Top

Open Access 03-05-2024 | COVID-19 | IM - ORIGINAL

Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients

Authors: Alessio Molfino, Emanuela Anastasi, Eleonora Assanto, Ludovica Toccini, Giovanni Imbimbo, Antonietta Gigante, Valentina Viggiani, Antonella Farina, Orietta Picconi, Antonio Angeloni, Maurizio Muscaritoli

Published in: Internal and Emergency Medicine

Abstract

To quantify the circulating levels of novel serum biomarkers including GDF-15, PIVKA-II, sdLDL, suPAR, and of CRP in hospitalized COVID-19 patients compared with healthy subjects, and to evaluate their association(s) with outcomes in COVID-19. We considered patients with confirmed COVID-19, hospitalized in an Internal Medicine ward. The clinical characteristics were collected, including the number and type of comorbidities. Serum levels of GDF-15, PIVKA-II, suPAR, sdLDL, as well as CRP were measured. As outcomes, we considered Intensive Care Unit (ICU) transfer or death, as well as the length of stay (days) and in-hospital complications. Data were statistically analyzed, as appropriate, and a p value < 0.05 was considered significant. Ninety-three patients and 20 healthy controls were enrolled. COVID-19 patients vs. controls showed higher median levels of GDF-15 (p < 0.0001), PIVKA-II (p < 0.0001) and sdLDL (p = 0.0002), whereas no difference was observed for suPAR. In COVID-19 patients, the most frequent comorbidities were arterial hypertension (62.4%) and cardiovascular disease (30.1%). GDF-15 levels positively correlated with age (r = 0.433, p < 0.0001), and this correlation was confirmed for suPAR (r = 0.308, p = 0.003) and CRP (Rho = 0.40 p < 0.0001), but not for PIVKA-II and sdLDL. Higher GDF-15 levels were associated with a higher number of comorbidities (p = 0.021). The median length of stay was 22 (15; 30) days. During hospitalization, 15 patients (16%) were ICU transferred, and 6 (6.45%) died. GDF-15 serum levels correlated with the length of stay (rho = 0.27 p = 0.010), and were associated with ICU transfer or death (p = 0.003), as well as PIVKA-II (p = 0.038) and CRP (p < 0.001). Moreover, higher GDF-15 and PIVKA-II serum levels were associated with infectious complications (p = 0.008 and p = 0.017, respectively). In this cohort of hospitalized COVID-19 patients, novel inflammatory biomarkers, including GDF-15, suPAR and PIVKA II were associated with some patient’s clinical characteristics, complications, and poor outcomes.

World Health Organization. Weekly operational update on COVID-19. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. Accessed Nov 2023

Osuchowski MF, Winkler MS, Skirecki T, Cajander S, Shankar-Hari M, Lachmann G, Monneret G, Venet F, Bauer M, Brunkhorst FM, Weis S, Garcia-Salido A, Kox M, Cavaillon JM, Uhle F, Weigand MA, Flohé SB, Wiersinga WJ, Almansa R, de la Fuente A, Martin-Loeches I, Meisel C, Spinetti T, Schefold JC, Cilloniz C, Torres A, Giamarellos-Bourboulis EJ, Ferrer R, Girardis M, Cossarizza A, Netea MG, van der Poll T, Bermejo-Martín JF, Rubio I (2021) The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity. Lancet Respir Med 9:622–642. https://doi.org/10.1016/S2213-2600(21)00218-6CrossRefPubMedPubMedCentral

Boulware DR, Lindsell CJ, Stewart TG, Hernandez AF, Collins S, McCarthy MW, Jayaweera D, Gentile N, Castro M, Sulkowski M, McTigue K, Felker GM, Ginde AA, Dunsmore SE, Adam SJ, DeLong A, Hanna G, Remaly A, Thicklin F, Wilder R, Wilson S, Shenkman E, Naggie S, ACTIV-6 Study Group and Investigators (2023) Inhaled fluticasone furoate for outpatient treatment of COVID-19. N Engl J Med 389:1085–1095. https://doi.org/10.1056/NEJMoa2209421CrossRefPubMedPubMedCentral

Hu B, Huang S, Yin L (2021) The cytokine storm and COVID-19. J Med Virol 93:250–256. https://doi.org/10.1002/jmv.26232CrossRefPubMed

Grasselli G, Pesenti A, Cecconi M (2020) Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response. JAMA 323:1545–1546. https://doi.org/10.1001/jama.2020.4031CrossRefPubMed

