C-reactive protein and clinical outcomes in patients with COVID-19

Nathaniel R Smilowitz, Dennis Kunichoff, Michael Garshick, Binita Shah, Michael Pillinger, Judith S Hochman, Jeffrey S Berger, Nathaniel R Smilowitz, Dennis Kunichoff, Michael Garshick, Binita Shah, Michael Pillinger, Judith S Hochman, Jeffrey S Berger

Abstract

Background: A systemic inflammatory response is observed in coronavirus disease 2019 (COVID-19). Elevated serum levels of C-reactive protein (CRP), a marker of systemic inflammation, are associated with severe disease in bacterial or viral infections. We aimed to explore associations between CRP concentration at initial hospital presentation and clinical outcomes in patients with COVID-19.

Methods and results: Consecutive adults aged ≥18 years with COVID-19 admitted to a large New York healthcare system between 1 March and 8 April 2020 were identified. Patients with measurement of CRP were included. Venous thrombo-embolism (VTE), acute kidney injury (AKI), critical illness, and in-hospital mortality were determined for all patients. Among 2782 patients hospitalized with COVID-19, 2601 (93.5%) had a CRP measurement [median 108 mg/L, interquartile range (IQR) 53-169]. CRP concentrations above the median value were associated with VTE [8.3% vs. 3.4%; adjusted odds ratio (aOR) 2.33, 95% confidence interval (CI) 1.61-3.36], AKI (43.0% vs. 28.4%; aOR 2.11, 95% CI 1.76-2.52), critical illness (47.6% vs. 25.9%; aOR 2.83, 95% CI 2.37-3.37), and mortality (32.2% vs. 17.8%; aOR 2.59, 95% CI 2.11-3.18), compared with CRP below the median. A dose response was observed between CRP concentration and adverse outcomes. While the associations between CRP and adverse outcomes were consistent among patients with low and high D-dimer levels, patients with high D-dimer and high CRP have the greatest risk of adverse outcomes.

Conclusions: Systemic inflammation, as measured by CRP, is strongly associated with VTE, AKI, critical illness, and mortality in COVID-19. CRP-based approaches to risk stratification and treatment should be tested.

Keywords: C-reactive protein; COVID-19; Coronavirus; Critical illness; Inflammation; Mortality.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Frequency distribution of initial CRP concentrations in patients hospitalized with COVID-19.
Figure 2
Figure 2
Mortality (A), critical illness (B), venous thrombo-embolism (C), and acute kidney injury (D) among patients with COVID-19, stratified by initial CRP measurement. Quartile 1: ≤53 mg/L. Quartile 2: >53 to ≤108 mg/L. Quartile 3: >108 to ≤169 mg/L. Quartile 4: >169 mg/L. Odds ratios adjusted for age, sex, race/ethnicity, body mass index, tobacco use, hypertension, hyperlipidaemia, chronic kidney disease, coronary artery disease, heart failure, and malignancy.
Figure 3
Figure 3
Associations between CRP and all-cause mortality, critical illness, venous thromb-oembolism, and acute kidney injury in subgroups by age, sex, race, and body mass index. Odds ratios adjusted for age, sex, race/ethnicity, body mass index, tobacco use, hypertension, hyperlipidaemia, chronic kidney disease, atrial fibrillation, coronary artery disease, heart failure, malignancy, initial ferritin, absolute lymphocyte count, D-dimer, and baseline use of statins, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and anticoagulants.
Figure 4
Figure 4
Associations between CRP and all-cause mortality, critical illness, venous thrombo-embolism, and acute kidney injury stratified by initial D-dimer measurement. The incidence (A) and adjusted odds (B) of adverse outcomes are shown. (low CRP <108 mg/dL; high CRP ≥108 mg/dL; low D-dimer ≤384 ng/mL; high D-dimer >384 ng/mL). (A) *P for trend <0.001 for all outcomes. (B) Odds ratios adjusted for age, sex, race/ethnicity, body mass index, tobacco use, hypertension, hyperlipidaemia, chronic kidney disease, atrial fibrillation, coronary artery disease, heart failure, malignancy, initial ferritin, absolute lymphocyte count, baseline use of statins, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers,and anticoagulants.
Figure 5
Figure 5
Trajectory of CRP levels over time among patients with and without fatal disease (A), critical illness (B), VTE (C), and AKI (D).

