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Smadja DM, Massonnaud CR, Philippe A, Rosa M, Luneau S, Rauch A, Peiffer-Smadja N, Gagneux-Brunon A, Poissy J, Gruest M, Ung A, Pourcher V, Raffi F, Piroth L, Bouiller K, Esperou H, Delmas C, Belhadi D, Diallo A, Saillard J, Dechanet A, Mercier N, Dupont A, Lescure FX, Goehringer F, Jaureguiberry S, Danion F, Tolsma V, Cabie A, Courjon J, Leroy S, Mootien J, Mourvillier B, Gallien S, Lanoix JP, Botelho-Nevers E, Wallet F, Richard JC, Reuter J, Gaymard A, Greil R, Martin-Blondel G, Andrejak C, Yazdanpanah Y, Burdet C, Diehl JL, Hites M, Ader F, Susen S, Mentré F, Dupont A. sST2 is a key outcome biomarker in COVID-19: insights from discovery randomized trial. Sci Rep 2025; 15:14348. [PMID: 40274842 PMCID: PMC12022249 DOI: 10.1038/s41598-025-95122-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 03/19/2025] [Indexed: 04/26/2025] Open
Abstract
We investigated whether baseline levels of biomarkers related to endotheliopathy, thromboinflammation, and fibrosis were associated with clinical outcomes in hospitalized COVID-19 patients. We analyzed the associations between baseline levels of 21 biomarkers and time to hospital discharge and change in NEWS-2 score in patients from DisCoVeRy trial. We fitted multivariate models adjusted for baseline ISARIC 4C score, disease severity, D-dimer values, and treatment regimen. Between March 22 and June 29, 2020, 603 participants were randomized; 454 had a sample collected at baseline and analyzed. The backward selection of multivariate models showed that higher baseline levels of soluble suppressor of tumorigenicity 2 (sST2) and nucleosomes were statistically associated with a lower chance of hospital discharge before day 29 (sST2: aHR 0.24, 95% CI [0.15-0.38], p < 10-9; nucleosomes: aHR 0.62, 95% CI [0.48-0.81], p < 10-3). Likewise, higher levels of baseline sST2 were statistically associated with lower changes in the NEWS-2 score between baseline and day 15 (adjusted beta 4.47, 95% CI [2.65-6.28], p < 10-5). Moreover, we evaluated sST2 involvement in a confirmation cohort (SARCODO study, 103 patients) and found that elevated baseline sST2 levels were significantly associated with lower rates of hospital discharge before day 29 and a higher model performance (AUC at day 29 of 92%) compared to models without sST2. sST2 emerged as an independent predictor of clinical outcomes in two large cohort of hospitalized COVID-19 patients, warranting further investigation to elucidate its role in disease progression and potential as a therapeutic target.
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Affiliation(s)
- David M Smadja
- Innovative Therapies in Hemostasis, INSERM, University Paris Cité, 75006, Paris, France.
- Hematology Department, AP-HP Centre, Georges Pompidou European Hospital, Université Paris Cité, 20 Rue Leblanc, 75015, Paris, France.
| | - Clément R Massonnaud
- Département d'Épidémiologie, Biostatistique et Recherche Clinique, AP-HP, Hôpital Bichat, 75018, Paris, France
- IAME, INSERM, Université de Paris, 75018, Paris, France
| | - Aurélien Philippe
- Innovative Therapies in Hemostasis, INSERM, University Paris Cité, 75006, Paris, France
- Hematology Department, AP-HP Centre, Georges Pompidou European Hospital, Université Paris Cité, 20 Rue Leblanc, 75015, Paris, France
| | - Mickael Rosa
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Université de Lille, 59000, Lille, France
| | - Sophie Luneau
- Hematology Department, AP-HP Centre, Georges Pompidou European Hospital, Université Paris Cité, 20 Rue Leblanc, 75015, Paris, France
| | - Antoine Rauch
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Université de Lille, 59000, Lille, France
| | - Nathan Peiffer-Smadja
- IAME, INSERM, Université de Paris, 75018, Paris, France
- Service de Maladies Infectieuses et Tropicales, AP-HP, Hôpital Bichat, 75018, Paris, France
| | - Amandine Gagneux-Brunon
- Department of Infectious Diseases, University Hospital of Saint-Etienne, Saint-Etienne, France
- CIC-INSERM 1408, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Julien Poissy
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Université de Lille, 59000, Lille, France
| | - Maxime Gruest
- Hematology Department, AP-HP Centre, Georges Pompidou European Hospital, Université Paris Cité, 20 Rue Leblanc, 75015, Paris, France
| | - Alexandre Ung
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Université de Lille, 59000, Lille, France
| | - Valérie Pourcher
- Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, Service de Maladies Infectieuses et Tropicales, INSERM 1136, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Sorbonne Université, 75013, Paris, France
| | - François Raffi
- Department of Infectious Diseases, CIC 1413, INSERM, CHU Nantes, Nantes Université, Nantes, France
| | - Lionel Piroth
- Infectious Diseases Department, CHU, Dijon, and INSERM CIC 1432, Université de Bourgogne-Franche Comté, Dijon, France
| | - Kévin Bouiller
- UMR-CNRS 6249 Chrono-Environnement, Department of Infectious and Tropical Diseases, CHU Besançon, Université de Franche-Comté, 25000, Besançon, France
| | - Hélène Esperou
- Institut de Santé Publique, INSERM, Pôle Recherche Clinique, Paris, France
| | | | - Drifa Belhadi
- Département d'Épidémiologie, Biostatistique et Recherche Clinique, AP-HP, Hôpital Bichat, 75018, Paris, France
- IAME, INSERM, Université de Paris, 75018, Paris, France
| | - Alpha Diallo
- ANRS, Maladies Infectieuses Émergentes, Paris, France
| | | | - Aline Dechanet
- Département d'Épidémiologie, Biostatistique et Recherche Clinique, AP-HP, Hôpital Bichat, 75018, Paris, France
- IAME, INSERM, Université de Paris, 75018, Paris, France
| | | | - Axelle Dupont
- IAME, INSERM, Université de Paris, 75018, Paris, France
- Service de Maladies Infectieuses et Tropicales, AP-HP, Hôpital Bichat, 75018, Paris, France
| | - François-Xavier Lescure
- IAME, INSERM, Université de Paris, 75018, Paris, France
- Service de Maladies Infectieuses et Tropicales, AP-HP, Hôpital Bichat, 75018, Paris, France
| | - François Goehringer
- Service de Maladies Infectieuses et Tropicales, CHRU-Nancy, Université de Lorraine, 54000, Nancy, France
| | - Stéphane Jaureguiberry
- AP-HP, Service Des Maladies Infectieuses, Hôpital Bicêtre, 94270, Le Kremlin Bicêtre, France
- AP-HP, Centre National de Référence du Paludisme, Paris, France
| | - François Danion
- Service des Maladies Infectieuses et Tropicales, Hôpitaux Universitaires de Strasbourg, 67091, Strasbourg, France
| | - Violaine Tolsma
- Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Annecy Genevois, 74374, Annecy, France
| | - André Cabie
- PCCEI, Inserm, EFS, Univ Montpellier, Univ Antilles, Montpellier, France
- Service des Maladies Infectieuses et Tropicales, Inserm CIC1424, CHU de Martinique, Martinique, France
| | - Johan Courjon
- Service des Maladies Infectieuses et Tropicales, CHU de Nice, Nice, France
- U1065, Centre Méditerranéen de Médecine Moléculaire, C3M, Virulence Microbienne et Signalisation Inflammatoire, INSERM, Université Côte d'Azur, Nice, France
| | - Sylvie Leroy
- Fédération Hospitalo-Universitaire OncoAge, Nice, France
- Département de Pneumologie et d'Oncologie, CHU de Nice, 06000, Nice, France
- CNRS UMR 7275, IPMC, Université Côte d'Azur, Sophia Antipolis, France
| | - Joy Mootien
- Service de Réanimation Médicale, Groupe Hospitalier de la Région Mulhouse Sud-Alsace, Mulhouse, France
| | - Bruno Mourvillier
- CHU de Reims, Service de Réanimation Médicale, Université de Reims Champagne-Ardenne, Reims, France
| | - Sébastien Gallien
- Service d'Immunologie et Maladies Infectieuses, AP-HP, Hôpital Henri Mondor, 94000, Créteil, France
- INSERM U955, Université Paris-Est Créteil, 94000, Créteil, France
| | - Jean-Philippe Lanoix
- Service de Maladies Infectieuses et Tropicales, CHU Amiens-Picardie, 80000, Amiens, France
- AGIR UR UPJV 4294, CURS, Université Picardie Jules Verne, 80000, Amiens, France
| | - Elisabeth Botelho-Nevers
- Department of Infectious Diseases, University Hospital of Saint-Etienne, Saint-Etienne, France
- CIC-INSERM 1408, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Florent Wallet
- Département de Soins Intensifs, Hospices Civils de Lyon, Hôpital Lyon-Sud Pierre-Bénite, 69000, Lyon, France
| | - Jean-Christophe Richard
- Service de Réanimation Médicale, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, 69000, Lyon, France
- CREATIS, CNRS UMR5220, INSERM U1044, INSA, Université Lyon I, 69000, Lyon, France
| | - Jean Reuter
- Service de Réanimation-Soins Intensifs, Centre Hospitalier de Luxembourg, 1210, Luxembourg, Luxembourg
| | - Alexandre Gaymard
- Laboratoire de Virologie, Institut des Agents Infectieux de Lyon, Centre National de Référence des Virus Respiratoires France Sud, Hospices Civils de Lyon, 69317, Lyon, France
- Virpath, CIRI, INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, 69372, Lyon, France
| | - Richard Greil
- Department of Internal Medicine III With Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University Salzburg, 5020, Salzburg, Austria
| | - Guillaume Martin-Blondel
- Service des Maladies Infectieuses et Tropicales, CHU de Toulouse, 31320, Toulouse, France
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity) INSERM UMR1291 - CNRS UMR5051, Université Toulouse III, 31320, Toulouse, France
| | - Claire Andrejak
- Département de Pneumologie, CHU d'Amiens, 80000, Amiens, France
| | - Yazdan Yazdanpanah
- IAME, INSERM, Université de Paris, 75018, Paris, France
- Service de Maladies Infectieuses et Tropicales, AP-HP, Hôpital Bichat, 75018, Paris, France
| | - Charles Burdet
- Département d'Épidémiologie, Biostatistique et Recherche Clinique, AP-HP, Hôpital Bichat, 75018, Paris, France
- IAME, INSERM, Université de Paris, 75018, Paris, France
| | - Jean-Luc Diehl
- Innovative Therapies in Hemostasis, INSERM, University Paris Cité, 75006, Paris, France
- Intensive Care Unit, AP-HP Centre Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France
| | - Maya Hites
- Clinic of Infectious Diseases, Hôpital Universitaire de Bruxelles (H.U.B), 1070, Brussels, Belgium
| | - Florence Ader
- Département des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, Lyon, France
- Département des Maladies Infectieuses et Tropicales, CIRI, INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Sophie Susen
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Université de Lille, 59000, Lille, France
| | - France Mentré
- Département d'Épidémiologie, Biostatistique et Recherche Clinique, AP-HP, Hôpital Bichat, 75018, Paris, France
- IAME, INSERM, Université de Paris, 75018, Paris, France
| | - Annabelle Dupont
- Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Université de Lille, 59000, Lille, France
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Öztürk G, Bayrakoğlu D, Haskoloğlu Ş, Baskın K, Deveci N, İnce E, İleri T, Çakmaklı H, Ertem M, İkincioğulları A, Doğu F. ST2 and Reg3α: Can they predict aGvHD, steroid refractoriness and transplant-related mortality in pediatric patients after HSCT? Hematol Transfus Cell Ther 2024; 46 Suppl 6:S129-S135. [PMID: 38658297 PMCID: PMC11726067 DOI: 10.1016/j.htct.2024.02.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 12/18/2023] [Accepted: 02/27/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND/AIM There are several complications of hematopoietic stem cell transplantation. Without any doubt, most important of these is aGvHD that increases transplant-related mortality. The aim of this study is to investigate whether ST-2 and Reg3α levels measured at an early stage in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation can be individual biomarkers identifying future GvHD and predicting treatment response. MATERIALS AND METHODS From January 2019 to January 2021, 27 patients undergoing hematopoietic stem cell transplantation for primary immunodeficiency or hematopoietic diseases formed the study group. During their follow-up, the patients were classified into two groups as those developing and those not developing aGvHD. Nineteen healthy volunteers from a similar age group who needed their blood samples drawn for other reasons and who did not have any history of chronic disease, infection or medication use formed the control group. Blood samples of patients scheduled to have allogeneic HSCT were obtained before the administration of the preparative regimen, on Day +7 post-transplant and on the day of diagnosis if they developed aGvHD. Serum samples were stored at -20ºC until the day of processing. ST2 and Reg3α levels were measured using the ELISA method. RESULTS For patients who developed aGvHD (n = 13), ST2 levels obtained before the transplantation, on Day +7 post-transplant and on the day of aGvHD diagnosis (in patients developing GvHD) were significantly higher compared to the healthy Control Group (p-value <0.05). As regards to the samples obtained on the same days, ST2 levels did not differ significantly among patients who developed and those who did not develop GvHD (n = 14; p-value >0.05). ST2 levels of samples obtained on the days that acute skin and gastrointestinal tract GvHD developed did not differ significantly between these two groups (p-value >0.05). Reg3α levels of the pre-transplant samples, on Day +7 after the transplantation and on the day of aGvHD diagnosis did not show any difference between any of the groups (p-value >0.05). As only two patients died after transplantation, thus correlation of ST2 and Reg3α levels with transplant-related mortality could not be proven. CONCLUSION The results of this study suggest that ST2 and Reg3α levels are neither diagnostic nor prognostic or predictive biomarkers of aGvHD, steroid resistance or transplant-related mortality in pediatric patients. This study can be regarded as a pilot study because of the small patient population; more research involving a larger patient population is required.