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y (2020) Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 180:934–943. https://doi.org/10.1001/jamainternmed.2020.0994CrossRefPubMed

Para O, Caruso L, Ronchetti M, Finocchi M, Guidi S, Spinicci M (2021) Superinfection with difficult-to-treat bacteria in COVID-19 patients: a call for compliance with diagnostic and antimicrobial stewardship. Intern Emerg Med 16:789–791. https://doi.org/10.1007/s11739-020-02537-3CrossRefPubMed

Li T, Wang X, Zhuang X, Wang H, Li A, Huang L, Zhang X, Xue Y, Wei F, Ma C (2021) Baseline characteristics and changes of biomarkers in disease course predict prognosis of patients with COVID-19. Intern Emerg Med 16:1165–1172. https://doi.org/10.1007/s11739-020-02560-4CrossRefPubMedPubMedCentral

Herminghaus A, Osuchowski MF (2022) How sepsis parallels and differs from COVID-19. EBioMedicine 86:104355. https://doi.org/10.1016/j.ebiom.2022.104355CrossRefPubMedPubMedCentral

10.

El Halabi M, Feghali J, Bahk J, Tallón de Lara P, Narasimhan B, Ho K, Sehmbhi M, Saabiye J, Huang J, Osorio G, Mathew J, Wisnivesky J, Steiger D (2022) A novel evidence-based predictor tool for hospitalization and length of stay: insights from COVID-19 patients in New York city. Intern Emerg Med 17:1879–1889. https://doi.org/10.1007/s11739-022-03014-9CrossRefPubMedPubMedCentral

11.

Pence BD (2022) Growth differentiation factor-15 in immunity and aging. Front Aging 3:837575. https://doi.org/10.3389/fragi.2022.837575CrossRefPubMedPubMedCentral

12.

Myhre PL, Prebensen C, Strand H, Røysland R, Jonassen CM, Rangberg A, Sørensen V, Søvik S, Røsjø H, Svensson M, Berdal JE, Omland T (2020) Growth differentiation factor 15 provides prognostic information superior to established cardiovascular and inflammatory biomarkers in unselected patients hospitalized with COVID-19. Circulation 142:2128–2137. https://doi.org/10.1161/CIRCULATIONAHA.120.050360CrossRefPubMedPubMedCentral

13.

Sudhini YR, Wei C, Reiser J (2022) suPAR: an inflammatory mediator for kidneys kidney. Dis (Basel) 8:265–274. https://doi.org/10.1159/000524965CrossRef

14.

Luo S, Vasbinder A, Du-Fay-de-Lavallaz JM, Gomez JMD, Suboc T, Anderson E, Tekumulla A, Shadid H, Berlin H, Pan M, Azam TU, Khaleel I, Padalia K, Meloche C, O’Hayer P, Catalan T, Blakely P, Launius C, Amadi KM, Pop-Busui R, Loosen SH, Chalkias A, Tacke F, Giamarellos-Bourboulis EJ, Altintas I, Eugen-Olsen J, Williams KA, Volgman AS, Reiser J, Hayek SS, ISIC (International Study of Inflammation in COVID‐19) Group (2022) Soluble urokinase plasminogen activator receptor and venous thromboembolism in COVID-19. J Am Heart Assoc 11:e025198. https://doi.org/10.1161/JAHA.122.025198CrossRefPubMedPubMedCentral

15.

Dofferhoff ASM, Piscaer I, Schurgers LJ, Visser MPJ, van den Ouweland JMW, de Jong PA, Gosens R, Hackeng TM, van Daal H, Lux P, Maassen C, Karssemeijer EGA, Vermeer C, Wouters EFM, Kistemaker LEM, Walk J, Janssen R (2021) Reduced vitamin K status as a potentially modifiable risk factor of severe coronavirus disease 2019. Clin Infect Dis 73:e4039–e4046. https://doi.org/10.1093/cid/ciaa1258CrossRefPubMed

16.

Mangge H, Prueller F, Dawczynski C, Curcic P, Sloup Z, Holter M, Herrmann M, Meinitzer A (2022) Dramatic decrease of vitamin K2 subtype menaquinone-7 in COVID-19 patients. Antioxidants (Basel) 11:1235. https://doi.org/10.3390/antiox11071235CrossRefPubMed

17.