References

    1. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, Tobin KA, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ 2020;369 : m1966.
    1. Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of Pneumococcus. J Exp Med 1930;52:561–571.
    1. Morley JJ, Kushner I. Serum C-reactive protein levels in disease. Ann N Y Acad Sci 1982;389:406–418.
    1. Murashima M, Nishimoto M, Kokubu M, Hamano T, Matsui M, Eriguchi M, Samejima KI, Akai Y, Tsuruya K. Inflammation as a predictor of acute kidney injury and mediator of higher mortality after acute kidney injury in non-cardiac surgery. Sci Rep 2019;9:20260.
    1. Folsom AR, Lutsey PL, Astor BC, Cushman M. C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thromb Haemost 2009;102:615–619.
    1. Vasileva D, Badawi A. C-reactive protein as a biomarker of severe H1N1 influenza. Inflamm Res 2019;68:39–46.
    1. Luo X, Zhou W, Yan X, Guo T, Wang B, Xia H, Ye L, Xiong J, Jiang Z, Liu Y, Zhang B, Yang W. Prognostic value of C-reactive protein in patients with COVID-19. Clin Infect Dis 2020;71:2174–2179.
    1. Gao Y, Li T, Han M, Li X, Wu D, Xu Y, Zhu Y, Liu Y, Wang X, Wang L. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 2020;92:791–796.
    1. Liang W, Liang H, Ou L, Chen B, Chen A, Li C, Li Y, Guan W, Sang L, Lu J, Xu Y, Chen G, Guo H, Guo J, Chen Z, Zhao Y, Li S, Zhang N, Zhong N, He J; China Medical Treatment Expert Group for COVID-19. Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. JAMA Intern Med 2020;180:1081–1089.
    1. Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y, Li B, Song X, Zhou X. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol 2020;127:104370.
    1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY,, Xiang J,, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J,, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–1720.
    1. 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. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934–943.
    1. Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA 2020;324:799–801.
    1. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001;38:189–197.
    1. Vanderschueren S, Deeren D, Knockaert DC, Bobbaers H, Bossuyt X, Peetermans W. Extremely elevated C-reactive protein. Eur J Intern Med 2006;17:430–433.
    1. Landry A, Docherty P, Ouellette S, Cartier LJ. Causes and outcomes of markedly elevated C-reactive protein levels. Can Fam Physician 2017;63:e316–e323.
    1. Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, Satlin MJ, Campion TR Jr, Nahid M, Ringel JB, Hoffman KL, Alshak MN, Li HA, Wehmeyer GT,, Rajan M, Reshetnyak E, Hupert N, Horn EM,, Martinez FJ, Gulick RM, Safford MM. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020;382:2372–2374.
    1. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:811–818.
    1. Lala A,, Johnson KW, Januzzi JL, Russak AJ, Paranjpe I, Richter F, Zhao S, Somani S, Van Vleck T, Vaid A, Chaudhry F, De Freitas JK, Fayad ZA, Pinney SP, Levin M, Charney A, Bagiella E, Narula J, Glicksberg BS, Nadkarni G, Mancini DM, Fuster V; Mount Sinai Covid Informatics Center. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 Infection. J Am Coll Cardiol 2020;76:533–546.
    1. Shi S, Qin M, Cai Y, Liu T, Shen B, Yang F, Cao S, Liu X, Xiang Y, Zhao Q, Huang H, Yang B, Huang C. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J 2020;41:2070–2079.
    1. Basso C, Leone O, Rizzo S, De Gaspari M, van der Wal AC, Aubry MC, Bois MC, Lin PT, Maleszewski JJ, Stone JR. Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Eur Heart J 2020;41:3827–3835.
    1. Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, Lavin Y, Swartz TH, Madduri D, Stock A, Marron TU, Xie H, Patel M, Tuballes K, Van Oekelen O, Rahman A, Kovatch P, Aberg JA, Schadt E, Jagannath S, Mazumdar M, Charney AW, Firpo-Betancourt A, Mendu DR, Jhang J, Reich D, Sigel K, Cordon-Cardo C, Feldmann M, Parekh S, Merad M, Gnjatic S. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 2020;26:1636–1643.
    1. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across Speciality Collaboration UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033–1034.
    1. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 2020;20:355–362.
    1. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007;131:954–063.
    1. Recovery Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med 2020;doi: 10.1056/NEJMoa2021436.
    1. Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost 2020;18:1559–1561.
    1. Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019;133:906–918.
    1. Rapkiewicz AV, Mai X, Carsons SE, Pittaluga S, Kleiner DE, Berger JS, Thomas S, Adler NM, Charytan DM, Gasmi B, Hochman JS, Reynolds HR. Megakaryocytes and platelet–fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series. EClinicalMedicine 2020;24:100434.
    1. Fauvel C, Weizman O, Trimaille A, Mika D, Pommier T, Pace N, Douair A, Barbin E, Fraix A, Bouchot O, Benmansour O, Godeau G, Mecheri Y, Lebourdon R, Yvorel C, Massin M, Leblon T, Chabbi C, Cugney E, Benabou L, Aubry M, Chan C, Boufoula I, Barnaud C, Bothorel L, Duceau B, Sutter W, Waldmann V, Bonnet G, Cohen A, Pezel T; Critical Covid-19 France Investigators. Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Eur Heart J 2020;41:3058–3068.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner