Abstract
Similar to other causes of acute respiratory distress syndrome, coronavirus disease 2019 (COVID‐19) is characterized by the aberrant expression of vascular injury biomarkers. We present the first report that circulating plasma bone morphogenetic proteins (BMPs), BMP9 and pBMP10, involved in vascular protection, are reduced in hospitalized patients with COVID‐19.
Keywords: BMPs, endothelial cell dysfunction, viral infections and pathogenesis
INTRODUCTION
The rapid spread of a severe acute respiratory syndrome coronavirus (SARS‐CoV‐2), first identified in 2019, led to a major worldwide public health crisis. For many individuals, coronavirus disease 2019 (COVID‐19) led to no or mild symptoms. However, for some patients, severe COVID‐19 resulted in respiratory failure, admission to intensive care, the requirement for mechanical ventilation, and death. According to the World Health Organization (WHO), infection with SARS‐CoV‐2 was observed in over 600 million individuals worldwide and accounted for more than 6 million deaths by October 2022.
Originally, SARS‐CoV‐2 was reported to directly infect pulmonary endothelial cells (ECs) via the angiotensin‐converting enzyme 2 receptors with sustained infection resulting in the destruction of ECs and vascular leak, causing tissue edema and thromboinflammation. 1 Patients with severe COVID‐19 often present with refractory hypoxemia arising from EC damage and pulmonary vasculature dysfunction. Severe cases have been associated with the upregulation of prothrombotic/inflammatory proteins. Two members of the transforming growth factor‐β family, bone morphogenetic protein 9 (BMP9) and BMP10, are recognized as vascular quiescence factors that guard against endothelial dysfunction. We have previously established that BMP9 protects against excess endothelial permeability associated with pulmonary arterial hypertension. 2 Furthermore, BMP9 administration protected mice from lung injury and vascular permeability in a murine experimental model of acute lung injury (ALI). In addition, plasma BMP9 concentrations were shown to be markedly reduced in both patients with sepsis and endotoxemic mice. 3 Given that COVID‐19 is a cause of acute respiratory distress syndrome (ARDS), we investigated circulating concentrations of BMP9 and prodomain‐BMP10 (pBMP10) in a cohort of patients with COVID‐19.
METHODS
Following informed consent, plasma was obtained from hospital inpatients at Cambridge University Hospitals NHS Trust, Cambridge, UK with a confirmed diagnosis of COVID‐19 via a nucleic acid amplification test, between October 2, 2020 and February 19, 2021. Healthy controls (n = 29) were recruited through the University of Cambridge COVID‐19 asymptomatic screening program. Recruitment of inpatients at Cambridge University Hospital NHS Foundation Trust and controls was undertaken by the NIHR Cambridge Clinical Research Facility Outreach Team and the NIHR BioResource research nurse team. Ethical approval was provided by the East of England—Cambridge Central Research Ethics Committee (REC ref. no.: 17/EE/0025 for the NIHR BioResource Research Tissue Bank). Structured electronic health record data were extracted from the EpiCov Database specifically created to support COVID‐19 relevant monitoring and research. The EpiCov database is regulated under NHS Research Ethics Committee (REC) permission (ref. no.: 20/EE/0270). Patients with COVID‐19 were recruited at or soon after admission to the hospital and were divided into two categories of clinical severity based upon the WHO clinical progression scale 4 : 4, 5, 6 = hospitalized with moderate/severe disease and oxygen therapy via mask, nasal prongs or noninvasive ventilation (n = 49); and 7, 8, 9 = hospitalized with severe disease requiring assisted ventilation (n = 22) (Table 1). Healthy controls were designated 0.
Table 1.
Clinical features of study participants.
| WHO clinical progression scale group | |||
|---|---|---|---|
| 0 | 4, 5, 6 | 7, 8, 9 | |
| Participants | 29 | 49 | 22 |
| Age (years), median (SD) | 29.0 (12.7) | 60.0 (11.6) | 65.5 (8.5) |
| Sex (% male) | 100 | 100 | 100 |
| Length of time in hospital (days), median (SD) | NA | 10.3 (14.0) | 33.4 (24.9) |
| Deceased in hospital (%) | NA | 8.2 | 45.5 |
| Days from hospital admission to sample receipt (days), median (SD) | NA | 4.1 (11.8) | 13.3 (7.7) |
| Alanine transaminase (U/L), median (SD) | NA | 64.0 (106.1) | 60.0 (161.7) |
| Albumin (g/L), median (SD) | NA | 25.0 (4.6) | 21.0 (4.4) |
| Bilirubin (µmol/L), median (SD) | NA | 9.0 (6.2) | 7.5 (100.0) |
| Creatinine (µmol/L), median (SD) | NA | 69.0 (51.9) | 75.0 (48.4) |
| Sodium (mmol/L), median (SD) | NA | 136.0 (3.8) | 142.5 (5.9) |
| Urea (mmol/L), median (SD) | NA | 7.3 (4.5) | 13.6 (7.6) |
| MELD score | NA | 8.7 (3.7) | 9.0 (5.6) |
| Comorbidities | |||
| Cardiovascular disease | 0 | 22 | 13 |
| Hypertension | 0 | 14 | 7 |
| Endocrine disease | 0 | 19 | 11 |
| Diabetes | 0 | 13 | 5 |
| Respiratory disease | 2 | 17 | 7 |
| Renal disease | 0 | 6 | 7 |
| Immunosuppression | 0 | 5 | 6 |
| Hepatic disease | 1 | 1 | 3 |
| Hematological disease | 2 | 9 | 2 |
| Rheumatological disease | 0 | 9 | 2 |
| Central nervous system disease | 0 | 8 | 1 |
| Gastrointestinal disease | 1 | 4 | 1 |
| Oncological disease | 0 | 8 | 0 |
| COVID therapies | |||
| Baricitinib | NA | 6 | 0 |
| Dapagliflozin | NA | 3 | 1 |
| Dexamethasone | NA | 49 | 21 |
| Hydrocortisone | NA | 9 | 10 |
| Remdesivir | NA | 16 | 6 |
| Tocilizumab | NA | 1 | 4 |
| Days on dexamethasone before sample receipt (days), median (SD) | NA | 14.0 (7.1) | 10.0 (6.4) |
Abbreviations: COVID, coronavirus disease; MELD, Model for End‐Stage Liver Disease; NA, not applicable; WHO, World Health Organization.
Blood samples were drawn into EDTA blood tubes (BD Biosciences) upon study enrollment and plasma samples were processed on the same day as receipt. Acellular banked plasma aliquots were stored at −80°C. A stock aliquot per participant was then defrosted and subaliquoted for this study, meaning the plasma provided had one freeze–thaw cycle. Enzyme‐linked immunosorbent assays (ELISAs) for BMP9 and pBMP10 were conducted as previously described. 5 , 6 The soluble endoglin Quantikine assay (R&D Systems) was performed according to the manufacturer's instructions. A range of angiogenesis and vascular injury biomarkers were measured using three MesoScale Discovery multiplex immunoassay panels following the manufacturer's protocol: V‐PLEX Angiogenesis Panel 1 kit (fibroblast growth factor [FGF] (basic), placental growth factor [PlGF], Tie‐2, vascular endothelial growth factor‐A [VEGF‐A], VEGF‐C, VEGF‐D, and VEGFR‐1/Flt‐1); Human Vascular Injury I kit (E‐selectin, intercellular adhesion molecule‐3 [ICAM‐3], P‐selectin, and thrombomodulin) and V‐PLEX Vascular Injury Panel 2 Human kit (C‐reactive protein [CRP], ICAM‐1, serum amyloid A [SAA], and vascular cell adhesion molecule‐1 [VCAM‐1]).
RESULTS
We confirmed many of the vascular injury and proangiogenesis markers previously reported to be associated with disease severity and mortality in COVID‐19. First, SAA and CRP were significantly elevated in all patients with COVID‐19 (Figure 1a and b, respectively).
Figure 1.
Circulating vascular injury and angiogenesis biomarkers after coronavirus disease 2019 (COVID‐19) infection. Plasma samples from healthy controls (0; n = 29), patients whose maximal respiratory support was supplemental oxygen (4, 5, 6; n = 49), and patients who required assisted ventilation (7, 8, 9; n = 22) were assessed for the following analytes using MesoScale Discovery multiplex immunoassays. (a) Serum amyloid A (SAA); (b) C‐reactive protein (CRP); (c) intercellular adhesion molecule 1 (ICAM‐1); (d) vascular cell adhesion molecule 1 (VCAM‐1); (e) E‐selectin; (f) thrombomodulin; (g) vascular endothelial growth factor A (VEGF‐A); (h) VEGFR1/Flt‐1; (i) placental growth factor (PlGF); (j) fibroblast growth factor (basic) (FGF(b)); (k) Tie‐2; (l) soluble endoglin (sENG) enzyme‐linked immunosorbent assay (ELISA); (m) bone morphogenetic protein 9 (BMP9) ELISA; (n) prodomain BMP10 (pBMP10) ELISA; (o) Pearson's correlation of circulating BMP9 and pBMP10 levels. p = 0.7415; (p) number of days patients were administered dexamethasone treatment before sample receipt; (q) Pearson's correlation of circulating BMP9 levels and dexamethasone treatment length. p = 0.3052; (r) circulating BMP9 levels of patient groups separated upon the time taken to be enrolled into the study. Sample receipt ≤7 days versus >7 days. All data presented as median–interquartile range. Kruskal–Wallis test. Dunn's multiple comparison test. ns, not significant; WHO, World Health Organization. p Values = *0.05; **0.01; ***0.001; ****0.0001.
Consistent with previous COVID‐19 biomarker studies, plasma concentrations of the proinflammatory adhesion molecules ICAM‐1, VCAM‐1, and E‐selectin were significantly elevated, and associated with disease severity. 7 Both ICAM‐1 and VCAM‐1 concentrations were elevated in nonventilated (4, 5, 6) and ventilated (7, 8, 9) patients (Figure 1c and d, respectively). Additionally, ICAM‐1 was significantly increased in ventilated patients compared to nonventilated (Figure 1c). Similarly, elevated concentrations of E‐selectin were only seen in severe (7, 8, 9) patients (Figure 1e). Elevated plasma thrombomodulin concentration correlated with decreased rates of hospital discharge and survival after COVID‐19 infection, 8 and was significantly increased in severe (7, 8, 9) disease (Figure 1f).
We also assessed the circulating concentrations of proangiogenesis markers that have been reported as predictive of COVID‐19 disease and severity. 9 , 10 VEGF pathway activation is associated with ARDS. Both nonventilated (4, 5, 6) and ventilated patients (7, 8, 9) had elevated plasma concentrations of VEGF‐A (Figure 1g). Increased VEGFR‐1/Flt‐1 has previously been reported to correlate with disease severity, but in this cohort both nonventilated (4, 5, 6) and ventilated (7, 8, 9) patients had significantly increased concentrations of the VEGF receptor, VEGFR‐1/Flt‐1 (Figure 1h). 11 PlGF release was increased in both nonventilated (4, 5, 6) and ventilated (7, 8, 9) patients (Figure 1i), and FGF (basic) was significantly increased in ventilated patients (Figure 1j). The plasma concentration of the vessel maturity receptor, Tie‐2 (Tek), 12 was markedly decreased in ventilated patients compared to healthy controls and nonventilated patients (Figure 1k). Interestingly, pro‐BMP9 treatment in a murine model of ALI increased the transcriptional expression of Tek. 3 Soluble endoglin (sEng) is associated with inflammation/endothelial dysfunction, 13 and increased sEng levels have been reported in people who do not survive COVID‐19 infection. 14 Surprisingly, sEng concentrations in this cohort were decreased in both nonventilated (4, 5, 6) and ventilated (7, 8, 9) subjects (Figure 1l). A reported increase of sEng was observed in nonsurvivors of COVID‐19. 14 In fact, sEng concentrations in survivors increased 14 days after study inclusion but were actually lower in patients than healthy controls at Day 0. 14 Our plasma samples were collected as close to hospital admission as possible, and possibly closer to the initial infection. Therefore, secretion of sEng may increase over the duration of COVID‐19, and may be associated with sustained endothelial dysfunction in patients with persistent illness.
The data from our cohort expands the previous evidence that biomarkers associated with vascular injury and EC dysfunction are increased in COVID‐19. Given the clear association between COVID‐19 severity and inflammation/endothelial dysfunction, we hypothesized that endothelial‐selective BMP ligands may be novel biomarkers for endothelial injury in COVID‐19. BMP9 plasma concentrations were significantly decreased in only nonventilated (4, 5, 6) patients compared to ventilated (7, 8, 9) patients and healthy controls (Figure 1m). Similarly, circulating pBMP10 concentrations were reduced in nonventilated patients (Figure 1n). As previously reported, there was a strong correlation between plasma BMP9 and pBMP10 concentrations (Figure 1o). 6
This is the first report that circulating concentrations of BMP9 and pBMP10 are decreased during COVID‐19. This is perhaps unsurprising given the association of inflammation and vascular dysfunction with BMP9 and pBMP10. In fact, BMP9 and pBMP10 have been shown to inhibit chemokine (C–C motif) ligand 2 secretion by vascular ECs, while endogenous circulating BMP9 is elevated in inflammation. 3 , 15 Induced endotoxemia by lipopolysaccharide (LPS) treatment revealed that liver BMP9 expression was reduced by 3–6 h, returning to normal levels by 18–24 h. 3 Plasma BMP9 levels gradually declined 24 h post‐LPS administration, but whether plasma BMP9 remained reduced was not investigated. 3 Therefore, it is plausible that circulating levels of BMP9 and pBMP10 are reduced by systemic inflammation. However, in this study, BMP9 and pBMP10 did not correlate with CRP and SAA, markers of systemic inflammation. Although not addressed here, the release of neutrophil elastase (NE) could be assessed and correlated with BMP9 plasma levels to further investigate the role of inflammation. It is known that neutrophils isolated from COVID‐19 patients have increased NE release, and BMP9 is a substrate of NE. 3 , 16 However, it is still unclear whether the downregulation of BMP9 and pBMP10 is due to SARS‐CoV‐2 infection or associated inflammatory factors.
Interestingly, plasma concentrations did not correlate with disease severity as individuals who required mechanical ventilation had similar plasma concentrations to control subjects. The principal limitations of our study are the small number of patients recruited into the ventilated (7, 8, 9) cohort and the lack of longitudinal follow‐up. Upon examination of the COVID‐19 medications prescribed, we discovered that all ventilated patients were administered dexamethasone for significantly longer before study enrollment than those individuals requiring noninvasive oxygen therapy (Figure 1p). Successful treatment of COVID‐19 with dexamethasone was originally highlighted by the Recovery Trial in the United Kingdom, 17 and we observed elevated BMP9 concentrations mildly correlated with the duration of dexamethasone treatment (Figure 1q).
Furthermore, due to the nature of patient recruitment, we also observed that several individuals in both the nonventilated and ventilated groups were not enrolled in the study until 7 days after hospital admission. Interestingly, plasma BMP9 (and pBMP10; data not shown) concentrations were decreased in patients recruited within 7 days of hospital admission, when compared to those recruited after 7 days (Figure 1r). We therefore cannot rule out that the administration of COVID‐19 therapies (Table 1) might lead to the normalization of BMP9 (or pBMP10) concentrations. We hypothesize that plasma BMP9 and pBMP10 concentrations may be novel biomarkers of endothelial injury observed in hospitalized patients with COVID‐19. However, longitudinal analysis would be required to determine whether these could predict disease severity and clinical outcome.
AUTHOR CONTRIBUTIONS
Benjamin J. Dunmore designed, performed, and analyzed the experiments, and wrote the manuscript; Paul D. Upton performed the ELISAs and contributed to writing the manuscript; Kate Auckland analyzed clinical data; R. J. Samant analyzed clinical data; CITIID‐NIHR BioResource COVID‐19 Collaboration enrolled patients, collected/processed samples, and analyzed clinical data. The EpiCov database collated electronic health record data. Paul A. Lyons devised and supervised the collection and processing of COVID‐19 samples. Kenneth G. C. Smith devised and supervised the collection and processing of COVID‐19 samples. Stefan Gräf devised and supervised the collation of electronic health records and supervised the analysis of clinical data. Charlotte Summers supervised the analysis of clinical data and wrote the manuscript. Nicholas W. Morrell devised the study and wrote the manuscript.
CITIID‐NIHR BioResource COVID‐19 Collaboration
Stephen Baker2,6, John Bradley1,3,6,10,14, Patrick Chinnery3,22,23, Daniel Cooper10, 24, Gordon Dougan2,6, Ian Goodfellow7, Ravindra Gupta2,6,12,15, Nathalie Kingston3,4, Paul J. Lehner2,6,12, Paul A. Lyons2,6, Nicholas J. Matheson2,6,12,26, Caroline Saunders9, Kenneth G. C. Smith2,6, Charlotte Summers6,11,25, James Thaventhiran18, M. Estee Torok 6,12,13, Mark R. Toshner6,8,25, Michael P. Weekes2,6,12,27, Gisele Alvio9, Sharon Baker9, Areti Bermperi9, Karen Brookes9, Ashlea Bucke, Jo Calder, Laura Canna, Cherry Crucusio, Isabel Cruz9, Ranalie de Jesus9, Katie Dempsey9, Giovanni Di Stephano9, Jason Domingo9, Anne Elmer9, Julie Harris, Sarah Hewitt, Heather Jones9, Sherly Jose9, Jane Kennet, Yvonne King,, Jenny Kourampa9, Emily Li, Caroline McMahon9, Anne Meadows, Vivien Mendoza9, Criona O'Brien, Charmain Ocaya9, Ciro Pasquale9, Marlyn Perales9, Jane Price, Rebecca Rastall, Carla Ribeiro9, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Phoebe Vargas9, Bensi Vergese9, Laura Watson9, Jieniean Worsley9, Julie‐Ann Zerrudo9, Laura Bergamashi2,6, Ariana Betancourt, Georgie Bower, Ben Bullman, Chiara Cossetti, Aloka De Sa, Benjamin J. Dunmore6,29, Maddie Epping, Stuart Fawke, Stefan Gräf 3,6,29, Richard Grenfell, Andrew Hinch, Josh Hodgson, Christopher Huang, Oisin Huhn, Kelvin Hunter2,6, Isobel Jarvis, Emma Jones, Maša Josipović, Ekaterina Legchenko, Daniel Lewis, Joe Marsden, Jennifer Martin, Federica Mescia2,6, Ciara O'Donnell, Ommar Omarjee, Marianne Perera, Linda Pointon, Nicole Pond, Nathan Richoz, Nika Romashova, Natalia Savinykh, Rahul Sharma, Joy Shih, Mateusz Strezlecki, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Lori Turner, Jennifer Wood, Marta Wylot, John Allison3,4, Heather Biggs3,17, John R. Bradley1,3,6,10,14, Helen Butcher3,5, Daniela Caputo3,5, Matt Chandler3,5, Patrick Chinnery3,22,23, Debbie Clapham‐Riley3,5, Eleanor Dewhurst3,5, Christian Fernandez3, Anita Furlong3,5, Barbara Graves3,5, Jennifer Gray3,5, Sabine Hein3,5, Tasmin Ivers3,5, Emma Le Gresley3,5, Rachel Linger3,5, Mary Kasanicki3,10, Rebecca King3,5, Nathalie Kingston3,4, Sarah Meloy3,5, Alexei Moulton3,5, Francesca Muldoon3,5, Nigel Ovington3,4, Sofia Papadia3,5, Christopher J. Penkett3,4, Isabel Phelan3,5, Venkatesh Ranganath3,4, Roxana Paraschiv3,4, Abigail Sage3,5, Jennifer Sambrook3,4, Ingrid Scholtes3,5, Katherine Schon3,16,17, Hannah Stark3,5, Kathleen E. Stirrups3,4, Paul Townsend3,4, Neil Walker3,4, Jennifer Webster3,5, Mayurun Selvan28, Petra, Polgarova11, Sarah L. Caddy2,6, Laura G. Caller19,20, Yasmin Chaudhry7, Martin D. Curran21, Theresa Feltwell6, Stewart Fuller19, Iliana Georgana7, Grant Hall7, William L. Hamilton6,12,13, Myra Hosmillo7, Charlotte J. Houldcroft6, Rhys Izuagbe7, Aminu S. Jahun7, Fahad A. Khokhar2,6, Anna G. Kovalenko7, Luke W. Meredith7, Surendra Parmar21, Malte L. Pinckert7, Anna Yakovleva7, Emily C. Horner18, Lucy Booth18, Alexander Ferreira18, Rebecca Boston18, Robert Hughes18, Juan Carlos Yam Puc18, Nonantzin Beristain‐Covarrubias18, Maria Rust18, Thevinya Gurugama18, Lihinya Gurugama18, Thomas Mulroney18, Sarah Spencer18, Zhaleh Hosseini18, Kate Williamson18, Neda Farahi6,29
1NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK
2Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
3NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
4Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
5Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
6Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
7Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK
8Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
9Cambridge Clinical Research Centre, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
10Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
11Intensive Care Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
12Department of Infectious Diseases, Addenbrooke's Hospital, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK
13Department of Microbiology, Addenbrooke's Hospital, Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK
14Department of Renal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
15Africa Health Research Institute, Durban, South Africa
16Clinical Genetics, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
17Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
18MRC Toxicology Unit, Gleeson Building, Tennis Court Road, Cambridge, UK
19University of Cambridge, Cambridge, UK
20The Francis Crick Institute, London, UK
21Public Health England, Clinical Microbiology and Public Health Laboratory, Cambridge, UK
22Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
23Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK
24Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
25Heart and Lung Research Institute, Cambridge Biomedical Campus, Cambridge, UK
26NHS Blood and Transplant, Cambridge, UK
27Cambridge Institute for Medical Research, Biomedical Campus, Hills Rd, Cambridge UK
28Department of Respiratory Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
29Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK
EpiCov Database Collaboration
Vince Taylor1, Helen Street1, Adam Loveday1, Habeebat Ibraheem1, Jacob Letowski1, Peter Driscoll1, Afzal Chaudhry1, Mark Sharpley2, Guilherme Balzana2, Wojciech J. Turek2, Stuart J. Rankin2, Paul Calleja2, Nicholas S. Gleadall1,3,4, Connor Rochford1,3,4, John R. Bradley1,3,4, Willem H. Ouwehand1,3,4, Stefan Gräf1,3,4
1Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
2Research Computing Service, University of Cambridge, Cambridge, UK
3NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK
4University of Cambridge, Cambridge, UK
CONFLICTS OF INTEREST STATEMENT
Paul D. Upton is a founder of, and scientific advisor to, Morphogen‐IX Ltd. Nicholas W. Morrell is a founder and CEO of Morphogen‐IX Ltd. Paul D. Upton and Nicholas W. Morrell have published US (US10336800) and EU (EP3166628B1) patents entitled: “Therapeutic Use of Bone Morphogenetic Proteins.” The remaining authors declare no conflicts of interest.
ETHICS STATEMENT
The ethics for this study were approved by the Cambridge Central Research Ethics Committee and the NHS Research Ethics Committee. All patients provided informed written consent.
ACKNOWLEDGMENTS
We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource Centres, NHS Trusts, and staff for their contribution. In particular, we thank Kathy Stirrups for sample collection and curation. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Program. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The work was funded by awards from NIHR to the NIHR BioResource (RG94028 and RG85445). Furthermore, we thank Keith Burling and Peter Barker at the NIHR Cambridge BRC Core Biochemical Assay Laboratory (CBAL), Cambridge University Hospitals NHS Foundation Trust for the metabolite analysis. We also thank Laura Bergamaschi and Federica Mescia for their help in collecting samples and clinical analysis. The results reported in this publication are in part or entirely based on the analysis of electronic health record (EHR) data collated in the EpiCov database. The EpiCov database has been established by Cambridge University Hospitals in partnership with the Research Computing Services (RCS) at the University of Cambridge and other stakeholders to support COVID‐19 relevant strategic monitoring and research analysis of EHR data with the aim to improve the care of individuals infected with SARS‐CoV‐2 at Cambridge University Hospitals and in other health and social care settings in the United Kingdom and beyond. Members of the clinical informatics team at CUH have been instrumental in preparing and pseudonymization of EHR data before transfer to the EpiCov database. Benjamin J. Dunmore and Paul D. Upton are funded by a British Heart Foundation Program Grant (RG/19/3/34265 to P. D. U. and N. W. M.). Charlotte Summers is funded by the National Institute for Health and Care Research (NIHR133788) and the Medical Research Council (MR/S035753/1, MR/X005070/1, and MR/P502091/1). This study was supported by Biomedical Research Centre funding (BRC‐1215‐20014*, April 2017–2022).
Dunmore BJ, Upton PD, Auckland K, Samanta RJ, CITIID‐NIHR BioResource COVID‐19 Collaboration, The EpiCov Database, Lyons PA, Smith KGC, Gräf S, Summers C, Morrell NW. Reduced circulating BMP9 and pBMP10 in hospitalized COVID‐19 patients. Pulm Circ. 2023;13:e12192. 10.1002/pul2.12192
Benjamin J. Dunmore and Paul D. Upton contributed equally to this study.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.