Lalosevic M, Kotur-Stevuljevic J, Vekic J, Rizzo M, Kosanovic T, Blagojevic IP, Zeljkovic A, Jeremic D, Mihajlovic M, Petkovic A, Hajdarpasic L, Djordjevic M, Dobrilovic V, Erceg S, Vujcic S, Marjanovic J, Jovanovic JM, Saponjski J, Bogavac-Stanojevic N (2022) Alteration in redox status and lipoprotein profile in COVID-19 patients with mild, moderate, and severe pneumonia. Oxid Med Cell Longev 2022:8067857. https://doi.org/10.1155/2022/8067857CrossRefPubMedPubMedCentral

18.

Karbalai Saleh S, Oraii A, Soleimani A, Hadadi A, Shajari Z, Montazeri M, Moradi H, Talebpour M, Sadat Naseri A, Balali P, Akhbari M, Ashraf H (2020) The association between cardiac injury and outcomes in hospitalized patients with COVID-19. Intern Emerg Med 15:1415–1424. https://doi.org/10.1007/s11739-020-02466-1CrossRefPubMedPubMedCentral

19.

COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed Nov 2023

20.

Corradini E, Ventura P, Ageno W, Cogliati CB, Muiesan ML, Girelli D, Pirisi M, Gasbarrini A, Angeli P, Querini PR, Bosi E, Tresoldi M, Vettor R, Cattaneo M, Piscaglia F, Brucato AL, Perlini S, Martelletti P, Pontremoli R, Porta M, Minuz P, Olivieri O, Sesti G, Biolo G, Rizzoni D, Serviddio G, Cipollone F, Grassi D, Manfredini R, Moreo GL, Pietrangelo A, SIMI-COVID-19 Collaborators (2021) Clinical factors associated with death in 3044 COVID-19 patients managed in internal medicine wards in Italy: results from the SIMI-COVID-19 study of the Italian Society of Internal Medicine (SIMI). Intern Emerg Med 16:1005–1015. https://doi.org/10.1007/s11739-021-02742-8CrossRefPubMedPubMedCentral

21.

Crisafulli E, Sartori G, Vianello A, Maroccia A, Lepori E, Quici M, Cogliati C, Salvetti M, Paini A, Aggiusti C, Bertacchini F, Busti F, Marchi G, Muiesan ML, Girelli D (2023) Use of non-invasive respiratory supports in high-intensity internal medicine setting during the first two waves of the COVID-19 pandemic emergency in Italy: a multicenter, real-life experience. Intern Emerg Med 18:1777–1787. https://doi.org/10.1186/s12916-020-01726-3CrossRefPubMedPubMedCentral

22.

Rees EM, Nightingale ES, Jafari Y, Waterlow NR, Clifford S, Pearson CA, Group CW, Jombart T, Procter SR, Knight GM (2020) COVID-19 length of hospital stay: a systematic review and data synthesis. BMC Med 18:270. https://doi.org/10.1186/s12916-020-01726-3CrossRefPubMedPubMedCentral

23.

Mir R, Jha CK, Khullar N, Maqbool M, Dabla PK, Mathur S, Moustafa A, Faridi UA, Hamadi A, Mir MM, Abu Duhier FM (2022) The role of inflammatory and cytokine biomarkers in the pathogenesis of frailty syndrome. Endocr Metab Immune Disord Drug Targets 22:1357–1366. https://doi.org/10.2174/1871530322666220304220522CrossRefPubMed

24.

Conte M, Giuliani C, Chiariello A, Iannuzzi V, Franceschi C, Salvioli S (2022) GDF15, an emerging key player in human aging. Ageing Res Rev 75:101569. https://doi.org/10.1016/j.arr.2022.101569CrossRefPubMed

25.

Luo X, Zhou W, Yan X, Guo T, Wang B, Xia H, Ye L, Xiong J, Jiang Z, Liu Y, Zhang B, Yang W (2020) Prognostic value of C-reactive protein in patients with coronavirus 2019. Clin Infect Dis 71:2174–2179. https://doi.org/10.1093/cid/ciaa641CrossRefPubMed

26.

García-Escobar A, Vera-Vera S, Tébar-Márquez D, Rivero-Santana B, Jurado-Román A, Jiménez-Valero S, Galeote G, Cabrera JÁ, Moreno R (2023) Neutrophil-to-lymphocyte ratio an inflammatory biomarker, and prognostic marker in heart failure, cardiovascular disease and chronic inflammatory diseases: New insights for a potential predictor of anti-cytokine therapy responsiveness. Microvasc Res 150:104598. https://doi.org/10.1016/j.mvr.2023.104598CrossRefPubMed

27.

Adela R, Banerjee SK (2015) GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res 2015:490842. https://doi.org/10.1155/2015/490842CrossRefPubMedPubMedCentral

28.

Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC (2020) Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 324:782–793. https://doi.org/10.1001/jama.2020.12839CrossRefPubMed

29.

Molfino A, Amabile MI, Imbimbo G, Rizzo V, Pediconi F, Catalano C, Emiliani A, Belli R, Ramaccini C, Parisi C, Nigri G, Muscaritoli M (2020) Association between growth differentiation factor-15 (GDF-15) serum levels, anorexia and low muscle mass among cancer patients. Cancers (Basel) 13:99. https://doi.org/10.3390/cancers13010099CrossRefPubMed

30.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395:1054–1062. https://doi.org/10.1016/S0140-6736(20)30566-3CrossRefPubMedPubMedCentral

31.

Moreno-Torres V, de Mendoza C, de la Fuente S, Sánchez E, Martínez-Urbistondo M, Herráiz J, Gutiérrez A, Gutiérrez Á, Hernández C, Callejas A, Maínez C, Royuela A, Cuervas-Mons V, de Hierro P (2022) Bacterial infections in patients hospitalized with COVID-19. Intern Emerg Med 17:431–438. https://doi.org/10.1007/s11739-021-02824-7CrossRefPubMed

32.

Lansbury L, Lim B, Baskaran V, Lim WS (2020) Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect 81:266–275. https://doi.org/10.1016/j.jinf.2020.05.046CrossRefPubMedPubMedCentral

33.

Van Laethem J, Wuyts S, Van Laere S, Koulalis J, Colman M, Moretti M, Seyler L, De Waele E, Pierard D, Lacor P, Allard SD (2022) Antibiotic prescriptions in the context of suspected bacterial respiratory tract superinfections in the COVID-19 era: a retrospective quantitative analysis of antibiotic consumption and identification of antibiotic prescription drivers. Intern Emerg Med 17:141–151. https://doi.org/10.1007/s11739-021-02790-0CrossRefPubMed

34.

Lippi G, Henry BM (2022) Prognostic value of growth differentiation factor 15 in COVID-19. Scand J Clin Lab Invest 82:170–172. https://doi.org/10.1080/00365513.2022.2034938CrossRefPubMed

35.

Notz Q, Schmalzing M, Wedekink F, Schlesinger T, Gernert M, Herrmann J, Sorger L, Weismann D, Schmid B, Sitter M, Schlegel N, Kranke P, Wischhusen J, Meybohm P, Lotz C (2020) Pro- and anti-inflammatory responses in severe COVID-19-induced acute respiratory distress syndrome-an observational pilot study. Front Immunol 11:581338. https://doi.org/10.3389/fimmu.2020.581338CrossRefPubMedPubMedCentral

36.

Zhan K, Wang L, Lin H, Fang X, Jia H, Ma X (2023) Novel inflammatory biomarkers in the prognosis of COVID-19. Ther Adv Respir Dis 17:17534666231199680. https://doi.org/10.1177/17534666231199679CrossRefPubMedPubMedCentral

37.

Anastasi E, Ialongo C, Labriola R, Ferraguti G, Lucarelli M, Angeloni A (2020) Vitamin K deficiency and covid-19. Scand J Clin Lab Invest 80:525–527. https://doi.org/10.1080/00365513.2020.1805122CrossRefPubMed

38.

Superko H, Garrett B (2022) Small dense LDL: scientific background, clinical relevance, and recent evidence still a risk even with ‘normal’ LDL-C levels. Biomedicines 10:829. https://doi.org/10.3390/biomedicines10040829CrossRefPubMedPubMedCentral

Title: Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients
Authors: Alessio Molfino
Emanuela Anastasi
Eleonora Assanto
Ludovica Toccini
Giovanni Imbimbo
Antonietta Gigante
Valentina Viggiani
Antonella Farina
Orietta Picconi
Antonio Angeloni
Maurizio Muscaritoli
Publication date: 03-05-2024
Publisher: Springer International Publishing
Keywords: COVID-19
Biomarkers
Published in: Internal and Emergency Medicine
Print ISSN: 1828-0447
Electronic ISSN: 1970-9366
DOI: https://doi.org/10.1007/s11739-024-03630-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com