CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(11): 1888-1898
DOI: 10.1055/a-1768-4371
Stroke, Systemic or Venous Thromboembolism

Adjusting D-dimer to Lung Disease Extent to Exclude Pulmonary Embolism in COVID-19 Patients (Co-LEAD)

Benjamin Planquette*
1   Innovative Therapies in Haemostasis, Université de Paris, INSERM, Paris, France
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
3   Department of Respiratory Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
4   F-CRIN INNOVTE, Saint-Étienne, France
,
Lina Khider*
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
5   Department of Vascular Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
6   Physics for Medicine Paris, INSERM U1273, ESPCI Paris, Paris, France
,
Alice Le Berre**
7   Department of Radiology, Groupe Hospitalier Paris Saint-Joseph, Paris, France
,
Simon Soudet**
8   EA7516 CHIMERE and Service de Médecine Vasculaire, Université Picardie Jules Verne, CHU Amiens-Picardie, Amiens, France
,
Gilles Pernod**
9   Service Universitaire de Médecine Vasculaire, CHU de Grenoble-Alpes, Université Grenoble-Alpes, CNRS/TIMC-IMAG UMR 5525/Thèmas 38043 Grenoble, F-CRIN INNOVTE, Saint-Étienne, France
,
Raphaël Le Mao**
10   Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, EA 3878, CIC INSERM 1412, Brest, F-CRIN INNOVTE, Saint-Étienne, France
,
Matthieu Besutti**
11   Department of Cardiology, University Hospital, Besançon, EA3920, University of Burgundy Franche Comté, Besançon, France
,
Nicolas Gendron
1   Innovative Therapies in Haemostasis, Université de Paris, INSERM, Paris, France
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
4   F-CRIN INNOVTE, Saint-Étienne, France
12   Department of Haematology, Assistance Publique Hôpitaux de Paris.Centre-Université de Paris (APHP-CUP), Paris, France
,
Alexandra Yanoutsos
13   Department of vascular medicine, Groupe hospitalier Paris Saint Joseph, Paris, France
14   Department of Vascular Medicine, INSERM CRESS UMR 1153, Paris, France
,
David M. Smadja
15   Department of Radiology, Université de Paris, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
,
Guillaume Goudot
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
5   Department of Vascular Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
6   Physics for Medicine Paris, INSERM U1273, ESPCI Paris, Paris, France
,
Salma Al Kahf
1   Innovative Therapies in Haemostasis, Université de Paris, INSERM, Paris, France
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
3   Department of Respiratory Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
4   F-CRIN INNOVTE, Saint-Étienne, France
,
Nassim Mohamedi
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
5   Department of Vascular Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
6   Physics for Medicine Paris, INSERM U1273, ESPCI Paris, Paris, France
,
Antoine Al Hamoud
1   Innovative Therapies in Haemostasis, Université de Paris, INSERM, Paris, France
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
3   Department of Respiratory Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
4   F-CRIN INNOVTE, Saint-Étienne, France
,
Aurélien Philippe
1   Innovative Therapies in Haemostasis, Université de Paris, INSERM, Paris, France
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
4   F-CRIN INNOVTE, Saint-Étienne, France
12   Department of Haematology, Assistance Publique Hôpitaux de Paris.Centre-Université de Paris (APHP-CUP), Paris, France
,
Laure Fournier
15   Department of Radiology, Université de Paris, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
,
Bastien Rance
16   Department of Medical Informatics, Université de Paris, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
,
Jean-Luc Diehl
1   Innovative Therapies in Haemostasis, Université de Paris, INSERM, Paris, France
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
17   Intensive Care Unit, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
,
Tristan Mirault
5   Department of Vascular Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
19   Department of Emergency, Université de Paris, PARCC, INSERM, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
,
Emmanuel Messas
5   Department of Vascular Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
7   Department of Radiology, Groupe Hospitalier Paris Saint-Joseph, Paris, France
18   Department of Vascular Medicine, Paris Research Cardiovascular Center, PARCC, INSERM UMR-S 970, Paris, France
,
Joseph Emmerich
13   Department of vascular medicine, Groupe hospitalier Paris Saint Joseph, Paris, France
14   Department of Vascular Medicine, INSERM CRESS UMR 1153, Paris, France
,
Richard Chocron
19   Department of Emergency, Université de Paris, PARCC, INSERM, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
,
Francis Couturaud
10   Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, EA 3878, CIC INSERM 1412, Brest, F-CRIN INNOVTE, Saint-Étienne, France
,
Gilbert Ferretti
20   Department of Radiology, CHU, Université Grenoble-Alpes, Saint-Étienne, France
,
Marie Antoinette Sevestre
8   EA7516 CHIMERE and Service de Médecine Vasculaire, Université Picardie Jules Verne, CHU Amiens-Picardie, Amiens, France
,
Nicolas Meneveau
11   Department of Cardiology, University Hospital, Besançon, EA3920, University of Burgundy Franche Comté, Besançon, France
,
Gilles Chatellier
21   Department of Statistics, Bioinformatics and Public Health, INSERM CIC 14-18, Paris, France
,
Olivier Sanchez
1   Innovative Therapies in Haemostasis, Université de Paris, INSERM, Paris, France
2   Biosurgical Research Lab (Carpentier Foundation), Université de Paris, Paris, France
3   Department of Respiratory Medicine, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France
4   F-CRIN INNOVTE, Saint-Étienne, France
› Institutsangaben
Funding The authors gratefully acknowledge the Assistance Publique – Hopitaux de Paris for their support in bringing this project to life, and the Groupe Hospitalier Paris Saint Joseph for sponsoring it.