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Affiliation(s)
- Gökcan Öztürk
- Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey.
| | - Deniz Bayrakoğlu
- Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey
| | - Şule Haskoloğlu
- Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey
| | - Kübra Baskın
- Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey
| | - Nazlı Deveci
- Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey
| | - Elif İnce
- Ankara University School of Medicine, Department of Pediatric Hematology, Ankara, Turkey
| | - Talia İleri
- Ankara University School of Medicine, Department of Pediatric Hematology, Ankara, Turkey
| | - Hasan Çakmaklı
- Ankara University School of Medicine, Department of Pediatric Hematology, Ankara, Turkey
| | - Mehmet Ertem
- Ankara University School of Medicine, Department of Pediatric Hematology, Ankara, Turkey
| | - Aydan İkincioğulları
- Ankara University School of Medicine, Department of Pediatric Hematology, Ankara, Turkey
| | - Figen Doğu
- Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey
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Srivastava A, Nalroad Sundararaj S, Bhatia J, Singh Arya D. Understanding long COVID myocarditis: A comprehensive review. Cytokine 2024; 178:156584. [PMID: 38508059 DOI: 10.1016/j.cyto.2024.156584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/21/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024]
Abstract
Infectious diseases are a cause of major concern in this twenty-first century. There have been reports of various outbreaks like severe acute respiratory syndrome (SARS) in 2003, swine flu in 2009, Zika virus disease in 2015, and Middle East Respiratory Syndrome (MERS) in 2012, since the start of this millennium. In addition to these outbreaks, the latest infectious disease to result in an outbreak is the SARS-CoV-2 infection. A viral infection recognized as a respiratory illness at the time of emergence, SARS-CoV-2 has wreaked havoc worldwide because of its long-lasting implications like heart failure, sepsis, organ failure, etc., and its significant impact on the global economy. Besides the acute illness, it also leads to symptoms months later which is called long COVID or post-COVID-19 condition. Due to its ever-increasing prevalence, it has been a significant challenge to treat the affected individuals and manage the complications as well. Myocarditis, a long-term complication of coronavirus disease 2019 (COVID-19) is an inflammatory condition involving the myocardium of the heart, which could even be fatal in the long term in cases of progression to ventricular dysfunction and heart failure. Thus, it is imperative to diagnose early and treat this condition in the affected individuals. At present, there are numerous studies which are in progress, investigating patients with COVID-19-related myocarditis and the treatment strategies. This review focuses primarily on myocarditis, a life-threatening complication of COVID-19 illness, and endeavors to elucidate the pathogenesis, biomarkers, and management of long COVID myocarditis along with pipeline drugs in detail.
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Affiliation(s)
- Arti Srivastava
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India
| | | | - Jagriti Bhatia
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Dharamvir Singh Arya
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India.
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Riccardi M, Myhre PL, Zelniker TA, Metra M, Januzzi JL, Inciardi RM. Soluble ST2 in Heart Failure: A Clinical Role beyond B-Type Natriuretic Peptide. J Cardiovasc Dev Dis 2023; 10:468. [PMID: 37998526 PMCID: PMC10672197 DOI: 10.3390/jcdd10110468] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023] Open
Abstract
Soluble (s)ST2 has been proposed as a useful biomarker for heart failure (HF) patient management. Myocardial damage or mechanical stress stimulate sST2 release. ST2 competes with a membrane bound receptor (ST2 ligand, or ST2L) for interleukin-33 (IL-33) binding, inhibiting the effects induced by the ST2L/IL-33 interaction so that excessive sST2 may contribute to myocardial fibrosis and ventricular remodeling. Compared to natriuretic peptides (NPs), sST2 concentration is not substantially affected by age, sex, body mass index, kidney function, atrial fibrillation, anemia, or HF etiology, and has low intra-individual variation. Its prognostic role as an independent marker is well reported in the literature. However, there is a gap on its use in combination with NPs, currently the only biomarkers recommended by European and American guidelines for HF management. Reflecting the activation of two distinct biological systems, a benefit from the use of sST2 and NP in combination is advocated. The aim of this review is to report the current scientific knowledge on sST2 in the acute and chronic HF settings with a particular attention to its additive role to natriuretic peptides (NPs).
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Affiliation(s)
- Mauro Riccardi
- Institute of Cardiology, ASST Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, 25121 Brescia, Italy; (M.R.); (M.M.)
| | - Peder L. Myhre
- Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, 1478 Nordbyhagen, Norway;
- K.G. Jebsen Center for Cardiac Biomarkers, Institute of Clinical Medicine, University of Oslo, 0313 Oslo, Norway
| | - Thomas A. Zelniker
- Department of Internal Medicine II, Division of Cardiology, Center of Cardiovascular Medicine, Medical University of Vienna, 1090 Vienna, Austria;
| | - Marco Metra
- Institute of Cardiology, ASST Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, 25121 Brescia, Italy; (M.R.); (M.M.)
| | - James L. Januzzi
- Cardiology Division, Massachusetts General Hospital, Harvard Medical School, and Baim Institute for Clinical Research, Boston, MA 02215, USA;
| | - Riccardo M. Inciardi
- Institute of Cardiology, ASST Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, 25121 Brescia, Italy; (M.R.); (M.M.)
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Arnaldos-Carrillo M, Noguera-Velasco JA, Martínez-Ardil IM, Riquelme-Pérez A, Cebreiros-López I, Hernández-Vicente Á, Ros-Lucas JA, Khan A, Bayes-Genís A, Pascual-Figal D. Value of increased soluble suppressor tumorigenicity biomarker 2 (sST2) on admission as an indicator of severity in patients with COVID-19. Med Clin (Barc) 2023; 161:185-191. [PMID: 37137804 PMCID: PMC10086099 DOI: 10.1016/j.medcli.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 03/31/2023] [Accepted: 04/01/2023] [Indexed: 05/05/2023]
Abstract
BACKGROUND Soluble suppressor of tumorigenicity-2 (sST2) is a biomarker for heart failure and pulmonary injury. We hypothesize that sST2 could help predict severity of SARS-CoV-2 infections. METHODS sST2 was analyzed in patients consecutively admitted for SARS-CoV-2 pneumonia. Other prognostic markers were also measured. In-hospital complications were registered, including death, ICU admission, and respiratory support requirements. RESULTS 495 patients were studied (53% male, age: 57.6±17.6). At admission, median sST2 concentrations was 48.5ng/mL [IQR, 30.6-83.1ng/mL] and correlated with male gender, older age, comorbidities, other severity biomarkers, and respiratory support requirements. sST2 levels were higher in patients who died (n=45, 9.1%) (45.6 [28.0, 75.9]ng/mL vs. 144 [82.6, 319] ng/mL, p<0.001) and those admitted to ICU (n=46, 9.3%) (44.7 [27.5, 71.3] ng/mL vs. 125 [69.0, 262]ng/mL, p<0.001). sST2 levels>210ng/mL were a strong predictor of complicated in-hospital courses, with higher risk of death (OR, 39.3, CI95% 15.9, 103) and death/ICU (OR 38.3, CI95% 16.3-97.5) after adjusting for all other risk factors. The addition of sST2 enhanced the predictive capacity of mortality risk models. CONCLUSIONS sST2 represents a robust severity predictor in COVID-19 and could be an important tool for identifying at-risk patients who may benefit from closer follow-up and specific therapies.
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Affiliation(s)
- María Arnaldos-Carrillo
- Clinical Laboratory Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Universidad de Murcia, Murcia, Spain
| | - José Antonio Noguera-Velasco
- Clinical Laboratory Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Universidad de Murcia, Murcia, Spain; IMIB Pascual Parrilla, Murcia, Spain
| | | | | | - Iria Cebreiros-López
- Clinical Laboratory Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Universidad de Murcia, Murcia, Spain; IMIB Pascual Parrilla, Murcia, Spain
| | | | - José Antonio Ros-Lucas
- Pneumology Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Universidad Católica de Murcia (UCAM), Murcia, Spain
| | - Amjad Khan
- Nuffield Division of Clinical Laboratory Sciences (NDCLS), Radcliffe Department of Medicine, John Radcliffe hospital, University of Oxford, Oxford, UK
| | - Antoni Bayes-Genís
- CIBER Cardiovascular, Madrid, Spain; Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Domingo Pascual-Figal
- Universidad de Murcia, Murcia, Spain; IMIB Pascual Parrilla, Murcia, Spain; Cardiology Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; CIBER Cardiovascular, Madrid, Spain.
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Hedbrant A, Engström C, Andersson L, Eklund D, Westberg H, Persson A, Särndahl E. Occupational quartz and particle exposure affect systemic levels of inflammatory markers related to inflammasome activation and cardiovascular disease. Environ Health 2023; 22:25. [PMID: 36907865 PMCID: PMC10009934 DOI: 10.1186/s12940-023-00980-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 03/07/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND The inflammatory responses are central components of diseases associated with particulate matter (PM) exposure, including systemic diseases such as cardiovascular diseases (CVDs). The aim of this study was to determine if exposure to PM, including respirable dust or quartz in the iron foundry environment mediates systemic inflammatory responses, focusing on the NLRP3 inflammasome and novel or established inflammatory markers of CVDs. METHODS The exposure to PM, including respirable dust, metals and quartz were determined in 40 foundry workers at two separate occasions per worker. In addition, blood samples were collected both pre-shift and post-shift and quantified for inflammatory markers. The respirable dust and quartz exposures were correlated to levels of inflammatory markers in blood using Pearson, Kendall τ and mixed model statistics. Analyzed inflammatory markers included: 1) general markers of inflammation, including interleukins, chemokines, acute phase proteins, and white blood cell counts, 2) novel or established inflammatory markers of CVD, such as growth/differentiation factor-15 (GDF-15), CD40 ligand, soluble suppressor of tumorigenesis 2 (sST2), intercellular/vascular adhesion molecule-1 (ICAM-1, VCAM-1), and myeloperoxidase (MPO), and 3) NLRP3 inflammasome-related markers, including interleukin (IL)-1β, IL-18, IL-1 receptor antagonist (IL-1Ra), and caspase-1 activity. RESULTS The average respirator adjusted exposure level to respirable dust and quartz for the 40 foundry workers included in the study was 0.65 and 0.020 mg/m3, respectively. Respirable quartz exposure correlated with several NLRP3 inflammasome-related markers, including plasma levels of IL-1β and IL-18, and several caspase-1 activity measures in monocytes, demonstrating a reverse relationship. Respirable dust exposure mainly correlated with non-inflammasome related markers like CXCL8 and sST2. CONCLUSIONS The finding that NLRP3 inflammasome-related markers correlated with PM and quartz exposure suggest that this potent inflammatory cellular mechanism indeed is affected even at current exposure levels in Swedish iron foundries. The results highlight concerns regarding the safety of current exposure limits to respirable dust and quartz, and encourage continuous efforts to reduce exposure in dust and quartz exposed industries.
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Affiliation(s)
- Alexander Hedbrant
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden.
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden.
| | - Christopher Engström
- Division of Mathematics and Physics, The School of Education, Culture and Communication, Mälardalen University, Box 883, 721 23, Västerås, Sweden
| | - Lena Andersson
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
- Department of Occupational and Environmental Medicine, Örebro University Hospital, 701 85, Örebro, Sweden
| | - Daniel Eklund
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
| | - Håkan Westberg
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
- Department of Occupational and Environmental Medicine, Örebro University Hospital, 701 85, Örebro, Sweden
| | - Alexander Persson
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
| | - Eva Särndahl
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
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7
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Astegolimab or Efmarodocokin Alfa in Patients With Severe COVID-19 Pneumonia: A Randomized, Phase 2 Trial. Crit Care Med 2023; 51:103-116. [PMID: 36519984 PMCID: PMC9749945 DOI: 10.1097/ccm.0000000000005716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia. DESIGN Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL). SETTING Hospitals. PATIENTS Hospitalized adults with severe COVID-19 pneumonia. INTERVENTIONS Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28. MEASUREMENTS AND MAIN RESULTS The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active. CONCLUSIONS Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.
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8
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Muthyala A, Sasidharan S, John KJ, Lal A, Mishra AK. Utility of cardiac bioenzymes in predicting cardiovascular outcomes in SARS-CoV-2. World J Virol 2022; 11:375-390. [PMID: 36188743 PMCID: PMC9523328 DOI: 10.5501/wjv.v11.i5.375] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/12/2022] [Accepted: 08/10/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cardiovascular complications have been increasingly recognized in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated coronavirus disease 2019 (COVID-19). Cardiac biomarkers are released because of this ongoing cardiovascular injury and can act as surrogate markers to assess the disease severity. AIM To review the variation and utility of these biomarkers in COVID-19 to ascertain their role in diagnosis, prognosis and clinical outcomes of the disease. METHODS We performed a literature search in PubMed, Medline and the Reference Citation Analysis (RCA), using the search terms "COVID-19" and "cardiac bioenzymes" or "cardiac biomarkers". Additionally, we also used the latest reference citation analysis tool to identify more articles. RESULTS Cardiac troponin has been consistently elevated in patients with COVID-19 associated myocarditis, and strongly correlated with adverse prognosis. Natri-uretic peptides including brain natriuretic peptide (BNP) and pro-BNP is elevated in patients with COVID-19 associated cardiac injury, irrespective of their prior heart failure status, and independently correlated with worst outcomes. Alongside these traditional biomarkers, novel cardiac bioenzymes including presepsin, soluble ST2 and copeptin, are also increasingly recognized as markers of cardiovascular injury in COVID-19 and can be associated with poor outcomes. CONCLUSION Assessment of cardiac bioenzymes at admission and their serial monitoring can help assess the severity of disease and predict mortality in patients with SARS-CoV-2 infection. Future studies are needed to elude the critical importance of novel biomarkers.
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Affiliation(s)
- Anjani Muthyala
- Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, United States
| | - Sandeep Sasidharan
- Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, United States
| | - Kevin John John
- Department of Critical Care, Belivers Church Medical College Hospital, Thiruvalla 689103, Kerela, India
| | - Amos Lal
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Ajay K Mishra
- Department of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, United States
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9
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Ngai HW, Kim DH, Hammad M, Gutova M, Aboody K, Cox CD. Stem Cell-based therapies for COVID-19-related acute respiratory distress syndrome. J Cell Mol Med 2022; 26:2483-2504. [PMID: 35426198 PMCID: PMC9077311 DOI: 10.1111/jcmm.17265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/24/2022] [Accepted: 02/28/2022] [Indexed: 11/30/2022] Open
Abstract
As the number of confirmed cases and resulting death toll of the COVID-19 pandemic continue to increase around the globe - especially with the emergence of new mutations of the SARS-CoV-2 virus in addition to the known alpha, beta, gamma, delta and omicron variants - tremendous efforts continue to be dedicated to the development of interventive therapeutics to mitigate infective symptoms or post-viral sequelae in individuals for which vaccines are not accessible, viable or effective in the prevention of illness. Many of these investigations aim to target the associated acute respiratory distress syndrome, or ARDS, which induces damage to lung epithelia and other physiologic systems and is associated with progression in severe cases. Recently, stem cell-based therapies have demonstrated preliminary efficacy against ARDS based on a number of preclinical and preliminary human safety studies, and based on promising outcomes are now being evaluated in phase II clinical trials for ARDS. A number of candidate stem cell therapies have been found to exhibit low immunogenicity, coupled with inherent tropism to injury sites. In recent studies, these have demonstrated the ability to modulate suppression of pro-inflammatory cytokine signals such as those characterizing COVID-19-associated ARDS. Present translational studies are aiming to optimize the safety, efficacy and delivery to fully validate stem cell-based strategies targeting COVID-19 associated ARDS for viable clinical application.
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Affiliation(s)
- Hoi Wa Ngai
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Dae Hong Kim
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Mohamed Hammad
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Margarita Gutova
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Karen Aboody
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
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10
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Crapnell RD, Dempsey NC, Sigley E, Tridente A, Banks CE. Electroanalytical point-of-care detection of gold standard and emerging cardiac biomarkers for stratification and monitoring in intensive care medicine - a review. Mikrochim Acta 2022; 189:142. [PMID: 35279780 PMCID: PMC8917829 DOI: 10.1007/s00604-022-05186-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/17/2022] [Indexed: 12/27/2022]
Abstract
Determination of specific cardiac biomarkers (CBs) during the diagnosis and management of adverse cardiovascular events such as acute myocardial infarction (AMI) has become commonplace in emergency department (ED), cardiology and many other ward settings. Cardiac troponins (cTnT and cTnI) and natriuretic peptides (BNP and NT-pro-BNP) are the preferred biomarkers in clinical practice for the diagnostic workup of AMI, acute coronary syndrome (ACS) and other types of myocardial ischaemia and heart failure (HF), while the roles and possible clinical applications of several other potential biomarkers continue to be evaluated and are the subject of several comprehensive reviews. The requirement for rapid, repeated testing of a small number of CBs in ED and cardiology patients has led to the development of point-of-care (PoC) technology to circumvent the need for remote and lengthy testing procedures in the hospital pathology laboratories. Electroanalytical sensing platforms have the potential to meet these requirements. This review aims firstly to reflect on the potential benefits of rapid CB testing in critically ill patients, a very distinct cohort of patients with deranged baseline levels of CBs. We summarise their source and clinical relevance and are the first to report the required analytical ranges for such technology to be of value in this patient cohort. Secondly, we review the current electrochemical approaches, including its sub-variants such as photoelectrochemical and electrochemiluminescence, for the determination of important CBs highlighting the various strategies used, namely the use of micro- and nanomaterials, to maximise the sensitivities and selectivities of such approaches. Finally, we consider the challenges that must be overcome to allow for the commercialisation of this technology and transition into intensive care medicine.
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Affiliation(s)
- Robert D Crapnell
- Faculty of Science and Engineering, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK
| | - Nina C Dempsey
- Faculty of Science and Engineering, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
| | - Evelyn Sigley
- Faculty of Science and Engineering, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK
| | - Ascanio Tridente
- Intensive Care Unit, Whiston Hospital, St Helens and Knowsley Teaching Hospitals NHS Trust, Warrington Road, Prescot, L35 5DR, UK
| | - Craig E Banks
- Faculty of Science and Engineering, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
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11
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Omland T, Prebensen C, Jonassen C, Svensson M, Berdal JE, Seljeflot I, Myhre PL. Soluble ST2 concentrations associate with in-hospital mortality and need for mechanical ventilation in unselected patients with COVID-19. Open Heart 2021; 8:openhrt-2021-001884. [PMID: 34933965 PMCID: PMC8692780 DOI: 10.1136/openhrt-2021-001884] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/30/2021] [Indexed: 01/28/2023] Open
Abstract
Objective Soluble ST2 (sST2) reflects inflammation, endothelial dysfunction and myocardial fibrosis, is produced in the lungs and is an established biomarker in heart failure. We sought to determine the role of sST2 in COVID-19 by assessing pathophysiological correlates and its association to in-hospital outcomes. Methods We enrolled 123 consecutive, hospitalised patients with COVID-19 in the prospective, observational COVID-19 MECH study. Biobank samples were collected at baseline, day 3 and day 9. The key exposure variable was sST2, and the outcome was ICU treatment with mechanical ventilation or in-hospital death. Results Concentrations of sST2 at baseline was median 48 (IQR 37–67) ng/mL, and 74% had elevated concentrations (>37.9 ng/mL). Higher baseline sST2 concentrations were associated with older age, male sex, white race, smoking, diabetes, hypertension and chronic kidney disease. Baseline sST2 also associated with the presence of SARS-CoV-2 viraemia, lower oxygen saturation, higher respiratory rate and increasing concentrations of biomarkers reflecting inflammation, thrombosis and cardiovascular disease. During the hospitalisation, 8 (7%) patients died and 27 (22%) survivors received intensive care unit (ICU) treatment. Baseline sST2 concentrations demonstrated a graded association with disease severity (median, IQR): medical ward 43 (36–59) ng/mL; ICU 67 (39–104) ng/mL and non-survivors 107 (72–116) ng/mL (p<0.001 for all comparisons). These associations persisted at day 3 and day 9. Conclusions sST2 concentrations associate with SARS-CoV-2 viraemia, hypoxaemia and concentrations of inflammatory and cardiovascular biomarkers. There was a robust association between baseline sST2 and disease severity that was independent of, and superior to, established risk factors. sST2 reflects key pathophysiology and may be a promising biomarker in COVID-19. Trial registration number NCT04314232.
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Affiliation(s)
- Torbjorn Omland
- Department of Cardiology, Akershus University Hospital, Lorenskog, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Christian Prebensen
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Infectious Diseases, Akershus University Hospital, Lorenskog, Norway
| | | | - My Svensson
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Division of Research and Innovation, Akershus University Hospital, Lørenskog, Norway
| | - Jan Erik Berdal
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Infectious Diseases, Akershus University Hospital, Lorenskog, Norway
| | - Ingebjørg Seljeflot
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Oslo, Norway
| | - Peder Langeland Myhre
- Department of Cardiology, Akershus University Hospital, Lorenskog, Norway .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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12
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Meijers WC, Bayes-Genis A, Mebazaa A, Bauersachs J, Cleland JGF, Coats AJS, Januzzi JL, Maisel AS, McDonald K, Mueller T, Richards AM, Seferovic P, Mueller C, de Boer RA. Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC). Eur J Heart Fail 2021; 23:1610-1632. [PMID: 34498368 PMCID: PMC9292239 DOI: 10.1002/ejhf.2346] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 08/13/2021] [Accepted: 09/07/2021] [Indexed: 12/18/2022] Open
Abstract
New biomarkers are being evaluated for their ability to advance the management of patients with heart failure. Despite a large pool of interesting candidate biomarkers, besides natriuretic peptides virtually none have succeeded in being applied into the clinical setting. In this review, we examine the most promising emerging candidates for clinical assessment and management of patients with heart failure. We discuss high-sensitivity cardiac troponins (Tn), procalcitonin, novel kidney markers, soluble suppression of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor-15 (GDF-15), cluster of differentiation 146 (CD146), neprilysin, adrenomedullin (ADM), and also discuss proteomics and genetic-based risk scores. We focused on guidance and assistance with daily clinical care decision-making. For each biomarker, analytical considerations are discussed, as well as performance regarding diagnosis and prognosis. Furthermore, we discuss potential implementation in clinical algorithms and in ongoing clinical trials.
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Affiliation(s)
- Wouter C Meijers
- Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands
| | - Antoni Bayes-Genis
- Heart Institute, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, CIBERCV, Barcelona, Spain
| | - Alexandre Mebazaa
- Inserm U942-MASCOT; Université de Paris; Department of Anesthesia and Critical Care, Hôpitaux Saint Louis & Lariboisière; FHU PROMICE, Paris, France.,Université de Paris, Paris, France.,Department of Anesthesia and Critical Care, Hôpitaux Saint Louis & Lariboisière, Paris, France.,FHU PROMICE, Paris, France
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - John G F Cleland
- Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow; National Heart & Lung Institute, Imperial College London, London, UK
| | - Andrew J S Coats
- Monash University, Melbourne, Australia.,University of Warwick, Coventry, UK
| | | | | | | | - Thomas Mueller
- Department of Clinical Pathology, Hospital of Bolzano, Bolzano, Italy
| | - A Mark Richards
- Christchurch Heart Institute, Christchurch, New Zealand.,Cardiovascular Research Institute, National University of Singapore, Singapore
| | - Petar Seferovic
- Faculty of Medicine, Belgrade University, Belgrade, Serbia.,Serbian Academy of Sciences and Arts, Belgarde, Serbia
| | | | - Rudolf A de Boer
- Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands
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13
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Sánchez-Marteles M, Rubio-Gracia J, Peña-Fresneda N, Garcés-Horna V, Gracia-Tello B, Martínez-Lostao L, Crespo-Aznárez S, Pérez-Calvo JI, Giménez-López I. Early Measurement of Blood sST2 Is a Good Predictor of Death and Poor Outcomes in Patients Admitted for COVID-19 Infection. J Clin Med 2021; 10:3534. [PMID: 34441830 PMCID: PMC8396994 DOI: 10.3390/jcm10163534] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/08/2021] [Accepted: 08/08/2021] [Indexed: 01/08/2023] Open
Abstract
Although several biomarkers have shown correlation to prognosis in COVID-19 patients, their clinical value is limited because of lack of specificity, suboptimal sensibility or poor dynamic behavior. We hypothesized that circulating soluble ST2 (sST2) could be associated to a worse outcome in COVID-19. In total, 152 patients admitted for confirmed COVID-19 were included in a prospective non-interventional, observational study. Blood samples were drawn at admission, 48-72 h later and at discharge. sST2 concentrations and routine blood laboratory were analyzed. Primary endpoints were admission at intensive care unit (ICU) and mortality. Median age was 57.5 years [Standard Deviation (SD: 12.8)], 60.4% males. 10% of patients (n = 15) were derived to ICU and/or died during admission. Median (IQR) sST2 serum concentration (ng/mL) rose to 53.1 (30.9) at admission, peaked at 48-72 h (79.5(64)) and returned to admission levels at discharge (44.9[36.7]). A concentration of sST2 above 58.9 ng/mL was identified patients progressing to ICU admission or death. Results remained significant after multivariable analysis. The area under the receiver operating characteristics curve (AUC) of sST2 for endpoints was 0.776 (p = 0.001). In patients admitted for COVID-19 infection, early measurement of sST2 was able to identify patients at risk of severe complications or death.
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Affiliation(s)
- Marta Sánchez-Marteles
- Department of Internal Medicine, Hospital Clínico Universitario, Lozano Blesa, 50009 Zaragoza, Spain; (J.R.-G.); (V.G.-H.); (B.G.-T.); (S.C.-A.); (J.I.P.-C.)
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
| | - Jorge Rubio-Gracia
- Department of Internal Medicine, Hospital Clínico Universitario, Lozano Blesa, 50009 Zaragoza, Spain; (J.R.-G.); (V.G.-H.); (B.G.-T.); (S.C.-A.); (J.I.P.-C.)
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
| | - Natacha Peña-Fresneda
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
- Facultad de Medicina, University of Zaragoza, 50009 Zaragoza, Spain
| | - Vanesa Garcés-Horna
- Department of Internal Medicine, Hospital Clínico Universitario, Lozano Blesa, 50009 Zaragoza, Spain; (J.R.-G.); (V.G.-H.); (B.G.-T.); (S.C.-A.); (J.I.P.-C.)
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
| | - Borja Gracia-Tello
- Department of Internal Medicine, Hospital Clínico Universitario, Lozano Blesa, 50009 Zaragoza, Spain; (J.R.-G.); (V.G.-H.); (B.G.-T.); (S.C.-A.); (J.I.P.-C.)
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
| | - Luis Martínez-Lostao
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
- Facultad de Medicina, University of Zaragoza, 50009 Zaragoza, Spain
- Department of Immunology, Hospital Clínico Universitario, Lozano Blesa, 50009 Zaragoza, Spain
| | - Silvia Crespo-Aznárez
- Department of Internal Medicine, Hospital Clínico Universitario, Lozano Blesa, 50009 Zaragoza, Spain; (J.R.-G.); (V.G.-H.); (B.G.-T.); (S.C.-A.); (J.I.P.-C.)
| | - Juan Ignacio Pérez-Calvo
- Department of Internal Medicine, Hospital Clínico Universitario, Lozano Blesa, 50009 Zaragoza, Spain; (J.R.-G.); (V.G.-H.); (B.G.-T.); (S.C.-A.); (J.I.P.-C.)
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
- Facultad de Medicina, University of Zaragoza, 50009 Zaragoza, Spain
| | - Ignacio Giménez-López
- Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; (N.P.-F.); (L.M.-L.); (I.G.-L.)
- Facultad de Medicina, University of Zaragoza, 50009 Zaragoza, Spain
- Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
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14
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Drohan CM, Nouraie SM, Bain W, Shah FA, Evankovich J, Zhang Y, Morris A, McVerry BJ, Kitsios GD. Biomarker-Based Classification of Patients With Acute Respiratory Failure Into Inflammatory Subphenotypes: A Single-Center Exploratory Study. Crit Care Explor 2021; 3:e0518. [PMID: 34476405 PMCID: PMC8378789 DOI: 10.1097/cce.0000000000000518] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES Hyper- and hypoinflammatory subphenotypes discovered in patients with acute respiratory distress syndrome predict clinical outcomes and therapeutic responses. These subphenotypes may be important in broader critically ill patient populations with acute respiratory failure regardless of clinical diagnosis. We investigated subphenotyping with latent class analysis in an inclusive population of acute respiratory failure, derived a parsimonious model for subphenotypic predictions based on a small set of variables, and examined associations with clinical outcomes. DESIGN Prospective, observational cohort study. SETTING Single-center, academic medical ICU. PATIENTS Mechanically ventilated patients with acute respiratory failure. MEASUREMENTS AND MAIN RESULTS We included 498 patients with acute respiratory failure (acute respiratory distress syndrome: 143, at-risk for acute respiratory distress syndrome: 198, congestive heart failure: 37, acute on chronic respiratory failure: 23, airway protection: 61, and multifactorial: 35) in our derivation cohort and measured 10 baseline plasma biomarkers. Latent class analysis considering clinical variables and biomarkers determined that a two-class model offered optimal fit (23% hyperinflammatory subphenotype). Distribution of hyperinflammatory subphenotype varied among acute respiratory failure etiologies (acute respiratory distress syndrome: 31%, at-risk for acute respiratory distress syndrome: 27%, congestive heart failure: 22%, acute on chronic respiratory failure 0%, airway protection: 5%, and multifactorial: 14%). Hyperinflammatory patients had higher Sequential Organ Failure Assessment scores, fewer ventilator-free days, and higher 30- and 90-day mortality (all p < 0.001). We derived a parsimonious model consisting of angiopoietin-2, soluble tumor necrosis factor receptor-1, procalcitonin, and bicarbonate and classified subphenotypes in a validation cohort (n = 139). Hyperinflammatory patients (19%) demonstrated higher levels of inflammatory biomarkers not included in the model (p < 0.01) and worse outcomes. CONCLUSIONS Host-response subphenotypes are observable in a heterogeneous population with acute respiratory failure and predict clinical outcomes. Simple, biomarker-based models can offer prognostic enrichment in patients with acute respiratory failure. The differential distribution of subphenotypes by specific etiologies of acute respiratory failure indicates that subphenotyping may be more relevant in patients with hypoxemic causes of acute respiratory failure and not in patients intubated for airway protection or acute on chronic decompensation.
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Affiliation(s)
- Callie M Drohan
- Division of General Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - S Mehdi Nouraie
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - William Bain
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
- Staff Physician, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA
| | - Faraaz A Shah
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
- Staff Physician, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA
| | - John Evankovich
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Yingze Zhang
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Alison Morris
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
- Center for Medicine and the Microbiome, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Bryan J McVerry
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
- Center for Medicine and the Microbiome, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Georgios D Kitsios
- Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
- Center for Medicine and the Microbiome, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
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15
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Alladina J, Levy SD, Cho JL, Brait KL, Rao SR, Camacho A, Hibbert KA, Harris RS, Medoff BD, Januzzi JL, Thompson BT, Bajwa EK. Plasma Soluble Suppression of Tumorigenicity-2 Associates with Ventilator Liberation in Acute Hypoxemic Respiratory Failure. Am J Respir Crit Care Med 2021; 203:1257-1265. [PMID: 33400890 DOI: 10.1164/rccm.202005-1951oc] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Rationale: Standard physiologic assessments of extubation readiness in patients with acute hypoxemic respiratory failure (AHRF) may not reflect lung injury resolution and could adversely affect clinical decision-making and patient outcomes. Objectives: We hypothesized that elevations in inflammatory plasma biomarkers sST2 (soluble suppression of tumorigenicity-2) and IL-6 indicate ongoing lung injury in AHRF and better inform patient outcomes compared with standard clinical assessments. Methods: We measured daily plasma biomarkers and physiologic variables in 200 patients with AHRF for up to 9 days after intubation. We tested the associations of baseline values with the primary outcome of unassisted breathing at Day 29. We analyzed the ability of serial biomarker measurements to inform successful ventilator liberation. Measurements and Main Results: Baseline sST2 concentrations were higher in patients dead or mechanically ventilated versus breathing unassisted at Day 29 (491.7 ng/ml [interquartile range (IQR), 294.5-670.1 ng/ml] vs. 314.4 ng/ml [IQR, 127.5-550.1 ng/ml]; P = 0.0003). Higher sST2 concentrations over time were associated with a decreased probability of ventilator liberation (hazard ratio, 0.80 per log-unit increase; 95% confidence interval [CI], 0.75-0.83; P = 0.03). Patients with higher sST2 concentrations on the day of liberation were more likely to fail liberation compared with patients who remained successfully liberated (320.9 ng/ml [IQR, 181.1- 495.6 ng/ml] vs. 161.6 ng/ml [IQR, 95.8-292.5 ng/ml]; P = 0.002). Elevated sST2 concentrations on the day of liberation decreased the odds of successful liberation when adjusted for standard physiologic parameters (odds ratio, 0.325; 95% CI, 0.119-0.885; P = 0.03). IL-6 concentrations did not associate with outcomes. Conclusions: Using sST2 concentrations to guide ventilator management may more accurately reflect underlying lung injury and outperform traditional measures of readiness for ventilator liberation.
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Affiliation(s)
| | - Sean D Levy
- Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Josalyn L Cho
- Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | | | - Sowmya R Rao
- Boston University School of Public Health, Boston, Massachusetts; and
| | - Alexander Camacho
- Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
| | | | - R Scott Harris
- Division of Pulmonary and Critical Care Medicine and.,Vertex Pharmaceuticals, Boston, Massachusetts
| | | | - James L Januzzi
- Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Ednan K Bajwa
- Division of Pulmonary and Critical Care Medicine and
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16
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A possible role for ST2 as prognostic biomarker for COVID-19. Vascul Pharmacol 2021; 138:106857. [PMID: 33746068 PMCID: PMC7970796 DOI: 10.1016/j.vph.2021.106857] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 02/11/2021] [Accepted: 03/17/2021] [Indexed: 01/08/2023]
Abstract
COVID-19 is a pandemic illness caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). It has been estimated that 80% of subject infected are asymptomatic or have mild to moderate symptoms. Differently, in severe cases of COVID-19, cytokine storm, acute respiratory distress syndrome (ARDS), severe systemic inflammatory response and cardiovascular diseases were observed Even if all molecular mechanisms leading to cardiovascular dysfunction in COVID-19 patients remain to be clarified, the evaluation of biomarkers of cardiac injury, stress and inflammation proved to be an excellent tool to identify the COVID-19 patients with worse outcome. However, the number of biomarkers used to manage COVID-19 patients is expected to increase with the increasing knowledge of the pathophysiology of the disease. It is our view that soluble suppressor of tumorigenicity 2 (sST2) can be used as biomarker in COVID-19. sST2 is routinely used as prognostic biomarker in patients with HF. Moreover, high circulating levels of sST2 have also been found in subjects with ARDS, pulmonary fibrosis and sepsis. Keeping in mind these considerations, in this review the possible mechanisms through which the SARS-CoV2 infection could damage the cardiovascular system were summarized and the possible role of sST2 in COVID-19 patients with CVD was discussed.
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17
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Miftode RS, Petriș AO, Onofrei Aursulesei V, Cianga C, Costache II, Mitu O, Miftode IL, Șerban IL. The Novel Perspectives Opened by ST2 in the Pandemic: A Review of Its Role in the Diagnosis and Prognosis of Patients with Heart Failure and COVID-19. Diagnostics (Basel) 2021; 11:diagnostics11020175. [PMID: 33530550 PMCID: PMC7911622 DOI: 10.3390/diagnostics11020175] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/01/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
The increasing incidence of coronavirus disease 19 (COVID-19) and its polymorphic clinical manifestations due to local and systemic inflammation represent a high burden for many public health systems. Multiple evidence revealed the interdependence between the presence of cardiovascular comorbidities and a severe course of COVID-19, with heart failure (HF) being incriminated as an independent predictor of mortality. Suppression of tumorigenicity-2 ST2 has emerged as one of the most promising biomarkers in assessing the evolution and prognosis of patients with HF. The uniqueness of ST2 is determined by its structural particularities. Its transmembrane isoform exerts cardioprotective effects, while the soluble isoform (sST2), which is detectable in serum, is associated with myocardial fibrosis and poor outcome in patients with HF. Some recent data also suggested the potential role of sST2 as a marker of inflammation, while other studies highlighted it as a valuable prognostic factor in patients with COVID-19. In this review, we summarized the pathways by which sST2 is related to myocardial injury and its connection to the severity of inflammation in patients with COVID-19. Also, we reviewed possible perspectives of using it as a dual cardio-inflammatory biomarker, for both early diagnosis, risk stratification and prognosis assessment of patients with concomitant HF and COVID-19.
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Affiliation(s)
- Radu-Stefan Miftode
- Department of Internal Medicine I (Cardiology), Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania; (R.-S.M.); (A.O.P.); (I.-I.C.); (O.M.)
| | - Antoniu Octavian Petriș
- Department of Internal Medicine I (Cardiology), Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania; (R.-S.M.); (A.O.P.); (I.-I.C.); (O.M.)
| | - Viviana Onofrei Aursulesei
- Department of Internal Medicine I (Cardiology), Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania; (R.-S.M.); (A.O.P.); (I.-I.C.); (O.M.)
- Correspondence:
| | - Corina Cianga
- Department of Immunology, Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania;
| | - Irina-Iuliana Costache
- Department of Internal Medicine I (Cardiology), Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania; (R.-S.M.); (A.O.P.); (I.-I.C.); (O.M.)
| | - Ovidiu Mitu
- Department of Internal Medicine I (Cardiology), Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania; (R.-S.M.); (A.O.P.); (I.-I.C.); (O.M.)
| | - Ionela-Larisa Miftode
- Department of Infectious Diseases, Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania;
| | - Ionela-Lăcrămioara Șerban
- Department of Morpho-Functional Sciences (II), Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania;
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18
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Hagens LA, Heijnen NFL, Smit MR, Schultz MJ, Bergmans DCJJ, Schnabel RM, Bos LDJ. Systematic review of diagnostic methods for acute respiratory distress syndrome. ERJ Open Res 2021; 7:00504-2020. [PMID: 33532455 PMCID: PMC7836439 DOI: 10.1183/23120541.00504-2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/18/2020] [Indexed: 01/10/2023] Open
Abstract
Rationale Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS. Methods Medline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising. Results Forty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72–0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population. Conclusion This systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed. Accuracy of diagnosis of acute respiratory distress syndrome (ARDS) is associated with risk of bias. There is a lack of validated diagnostic tests in an unbiased setting, emphasising the need for quality driven diagnostic research in ARDS.https://bit.ly/2GfPAvf
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Affiliation(s)
- Laura A Hagens
- Dept of Intensive Care, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Nanon F L Heijnen
- Dept of Intensive Care, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Marry R Smit
- Dept of Intensive Care, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Marcus J Schultz
- Dept of Intensive Care, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands.,Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand.,Nuffield Dept of Medicine, University of Oxford, Oxford, UK
| | - Dennis C J J Bergmans
- Dept of Intensive Care, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | | | - Lieuwe D J Bos
- Dept of Intensive Care, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands.,Dept of Respiratory Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands
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19
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Ruiz-Castilla M, Dos Santos B, Vizcaíno C, Baena J, Guilabert P, Marin-Corral J, Masclans JR, Roca O, Barret JP. Soluble suppression of tumorigenicity-2 predicts pneumonia in patients with inhalation injury: Results of a pilot study. Burns 2020; 47:906-913. [PMID: 33143991 DOI: 10.1016/j.burns.2020.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 08/25/2020] [Accepted: 10/08/2020] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Several mechanisms play a role in the development of pneumonia after inhalation injury. Our aim was to analyze whether higher concentrations of inflammatory markers or of biomarkers of epithelial injury are associated with a higher incidence of pneumonia in patients with inhalation injury. MATERIAL AND METHODS Secondary analysis of a single-center prospective observational cohort pilot study, performed over a two-year period (2015-2017) at the Burns Unit of the Plastic and Reconstructive Surgery Department of Vall d'Hebron University Hospital. All patients aged 18 with suspected inhalation injury undergoing admission to the Burns Unit were included. Plasma biomarkers of the lung epithelium (RAGE and SP-D), inflammation markers (IL6, IL8), and IL33, as well as soluble suppression of tumorigenicity-2 (sST2) levels, were measured within the first 24 h of admission. RESULTS Twenty-four patients with inhalation injury were included. Eight (33.3%) developed pneumonia after a median of 7 (4-8) days of hospital stay. Patients with pneumonia presented higher plasma concentrations of sST2 (2853 [2356-3351] ng/mL vs 1352 [865-1839] ng/mL; p < 0.001), IL33 (1.95 [1.31-2.59] pg/mL vs 1.26 [1.07-1.45] pg/mL; p = 0.002) and IL8 (325.7 [221.6-430.0] pg/mL vs 174.1 [95.2-253.0] pg/mL; p = 0.017) on day 1 of inclusion. Plasma sST2 concentration in the first 24 h demonstrated excellent diagnostic accuracy for predicting the occurrence of pneumonia in patients with smoke inhalation (AUROC 0.929 [95%CI 0.818-1.000]). A cutoff point of ≥2825 ng/mL for sST2 had a sensitivity of 75% and a specificity of 100%. The risk ratio of pneumonia in patients with sST2 ≥ 2825 ng/mL was 7.14 ([95% CI 1.56-32.61]; p = 0.016). CONCLUSIONS Plasma sST2 in the first 24 h of admission predicts the occurrence of pneumonia in patients with inhalation injury.
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Affiliation(s)
- Mireia Ruiz-Castilla
- Plastic and Reconstructive Surgery Department, Hospital Quirónsalud Barcelona, Barcelona, Spain; Plastic and Reconstructive Surgery Department and Burns Unit, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain.
| | - Bruce Dos Santos
- Plastic and Reconstructive Surgery Department and Burns Unit, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Claudia Vizcaíno
- Critical Care Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Jacinto Baena
- Critical Care Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Patricia Guilabert
- Anesthesiology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Judith Marin-Corral
- Critical Care Department, Parc de Salut Mar (Hospital del Mar) de Barcelona, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Joan R Masclans
- Critical Care Department, Parc de Salut Mar (Hospital del Mar) de Barcelona, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; Ciber Enfermedades Respiratorias (Ciberes), Instituto de Salud Carlos III, Madrid, Spain
| | - Oriol Roca
- Critical Care Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain; Ciber Enfermedades Respiratorias (Ciberes), Instituto de Salud Carlos III, Madrid, Spain
| | - Juan P Barret
- Plastic and Reconstructive Surgery Department and Burns Unit, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain
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20
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van der Zee P, Rietdijk W, Somhorst P, Endeman H, Gommers D. A systematic review of biomarkers multivariately associated with acute respiratory distress syndrome development and mortality. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2020; 24:243. [PMID: 32448370 PMCID: PMC7245629 DOI: 10.1186/s13054-020-02913-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 04/22/2020] [Indexed: 12/13/2022]
Abstract
Background Heterogeneity of acute respiratory distress syndrome (ARDS) could be reduced by identification of biomarker-based phenotypes. The set of ARDS biomarkers to prospectively define these phenotypes remains to be established. Objective To provide an overview of the biomarkers that were multivariately associated with ARDS development or mortality. Data sources We performed a systematic search in Embase, MEDLINE, Web of Science, Cochrane CENTRAL, and Google Scholar from inception until 6 March 2020. Study selection Studies assessing biomarkers for ARDS development in critically ill patients at risk for ARDS and mortality due to ARDS adjusted in multivariate analyses were included. Data extraction and synthesis We included 35 studies for ARDS development (10,667 patients at risk for ARDS) and 53 for ARDS mortality (15,344 patients with ARDS). These studies were too heterogeneous to be used in a meta-analysis, as time until outcome and the variables used in the multivariate analyses varied widely between studies. After qualitative inspection, high plasma levels of angiopoeitin-2 and receptor for advanced glycation end products (RAGE) were associated with an increased risk of ARDS development. None of the biomarkers (plasma angiopoeitin-2, C-reactive protein, interleukin-8, RAGE, surfactant protein D, and Von Willebrand factor) was clearly associated with mortality. Conclusions Biomarker data reporting and variables used in multivariate analyses differed greatly between studies. Angiopoeitin-2 and RAGE in plasma were positively associated with increased risk of ARDS development. None of the biomarkers independently predicted mortality. Therefore, we suggested to structurally investigate a combination of biomarkers and clinical parameters in order to find more homogeneous ARDS phenotypes. PROSPERO identifier PROSPERO, CRD42017078957
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Affiliation(s)
- Philip van der Zee
- Department of Adult Intensive Care, Erasmus Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
| | - Wim Rietdijk
- Department of Adult Intensive Care, Erasmus Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Peter Somhorst
- Department of Adult Intensive Care, Erasmus Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Henrik Endeman
- Department of Adult Intensive Care, Erasmus Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Diederik Gommers
- Department of Adult Intensive Care, Erasmus Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
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21
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Kotok D, Yang L, Evankovich JW, Bain W, Dunlap DG, Shah F, Zhang Y, Manatakis DV, Benos PV, Barbash IJ, Rapport SF, Lee JS, Morris A, McVerry BJ, Kitsios GD. The evolution of radiographic edema in ARDS and its association with clinical outcomes: A prospective cohort study in adult patients. J Crit Care 2020; 56:222-228. [PMID: 32028223 PMCID: PMC7136845 DOI: 10.1016/j.jcrc.2020.01.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 12/13/2019] [Accepted: 01/12/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE To assess the longitudinal evolution of radiographic edema using chest X-rays (CXR) in patients with Acute Respiratory Distress Syndrome (ARDS) and to examine its association with prognostic biomarkers, ARDS subphenotypes and outcomes. MATERIALS AND METHODS We quantified radiographic edema on CXRs from patients with ARDS or cardiogenic pulmonary edema (controls) using the Radiographic Assessment of Lung Edema (RALE) score on day of intubation and up to 10 days after. We measured baseline plasma biomarkers and recorded clinical variables. RESULTS The RALE score had good inter-rater agreement (r = 0.83, p < 0.0001) applied on 488 CXRs from 129 patients, with higher RALE scores in patients with ARDS (n = 108) compared to controls (n = 21, p = 0.01). Baseline RALE scores were positively correlated with levels of the receptor for end-glycation end products (RAGE) in ARDS patients (p < 0.05). Baseline RALE scores were not predictive of 30- or 90-day survival. Persistently elevated RALE scores were associated with prolonged need for mechanical ventilation (p = 0.002). CONCLUSIONS The RALE score is easily implementable with high inter-rater reliability. Longitudinal RALE scoring appears to be a reproducible approach to track the evolution of radiographic edema in patients with ARDS and can potentially predict prolonged need for mechanical ventilation.
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Affiliation(s)
- Daniel Kotok
- Internal Medicine Residency Program, University of Pittsburgh Medical Center McKeesport, USA
| | - Libing Yang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - John W Evankovich
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - William Bain
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Daniel G Dunlap
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Faraaz Shah
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Yingze Zhang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Dimitris V Manatakis
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Panayiotis V Benos
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ian J Barbash
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Sarah F Rapport
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Janet S Lee
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Alison Morris
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Center for Medicine and the Microbiome, University of Pittsburgh, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Bryan J McVerry
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Center for Medicine and the Microbiome, University of Pittsburgh, USA
| | - Georgios D Kitsios
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Center for Medicine and the Microbiome, University of Pittsburgh, USA.
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22
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Soluble Suppression Of Tumorigenicity-2 Predicts Hospital Mortality in Burn Patients: An Observational Prospective Cohort Pilot Study. Shock 2020; 51:194-199. [PMID: 29642231 DOI: 10.1097/shk.0000000000001155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The IL33/ST2 pathway has been implicated in the pathogenesis of different inflammatory diseases. Our aim was to analyze whether plasma levels of biomarkers involved in the IL33/ST2 axis might help to predict mortality in burn patients. METHODS Single-center prospective observational cohort pilot study performed at the Burns Unit of the Plastic and Reconstructive Surgery Department of the Vall d'Hebron University Hospital (Barcelona). All patients aged ≥18 years old with second or third-degree burns requiring admission to the Burns Unit were considered for inclusion. Blood samples were taken to measure levels of interleukins (IL)6, IL8, IL33, and soluble suppression of tumorigenicity-2 (sST2) within 24 h of admission to the Burns Unit and at day 3. Results are expressed as medians and interquartile ranges or as frequencies and percentages. RESULTS Sixty-nine patients (58 [84.1%] male, mean age 52 [35-63] years, total body surface area burned 21% [13%-30%], Abbreviated Burn Severity Index 6 [4-8]) were included. Thirteen (18.8%) finally died in the Burns Unit. Plasma levels of sST2 measured at day 3 after admission demonstrated the best prediction accuracy for survival (area under the receiver-operating curve 0.85 [0.71-0.99]; P < 0.001). The best cutoff point for the area under the receiver-operating curve index was estimated to be 2,561. In the Cox proportional hazards model, after adjusting for potential confounding, a plasma sST2 level ≥2,561 measured at day 3 was significantly associated with mortality (hazard ratio 6.94 [1.73-27.74]; P = 0.006). CONCLUSIONS Plasma sST2 at day 3 predicts hospital mortality in burn patients.
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23
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Kitsios GD, Yang L, Manatakis DV, Nouraie M, Evankovich J, Bain W, Dunlap DD, Shah F, Barbash IJ, Rapport SF, Zhang Y, DeSensi RS, Weathington NM, Chen BB, Ray P, Mallampalli RK, Benos PV, Lee JS, Morris A, McVerry BJ. Host-Response Subphenotypes Offer Prognostic Enrichment in Patients With or at Risk for Acute Respiratory Distress Syndrome. Crit Care Med 2019; 47:1724-1734. [PMID: 31634231 PMCID: PMC6865808 DOI: 10.1097/ccm.0000000000004018] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
OBJECTIVES Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes. DESIGN Prospective, observational cohort study. SETTING Medical ICU at a tertiary academic medical center. PATIENTS Mechanically ventilated patients with acute respiratory distress syndrome or ARFA. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p < 0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation. CONCLUSIONS Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care.
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Affiliation(s)
- Georgios D. Kitsios
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Center for Medicine and the Microbiome, University of Pittsburgh
| | - Libing Yang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Dimitris V. Manatakis
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Mehdi Nouraie
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - John Evankovich
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - William Bain
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Daniel D. Dunlap
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Faraaz Shah
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ian J Barbash
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Sarah F. Rapport
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Yingze Zhang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Rebecca S. DeSensi
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Nathaniel M. Weathington
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Bill B. Chen
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Prabir Ray
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Rama K. Mallampalli
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Veterans Affairs Pittsburgh Healthcare System
| | - Panayiotis V. Benos
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Janet S. Lee
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Alison Morris
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Center for Medicine and the Microbiome, University of Pittsburgh
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Bryan J. McVerry
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Center for Medicine and the Microbiome, University of Pittsburgh
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Beaudoin J, Szymonifka J, Lavender Z, Deaño RC, Zhou Q, Januzzi JL, Singh JP, Truong QA. Relationship of soluble ST2 to pulmonary hypertension severity in patients undergoing cardiac resynchronization therapy. J Thorac Dis 2019; 11:5362-5371. [PMID: 32030254 DOI: 10.21037/jtd.2019.11.66] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Background Pulmonary hypertension (PH) is an adverse prognostic marker in patients undergoing cardiac resynchronization therapy (CRT). We sought to determine the relation of biomarkers of fibrosis [soluble ST2 (sST2), galectin-3], wall stretch [amino terminal pro-brain natriuretic peptide (NT-proBNP)], and necrosis [high-sensitivity troponin-I (hsTnI)] to PH severity in CRT patients. Methods Biomarkers and right ventricular systolic pressure (RVSP) were measured at CRT implant and 6-month later (n=111). PH was categorized into 3 groups based on RVSP: no (<35 mmHg), mild-moderate (35-60 mmHg), and severe (>60 mmHg). Patients were categorized as progressors (worsened PH), persistent PH (no change) and regressors (improved PH). Endpoints were 6-month CRT response and 2-year major adverse cardiac event (MACE). Results RVSP was associated with CRT nonresponse (P=0.02) and MACE (P=0.03). Severe PH patients had 5-fold increase risk for CRT nonresponse (OR 5.0, P=0.04) and MACE (HR 5.7, P=0.04) over non-PH patients. Progressors and persistent PH patients had >2-fold odds for CRT non-response (OR 2.8, P=0.45) and >11-fold increase in MACE compared to no PH patients or regressors (HR 11.6, P=0.02). Only NT-proBNP and sST2 were discernable between PH groups, with graded increase based on PH severity (both P≤0.02), and lower values in regressors versus non-regressors (both P≤0.01). Levels of sST2 decreased at 6 months in regressors (15 ng/mL, P=0.03) and increased slightly (3-8 ng/mL) in non-regressors, without difference for NT-proBNP (P=0.08). Conclusions sST2 levels are related with PH severity in CRT patients. Serial sST2 changes after CRT implant suggests potential role to monitor PH after CRT.
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Affiliation(s)
- Jonathan Beaudoin
- Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval, Québec City, QC, Canada
| | | | | | - Roderick C Deaño
- Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Qing Zhou
- Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - James L Januzzi
- Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jagmeet P Singh
- Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Quynh A Truong
- Department of Biostatistics, New York University, New York, NY, USA.,Division of Cardiology, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY, USA
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25
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Pleural Effusion IL-33/sST2 Levels and Effects of Low and High IL-33/sST2 Levels on Human Mesothelial Cell Adhesion and Migration. Inflammation 2019; 42:2072-2085. [DOI: 10.1007/s10753-019-01070-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Haider T, Simader E, Hacker P, Ankersmit HJ, Heinz T, Hajdu S, Negrin LL. Increased serum concentrations of soluble ST2 are associated with pulmonary complications and mortality in polytraumatized patients. Clin Chem Lab Med 2019; 56:810-817. [PMID: 29341938 DOI: 10.1515/cclm-2017-0762] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND We sought to evaluate the role of soluble ST2 (suppression of tumorigenicity) serum concentrations in polytraumatized patients and its potential role as biomarker for pulmonary complications. METHODS We included severely injured patients (injury severity score≥16) admitted to our level I trauma center and analyzed serum samples obtained on the day of admission and on day 2. Furthermore, patients with isolated thoracic injury and healthy probands were included and served as control groups. Serum samples were analyzed for soluble ST2 concentrations with a commercially available ELISA kit. RESULTS A total of 130 patients were included in the present study. Five patients with isolated thoracic injury and eight healthy probands were further included. Serum analyses revealed significantly elevated concentrations of soluble ST2 in polytraumatized patients compared to patients suffering from isolated thoracic trauma and healthy probands. In polytraumatized patients who developed pulmonary complications (acute respiratory distress syndrome and pneumonia) and in patients who died, significantly higher serum concentrations of soluble ST2 were found on day 2 (p<0.001). Serum concentrations of soluble ST2 on day 2 were of prognostic value to predict pulmonary complications in polytraumatized patients (area under the curve=0.720, 95% confidence interval=0.623-0.816). Concomitant thoracic trauma had no further impact on serum concentrations of soluble ST2. CONCLUSIONS Serum concentrations of soluble ST2 are upregulated following polytrauma. Increased concentrations were associated with worse outcome.
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Affiliation(s)
- Thomas Haider
- Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Simader
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Philipp Hacker
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Hendrik J Ankersmit
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Heinz
- Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Hajdu
- Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas L Negrin
- Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria
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Abstract
Suppression of tumorigenicity 2 (ST2) is a member of the interleukin (IL)-1 receptor family, whose role was originally established in the context of inflammatory and autoimmune diseases. More recently, testing for ST2 has been used in the setting of cardiovascular disease. The soluble form of ST2 is a decoy receptor that inhibits beneficial cardioprotective effects of IL-33; such inhibition results in cardiac hypertrophy, myocardial fibrosis, and ventricular dysfunction. Measurement of soluble ST2 has utility for assessing heart failure severity and prognosis. In this review, we examine the role of soluble ST2 in both acute and chronic heart failure.
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Affiliation(s)
- Cian P McCarthy
- Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - James L Januzzi
- Division of Cardiology, Department of Medicine, Massachusetts General Hospital, 32 Fruit Street, Yawkey 5984, Boston, MA 02114, USA; Baim Institute for Clinical Research, Cardiometabolic Trials, 930 Commonwealth Avenue, Boston, MA 02115, USA.
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28
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Zhao J, Zhao Y. Interleukin-33 and its Receptor in Pulmonary Inflammatory Diseases. Crit Rev Immunol 2018; 35:451-61. [PMID: 27279043 DOI: 10.1615/critrevimmunol.2016015865] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Interleukin-33 (IL-33) is a member of the IL-1 cytokine family. It modulates immune responses and biological functions through binding to its membrane receptor, ST2L. ST2L is a member of the Toll-like/IL-1 (TIR)-receptor superfamily, and its isoform, soluble ST2 (sST2), functions as an inhibitor of the IL-33/ST2L pathway. Levels of IL-33 and sST2 in serum and bronchoalveolar lavage fluid (BAL) are known biomarkers for a variety of disorders such as heart failure, non-small-cell lung cancer, and pulmonary inflammatory diseases. IL-33 also exists in the nuclei, and nuclear IL-33 seems to regulate cytokine gene expression. In this review, we focus on the role of IL-33/ST2 in the pathogenesis of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), and lung injury.
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Affiliation(s)
- Jing Zhao
- Department of Medicine, University of Pittsburgh School of Medicine, Acute Lung Injury Center of Excellence, and Vascular Medical Institute, University of Pittsburgh, Pittsburgh, PA, United States
| | - Yutong Zhao
- Department of Medicine, University of Pittsburgh School of Medicine, Acute Lung Injury Center of Excellence, and Vascular Medical Institute, University of Pittsburgh, Pittsburgh, PA, United States
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Seo S, Yu J, Jenkins IC, Leisenring WM, Steven-Ayers T, Kuypers JM, Huang ML, Jerome KR, Boeckh M, Paczesny S. Diagnostic and Prognostic Plasma Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2017; 24:678-686. [PMID: 29223372 DOI: 10.1016/j.bbmt.2017.11.039] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 11/28/2017] [Indexed: 11/16/2022]
Abstract
Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication after hematopoietic cell transplantation (HCT) and is difficult to diagnose. In 41 patients with IPS, we evaluated 6 candidate proteins in plasma samples at day 7 post-HCT and at onset of IPS to identify potential diagnostic or prognostic biomarkers for IPS. Samples at similar times from 162 HCT recipients without documented infections and 37 HCT recipients with respiratory viral pneumonia served as controls. In multivariable models, a combination of Stimulation-2 (ST2; odds ratio [OR], 2.8; P < .001) and IL-6 (OR, 1.4; P = .025) was the best panel for distinguishing IPS at diagnosis from unaffected controls, whereas tumor necrosis factor receptor 1 (TNFR1; OR, 2.9; P = .002) was the best marker when comparing patients with IPS and viral pneumonia. The areas under the curve of the receiver operating characteristic (ROC) curves for discriminating between IPS and unaffected controls at day 7 post-HCT were .8 for ST2, .75 for IL-6, and .68 for TNFR1. Using estimated sensitivity and specificity values from cutoffs determined with the ROC analysis (cutoff level: ST2, 21 ng/mL; IL-6, 61 pg/mL; TNFR1, 3421 pg/mL), we calculated positive predictive values (PPV) for a range of estimated population prevalence values of IPS. Among the 3 markers, ST2 showed the highest PPV for IPS occurrence. Based on an assumed prevalence of 8%, a positive ST2 test increased likelihood of IPS to 50%. We conclude that a prospective validation study is warranted to determine whether a plasma biomarker panel can aid the noninvasive diagnosis and prognosis of IPS.
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Affiliation(s)
- Sachiko Seo
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Hematology and Oncology, National Cancer Research Center East, Chiba, Japan
| | - Jeffrey Yu
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Isaac C Jenkins
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Wendy M Leisenring
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Terry Steven-Ayers
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jane M Kuypers
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
| | - Meei-Li Huang
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
| | - Keith R Jerome
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Laboratory Medicine, University of Washington, Seattle, Washington
| | - Michael Boeckh
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.
| | - Sophie Paczesny
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
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Hypoxemic Patients With Bilateral Infiltrates Treated With High-Flow Nasal Cannula Present a Similar Pattern of Biomarkers of Inflammation and Injury to Acute Respiratory Distress Syndrome Patients*. Crit Care Med 2017; 45:1845-1853. [DOI: 10.1097/ccm.0000000000002647] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Komiya K, Akaba T, Kozaki Y, Kadota JI, Rubin BK. A systematic review of diagnostic methods to differentiate acute lung injury/acute respiratory distress syndrome from cardiogenic pulmonary edema. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2017; 21:228. [PMID: 28841896 PMCID: PMC6389074 DOI: 10.1186/s13054-017-1809-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 08/03/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Discriminating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema (CPE) is often challenging. This systematic review examines studies using biomarkers or images to distinguish ALI/ARDS from CPE. METHODS Three investigators independently identified studies designed to distinguish ALI/ARDS from CPE in adults. Studies were identified from PubMed, and the Cochrane Central Register of Controlled Trials database until July 3, 2017. RESULTS Of 475 titles and abstracts screened, 38 full texts were selected for review, and we finally included 24 studies in this systematic review: 21 prospective observational studies, two retrospective observational studies, and one retrospective combined with prospective study. These studies compared various biomarkers to differentiate subjects with ALI/ARDS and in those with CPE, and 13 calculated the area under the receiver operator characteristic curve (AUC). The most commonly studied biomarker (four studies) was brain natriuretic peptide (BNP) and the discriminatory ability ranged from AUC 0.67-0.87 but the timing of measurement varied. Other potential biomarkers or tools have been reported, but only as single studies. CONCLUSIONS There were no identified biomarkers or tools with high-quality evidence for differentiating ALI/ARDS from CPE. Combining clinical criteria with validated biomarkers may improve the predictive accuracy.
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Affiliation(s)
- Kosaku Komiya
- Children's Hospital of Richmond at Virginia Commonwealth, Richmond, VA, 23298, USA. .,Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan. .,Clinical Research Center of Respiratory Medicine, Tenshindo Hetsugi Hospital, 5956 Nihongi, Nakahetsugi, Oita, 879-7761, Japan.
| | - Tomohiro Akaba
- Children's Hospital of Richmond at Virginia Commonwealth, Richmond, VA, 23298, USA
| | - Yuji Kozaki
- Children's Hospital of Richmond at Virginia Commonwealth, Richmond, VA, 23298, USA
| | - Jun-Ichi Kadota
- Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Bruce K Rubin
- Children's Hospital of Richmond at Virginia Commonwealth, Richmond, VA, 23298, USA
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Plasma Concentrations of Soluble Suppression of Tumorigenicity-2 and Interleukin-6 Are Predictive of Successful Liberation From Mechanical Ventilation in Patients With the Acute Respiratory Distress Syndrome. Crit Care Med 2017; 44:1735-43. [PMID: 27525994 DOI: 10.1097/ccm.0000000000001814] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVES Soluble suppression of tumorigenicity-2 and interleukin-6 concentrations have been associated with the inflammatory cascade of acute respiratory distress syndrome. We determined whether soluble suppression of tumorigenicity-2 and interleukin-6 levels can be used as prognostic biomarkers to guide weaning from mechanical ventilation and predict the need for reintubation. DESIGN, SETTING, AND PATIENTS We assayed plasma soluble suppression of tumorigenicity-2 (n = 826) concentrations and interleukin-6 (n = 755) concentrations in the Fluid and Catheter Treatment Trial, a multicenter randomized controlled trial of conservative fluid management in acute respiratory distress syndrome. We tested whether soluble suppression of tumorigenicity-2 and interleukin-6 levels were associated with duration of mechanical ventilation, the probability of passing a weaning assessment, and the need for reintubation. MEASUREMENTS AND MAIN RESULTS In models adjusted for Acute Physiology and Chronic Health Evaluation score and other relevant variables, patients with higher day 0 and day 3 median soluble suppression of tumorigenicity-2 and interleukin-6 concentrations had decreased probability of extubation over time (day 0 soluble suppression of tumorigenicity-2: hazard ratio, 0.85; 95% CI, 0.72-1.00; p = 0.05; day 0 interleukin-6: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; day 3 soluble suppression of tumorigenicity-2: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; and day 3 interleukin-6: hazard ratio, 0.73; 95% CI, 0.62-0.85; p = 0.0001). Higher biomarker concentrations were also predictive of decreased odds of passing day 3 weaning assessments (soluble suppression of tumorigenicity-2: odds ratio, 0.62: 95% CI, 0.44-0.87; p = 0.006 and interleukin-6: odds ratio, 0.61; 95% CI, 0.43-0.85; p = 0.004) and decreased odds of passing a spontaneous breathing trial (soluble suppression of tumorigenicity-2: odds ratio, 0.45; 95% CI, 0.28-0.71; p = 0.0007 and interleukin-6 univariate analysis only: odds ratio, 0.55; 95% CI, 0.36-0.83; p = 0.005). Finally, higher biomarker levels were significant predictors of the need for reintubation for soluble suppression of tumorigenicity-2 (odds ratio, 3.23; 95% CI, 1.04-10.07; p = 0.04) and for interleukin-6 (odds ratio, 2.58; 95% CI, 1.14-5.84; p = 0.02). CONCLUSIONS Higher soluble suppression of tumorigenicity-2 and interleukin-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with acute respiratory distress syndrome. Biomarker-directed ventilator management may lead to improved outcomes in weaning of mechanical ventilation in patients with acute respiratory distress syndrome.
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Griesenauer B, Paczesny S. The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases. Front Immunol 2017; 8:475. [PMID: 28484466 PMCID: PMC5402045 DOI: 10.3389/fimmu.2017.00475] [Citation(s) in RCA: 436] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 04/05/2017] [Indexed: 12/16/2022] Open
Abstract
Il1rl1 (also known as ST2) is a member of the IL-1 superfamily, and its only known ligand is IL-33. ST2 exists in two forms as splice variants: a soluble form (sST2), which acts as a decoy receptor, sequesters free IL-33, and does not signal, and a membrane-bound form (ST2), which activates the MyD88/NF-κB signaling pathway to enhance mast cell, Th2, regulatory T cell (Treg), and innate lymphoid cell type 2 functions. sST2 levels are increased in patients with active inflammatory bowel disease, acute cardiac and small bowel transplant allograft rejection, colon and gastric cancers, gut mucosal damage during viral infection, pulmonary disease, heart disease, and graft-versus-host disease. Recently, sST2 has been shown to be secreted by intestinal pro-inflammatory T cells during gut inflammation; on the contrary, protective ST2-expressing Tregs are decreased, implicating that ST2/IL-33 signaling may play an important role in intestinal disease. This review will focus on what is known on its signaling during various inflammatory disease states and highlight potential avenues to intervene in ST2/IL-33 signaling as treatment options.
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Affiliation(s)
- Brad Griesenauer
- Department of Pediatrics, Indiana University, Indianapolis, IN, USA
- Department of Microbiology Immunology, Indiana University, Indianapolis, IN, USA
- Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA
| | - Sophie Paczesny
- Department of Pediatrics, Indiana University, Indianapolis, IN, USA
- Department of Microbiology Immunology, Indiana University, Indianapolis, IN, USA
- Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA
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AbouEzzeddine OF, McKie PM, Dunlay SM, Stevens SR, Felker GM, Borlaug BA, Chen HH, Tracy RP, Braunwald E, Redfield MM. Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc 2017; 6:JAHA.116.004382. [PMID: 28214792 PMCID: PMC5523750 DOI: 10.1161/jaha.116.004382] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Soluble suppression of tumorigenicity 2 (sST2) receptor is a biomarker that is elevated in certain systemic inflammatory diseases. Comorbidity-driven microvascular inflammation is postulated to play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology, but data on how sST2 relates to clinical characteristics or inflammatory conditions or biomarkers in HFpEF are limited. We sought to determine circulating levels and clinical correlates of sST2 in HFpEF. METHODS AND RESULTS At enrollment, patients (n=174) from the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial of sildenafil in HFpEF had sST2 levels measured. Clinical characteristics; cardiac structure and function; exercise performance; and biomarkers of neurohumoral activation, systemic inflammation and fibrosis, and myocardial necrosis were assessed in relation to sST2 levels. Median sST2 levels in male and female HFpEF patients were 36.7 ng/mL (range 30.9-49.2 ng/mL; reference range 4-31 ng/mL) and 30.8 ng/mL (range 25.3-39.3 ng/mL; reference range 2-21 ng/mL), respectively. Among HFpEF patients, higher sST2 levels were associated with the presence of diabetes mellitus; atrial fibrillation; renal dysfunction; right ventricular pressure overload and dysfunction; systemic congestion; exercise intolerance; and biomarkers of systemic inflammation and fibrosis, neurohumoral activation, and myocardial necrosis (P<0.05 for all). sST2 was not associated with left ventricular structure or left ventricular systolic or diastolic function. CONCLUSIONS In HFpEF, sST2 levels were associated with proinflammatory comorbidities, right ventricular pressure overload and dysfunction, and systemic congestion but not with left ventricular geometry or function. These data suggest that ST2 may be a marker of systemic inflammation in HFpEF and potentially of extracardiac origin. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Eugene Braunwald
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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Lin SH, Fu J, Wang CJ, Gao F, Feng XY, Liu Q, Cao J, Xu F. Inflammation elevated IL-33 originating from the lung mediates inflammation in acute lung injury. Clin Immunol 2016; 173:S1521-6616(16)30535-6. [PMID: 27989898 DOI: 10.1016/j.clim.2016.10.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 07/23/2016] [Accepted: 10/24/2016] [Indexed: 01/09/2023]
Abstract
Excessive inflammatory reactions occur with acute respiratory distress syndrome (ARDS), however, the underlying mechanisms of ARDS remain incompletely understood. Here we investigated whether interleukin (IL)-33 was elevated in ARDS patients. Serum samples were obtained from 14 ARDS patients and 24 control healthy volunteers. ELISA was used to measure the concentrations of IL-33. Besides, we established pulmonary ARDS and extrapulmonary ARDS models in mice, and serum and lung tissue samples were collected for analyses. The results showed that serum IL-33 concentrations were significantly higher in pulmonary ARDS patients compared to controls. Also, the levels of IFN-γ and IL-2 were positively correlated with IL-33 levels. We also showed that there were increased IL-33 levels in both the serum and lungs in the pulmonary ARDS model. This was not the case, however, in the extrapulmonary ARDS model. Pulmonary inflammation and injury in the pulmonary ARDS model was reduced with IL-33 neutralizing antibody treatment.
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Affiliation(s)
- Shi-Hui Lin
- Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Juan Fu
- Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Chuan-Jiang Wang
- Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Feng Gao
- Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Xuan-Yun Feng
- Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Qiong Liu
- Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Ju Cao
- Department ofLaboratory Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Fang Xu
- Department of Emergency, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.
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Parikh RH, Seliger SL, Christenson R, Gottdiener JS, Psaty BM, deFilippi CR. Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community-Dwelling Population. J Am Heart Assoc 2016; 5:e003188. [PMID: 27481133 PMCID: PMC5015272 DOI: 10.1161/jaha.115.003188] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 07/08/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Soluble ST2 (sST2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST2 levels are associated with incident heart failure (HF), including subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fraction, and cardiovascular death. METHODS AND RESULTS Baseline serum sST2 was measured in 3915 older, community-dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac-specific biomarker, N-terminal pro-type B natriuretic peptide, these associations were attenuated. In these models, an sST2 level above the US Food and Drug Administration-approved cut-off value (>35 ng/mL) was significantly associated with incident HF (hazard ratio [HR], 1.20; 95% CI, 1.02-1.43) and cardiovascular death (HR, 1.21; 95% CI, 1.02-1.44), and greater sST2 was continuously associated with cardiovascular death (per 1-ln increment: HR, 1.24; 95% CI, 1.02-1.50). sST2 was not associated with the HF subtypes of HFpEF and HFrEF in adjusted analysis. Addition of sST2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk. CONCLUSIONS The predictive value of sST2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross-sectional associations with risk factors and underlying cardiac pathology.
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Affiliation(s)
- Ravi H Parikh
- Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Stephen L Seliger
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Robert Christenson
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD
| | - John S Gottdiener
- Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA
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Semler MW, Marney AM, Rice TW, Nian H, Yu C, Wheeler AP, Brown NJ. B-Type Natriuretic Peptide, Aldosterone, and Fluid Management in ARDS. Chest 2016; 150:102-11. [PMID: 27018313 DOI: 10.1016/j.chest.2016.03.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 03/02/2016] [Accepted: 03/07/2016] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival. METHODS This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality. RESULTS Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49 ng/dL (interquartile range, 1.1-4.3 ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vs liberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs 12.5 ± 10.3, P < .001) and decreased mortality (19% vs 30%, P = .03) (P value for interaction = .01). CONCLUSIONS In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.
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Affiliation(s)
- Matthew W Semler
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN.
| | | | - Todd W Rice
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Hui Nian
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Chang Yu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Arthur P Wheeler
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Nancy J Brown
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
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Rudolf JW, Lewandrowski EL, Lewandrowski KB, Januzzi JL, Bajwa EK, Baron JM. ST2 Predicts Mortality and Length of Stay in a Critically Ill Noncardiac Intensive Care Unit Population. Am J Clin Pathol 2016; 145:203-10. [PMID: 26857195 DOI: 10.1093/ajcp/aqv082] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVES The biomarker suppression of tumorigenicity 2 (ST2) is a well-established clinical biomarker of cardiac strain and is frequently elevated in a variety of cardiac conditions. Here, we sought to evaluate the prognostic value of ST2 in critically ill medical intensive care unit (MICU) patients without primary cardiac illness. METHODS We measured ST2 and high-sensitivity troponin T (hsTnT) on plasma specimens collected on 441 patients following admission to a noncardiac MICU and evaluated the prognostic power of ST2 both alone and in multivariate models. RESULTS Of these critically ill patients, 96% exhibited ST2 concentrations above the reference interval. ST2 concentrations were highly predictive of intensive care unit and hospital length of stay, as well as in-hospital mortality, with high concentrations predicting a poor prognosis. Rates of in-hospital mortality were more than four times higher in patients with ST2 concentrations in the highest compared with the lowest quartile. In multivariate analysis, ST2 remained an important predictor of death after adjustment for age, hsTnT, and common diagnoses. CONCLUSIONS ST2 is increased and predictive of prognosis in critically ill patients without primary cardiac disease, suggesting that critically ill patients may often have unrecognized cardiac injury. Clinical decision support algorithms incorporating ST2 and hsTnT results may be useful in patient risk stratification.
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Affiliation(s)
- Joseph W Rudolf
- From the Department of Pathology and Divisions of Harvard Medical School, Boston, MA
| | | | - Kent B Lewandrowski
- From the Department of Pathology and Divisions of Harvard Medical School, Boston, MA
| | | | - Ednan K Bajwa
- Harvard Medical School, Boston, MA. Pulmonary/Critical Care, Massachusetts General Hospital
| | - Jason M Baron
- From the Department of Pathology and Divisions of Harvard Medical School, Boston, MA.
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Cardio-Pulmonary-Renal Interactions: A Multidisciplinary Approach. J Am Coll Cardiol 2015; 65:2433-48. [PMID: 26046738 DOI: 10.1016/j.jacc.2015.04.024] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 04/18/2015] [Accepted: 04/20/2015] [Indexed: 12/16/2022]
Abstract
Over the past decade, science has greatly advanced our understanding of interdependent feedback mechanisms involving the heart, lung, and kidney. Organ injury is the consequence of maladaptive neurohormonal activation, oxidative stress, abnormal immune cell signaling, and a host of other mechanisms that precipitate adverse functional and structural changes. The presentation of interorgan crosstalk may include an acute, chronic, or acute on chronic timeframe. We review the current, state-of-the-art understanding of cardio-pulmonary-renal interactions and their related pathophysiology, perpetuating nature, and cycles of increased susceptibility and reciprocal progression. To this end, we present a multidisciplinary approach to frame the diverse spectrum of published observations on the topic. Assessment of organ functional reserve and use of biomarkers are valuable clinical strategies to screen and detect disease, assist in diagnosis, assess prognosis, and predict recovery or progression to chronic disease.
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Abstract
Biomarkers have emerged as indispensable tools for diagnosis and prognostication in a variety of cardiovascular diseases, and several are now standard of care. New markers are constantly being developed, but few are able to significantly improve upon already established markers. ST2 is a marker of cardiomyocyte stress and fibrosis, which provides incremental value to natriuretic peptides for risk stratification of patients across a wide spectrum of cardiovascular diseases. Based upon the totality of data, measurement of ST2 is now recommended for additive risk stratification in patients with acute or ambulatory heart failure in the 2013 American College of Cardiology Foundation and American Heart Association joint guidelines. Looking forward, ST2 levels may be useful for tailoring medical therapy in those with or at risk for developing heart failure. This paper provides an up-to-date overview of the clinical studies that led to the endorsement of ST2 as a cardiovascular prognostic marker, and provides insight into the application of ST2 now and in the future.
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Affiliation(s)
- Lori B Daniels
- Division of Cardiology, Department of Medicine, University of California at San Diego, La Jolla, CA 92037-7411, USA
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Mallick A, Januzzi JL. ST2 in Heart Failure: Where Does This New Marker Fit in? CURRENT EMERGENCY AND HOSPITAL MEDICINE REPORTS 2015. [DOI: 10.1007/s40138-015-0069-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
In recent years, numerous studies have focused on the use of soluble ST2 (sST2) as a clinical biomarker for cardiovascular disease. However, much preclinical data points to involvement of the ST2 pathway in inflammation, and specifically in pulmonary inflammation. This report summarizes the current body of clinical data suggesting the potential role of the ST2 pathway in clinical disease, including evidence that sST2 could be a useful biomarker in both allergic and nonallergic pulmonary disease.
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Affiliation(s)
- Ednan K Bajwa
- Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
| | - Alexandre Mebazaa
- Department of Anesthesiology and Critical Care Medicine, University of Paris Diderot, Paris, France
| | - James L Januzzi
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
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Abstract
Suppression of tumorigenicity 2 (ST2, also known as interleukin [IL]-1 receptor-like-1) is an IL-1 receptor family member with transmembrane (ST2L) and soluble isoforms (sST2). ST2L is a membrane-bound receptor, and IL-33 is the functional ligand for ST2L. sST2, a soluble truncated form of ST2L, is secreted into the circulation and functions as a "decoy" receptor for IL-33, inhibiting IL-33/ST2L signaling. Blood concentrations of sST2 are increased in inflammatory diseases and heart disease and are considered a valuable prognostic marker in both conditions. In multiple clinical trials, sST2 has emerged as a clinically useful prognostic biomarker in patients with cardiac diseases. Interestingly, sST2 even provides prognostic information in low-risk community-based populations. In this review, we will discuss analytical considerations of measuring circulating sST2 including pre-analytical issues, such as in vitro stability of sST2, biological variation of sST2, and postanalytical issues, such as reference ranges and comparisons to diseased cohorts.
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Dieplinger B, Mueller T. Soluble ST2 in heart failure. Clin Chim Acta 2014; 443:57-70. [PMID: 25269091 DOI: 10.1016/j.cca.2014.09.021] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 08/27/2014] [Accepted: 09/16/2014] [Indexed: 12/12/2022]
Abstract
In addition to routine clinical laboratory tests (including natriuretic peptides and cardiac troponins), other biomarkers are gaining attention for their utility in heart failure (HF) management. Among them, soluble ST2 (sST2) a novel biomarker integrating inflammation, fibrosis, and cardiac stress has been included in the 2013 ACCF/AHA guideline for additive risk stratification of patients with acute and chronic HF. sST2 is an interleukin-1 (IL-1) receptor family member, is secreted into the circulation and functions as a "decoy" receptor for IL-33, inhibiting IL-33/ST2 signaling. Blood concentrations of sST2 are increased in various diseases such as inflammatory diseases and heart diseases and are considered a valuable prognostic marker in both conditions. sST2 lacks disease specificity and, therefore, is not a valuable marker for the diagnosis of HF. In acute and chronic HF, however, sST2 is strongly associated with measures of HF severity and poor outcome. Several studies in patients with HF indicate that serial measurement of sST2 has prognostic value and could have a potential role in future biomarker-directed therapy. In this review, the role of sST2 as a HF biomarker will be discussed, specifically addressing analytical considerations of measuring sST2 as well as the clinical applications of measurement of sST2 for the diagnosis, prognosis and monitoring of acute and chronic HF.
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Affiliation(s)
- Benjamin Dieplinger
- Department of Laboratory Medicine, Konventhospital Barmherzige Brueder, Linz, Austria.
| | - Thomas Mueller
- Department of Laboratory Medicine, Konventhospital Barmherzige Brueder, Linz, Austria
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Legrand M, Januzzi JL, Mebazaa A. Critical research on biomarkers: what's new? Intensive Care Med 2013; 39:1824-8. [PMID: 23828026 DOI: 10.1007/s00134-013-3008-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Accepted: 06/20/2013] [Indexed: 01/28/2023]
Affiliation(s)
- Matthieu Legrand
- Department of Anesthesiology and Critical Care and SMUR, and Burn Center, AP-HP, Hôpitaux Universitaires Saint-Louis-Lariboisiere, St-Louis Hospital, 75010, Paris, France,
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