerman, Jerry J., Kissoon, Niranjan, and Tissieres, Pierre

Published
2020
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34. Executive summary: surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children

Author

Weiss, Scott L., Peters, Mark J., Alhazzani, Waleed, Agus, Michael S. D., Flori, Heidi R., Inwald, David P., Nadel, Simon, Schlapbach, Luregn J., Tasker, Robert C., Argent, Andrew C., Brierley, Joe, Carcillo, Joseph, Carrol, Enitan D., Carroll, Christopher L., Cheifetz, Ira M., Choong, Karen, Cies, Jeffry J., Cruz, Andrea T., De Luca, Daniele, Deep, Akash, Faust, Saul N., De Oliveira, Claudio Flauzino, Hall, Mark W., Ishimine, Paul, Javouhey, Etienne, Joosten, Koen F. M., Joshi, Poonam, Karam, Oliver, Kneyber, Martin C. J., Lemson, Joris, MacLaren, Graeme, Mehta, Nilesh M., Møller, Morten Hylander, Newth, Christopher J. L., Nguyen, Trung C., Nishisaki, Akira, Nunnally, Mark E., Parker, Margaret M., Paul, Raina M., Randolph, Adrienne G., Ranjit, Suchitra, Romer, Lewis H., Scott, Halden F., Tume, Lyvonne N., Verger, Judy T., Williams, Eric A., Wolf, Joshua, Wong, Hector R., Zimmerman, Jerry J., Kissoon, Niranjan, and Tissieres, Pierre

Published
2020
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41. Evaluation of "IFITM3" rs12252 Association With Severe Pediatric Influenza Infection

Author

Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Pediatric Influenza (PICFLU) Investigators, Randolph, Adrienne G., Yip, Wai-Ki, Allen, Emma Kaitlynn, Rosenberger, Carrie M., Agan, Anna A., Ash, Stephanie A., Zhang, Yu, Bhangale, Tushar R., Finkelstein, David, Cvijanovich, Natalie Z., Mourani, Peter M., Hall, Mark W., Su, Helen C., and Thomas, Paul G.

Published
2017

42. Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza

Author

Novak, Tanya, primary, Crawford, Jeremy Chase, additional, Hahn, Georg, additional, Hall, Mark W., additional, Thair, Simone A., additional, Newhams, Margaret M., additional, Chou, Janet, additional, Mourani, Peter M., additional, Tarquinio, Keiko M., additional, Markovitz, Barry, additional, Loftis, Laura L., additional, Weiss, Scott L., additional, Higgerson, Renee, additional, Schwarz, Adam J., additional, Pinto, Neethi P., additional, Thomas, Neal J., additional, Gedeit, Rainer G., additional, Sanders, Ronald C., additional, Mahapatra, Sidharth, additional, Coates, Bria M., additional, Cvijanovich, Natalie Z., additional, Ackerman, Kate G., additional, Tellez, David W., additional, McQuillen, Patrick, additional, Kurachek, Stephen C., additional, Shein, Steven L., additional, Lange, Christoph, additional, Thomas, Paul G., additional, and Randolph, Adrienne G., additional

Published
2023
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44. Characteristics and Clinical Outcomes of Vaccine-Eligible US Children Under-5 Years Hospitalized for Acute COVID-19 in a National Network

Author

Zambrano, Laura D., Newhams, Margaret M., Simeone, Regina M., Fleming-Dutra, Katherine E., Halasa, Natasha, Wu, Michael, Orzel-Lockwood, Amber O., Kamidani, Satoshi, Pannaraj, Pia S., Chiotos, Kathleen, Cameron, Melissa A., Maddux, Aline B., Schuster, Jennifer E., Crandall, Hillary, Kong, Michele, Nofziger, Ryan A., Staat, Mary A., Bhumbra, Samina S., Irby, Katherine, Boom, Julie A., Sahni, Leila C., Hume, Janet R., Gertz, Shira J., Maamari, Mia, Bowens, Cindy, Levy, Emily R., Bradford, Tamara T., Walker, Tracie C., Schwartz, Stephanie P., Mack, Elizabeth H., Guzman-Cottrill, Judith A., Hobbs, Charlotte V., Zinter, Matt S., Cvijanovich, Natalie Z., Bline, Katherine E., Hymes, Saul R., Campbell, Angela P., and Randolph, Adrienne G.

Published
2024
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