Abstract

Objective D-dimer measurement is a safe tool to exclude pulmonary embolism (PE), but its specificity decreases in coronavirus disease 2019 (COVID-19) patients. Our aim was to derive a new algorithm with a specific D-dimer threshold for COVID-19 patients.

Methods We conducted a French multicenter, retrospective cohort study among 774 COVID-19 patients with suspected PE. D-dimer threshold adjusted to extent of lung damage found on computed tomography (CT) was derived in a patient set (n = 337), and its safety assessed in an independent validation set (n = 337).

Results According to receiver operating characteristic curves, in the derivation set, D-dimer safely excluded PE, with one false negative, when using a 900 ng/mL threshold when lung damage extent was <50% and 1,700 ng/mL when lung damage extent was ≥50%. In the derivation set, the algorithm sensitivity was 98.2% (95% confidence interval [CI]: 94.7–100.0) and its specificity 28.4% (95% CI: 24.1–32.3). The negative likelihood ratio (NLR) was 0.06 (95% CI: 0.01–0.44) and the area under the curve (AUC) was 0.63 (95% CI: 0.60–0.67). In the validation set, sensitivity and specificity were 96.7% (95% CI: 88.7–99.6) and 39.2% (95% CI: 32.2–46.1), respectively. The NLR was 0.08 (95% CI; 0.02–0.33), and the AUC did not differ from that of the derivation set (0.68, 95% CI: 0.64–0.72, p = 0.097). Using the Co-LEAD algorithm, 76 among 250 (30.4%) COVID-19 patients with suspected PE could have been managed without CT pulmonary angiography (CTPA) and 88 patients would have required two CTs.

Conclusion The Co-LEAD algorithm could safely exclude PE, and could reduce the use of CTPA in COVID-19 patients. Further prospective studies need to validate this strategy.

* These two authors contributed equally.


** These five authors contributed equally.


Supplementary Material



Publikationsverlauf

Eingereicht: 31. Juli 2021

Angenommen: 08. Februar 2022

Accepted Manuscript online:
10. Februar 2022

Artikel online veröffentlicht:
17. Oktober 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Klok FA, Kruip MJHA, van der Meer NJM. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020; 191: 148-150
  • 2 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
  • 3 Lodigiani C, Iapichino G, Carenzo L. et al; Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191: 9-14
  • 4 Leonard-Lorant I, Delabranche X, Severac F. et al. Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to D-dimer levels. Radiology 2020; 296 (03) E189-E191
  • 5 Nopp S, Moik F, Jilma B. et al. Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis. Res Pract Thromb Haemost 2020; 4 (07) 1178-1191
  • 6 Jiménez D, García-Sanchez A, Rali P. et al. Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Chest 2021; 159 (03) 1182-1196
  • 7 Planquette B, Le Berre A, Khider L. et al. Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: a nested case-control study. Thromb Res 2021; 197: 94-99
  • 8 Stals M, Kaptein F, Kroft L, Klok FA, Huisman MV. Challenges in the diagnostic approach of suspected pulmonary embolism in COVID-19 patients. Postgrad Med 2021; 133 (Suppl. 01) 36-41
  • 9 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
  • 10 Tang N, Li D, Wang X. et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
  • 11 Khider L, Gendron N, Goudot G. et al. Curative anticoagulation prevents endothelial lesion in COVID-19 patients. J Thromb Haemost 2020; 18 (09) 2391-2399
  • 12 Spyropoulos AC, Levy JH, Ageno W. et al. Scientific and Standardization Committee Communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
  • 13 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
  • 14 Roy P-M, Friou E, Germeau B. et al. Derivation and validation of a 4-level clinical pretest probability score for suspected pulmonary embolism to safely decrease imaging testing. JAMA Cardiol 2021; 6 (06) 669-677
  • 15 Righini M, Van Es J, Den Exter PL. et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311 (11) 1117-1124
  • 16 van der Hulle T, Cheung WY, Kooij S. et al; YEARS study group. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet 2017; 390 (10091): 289-297
  • 17 Cheng Y, Luo R, Wang K. et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020; 97 (05) 829-838
  • 18 Cacciapaglia G, Cot C, Sannino F. Second wave COVID-19 pandemics in Europe: a temporal playbook. Sci Rep 2020; 10 (01) 15514
  • 19 Revel M-P, Parkar AP, Prosch H. et al; European Society of Radiology (ESR) and the European Society of Thoracic Imaging (ESTI). COVID-19 patients and the radiology department - advice from the European Society of Radiology (ESR) and the European Society of Thoracic Imaging (ESTI). Eur Radiol 2020; 30 (09) 4903-4909
  • 20 Grillet F, Behr J, Calame P, Aubry S, Delabrousse E. Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography. Radiology 2020; 296 (03) E186-E188
  • 21 Di Nisio M, Squizzato A, Rutjes AWS, Büller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost 2007; 5 (02) 296-304
  • 22 Douma RA, le Gal G, Söhne M. et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010; 340: c1475
  • 23 Dronkers CEA, van der Hulle T, Le Gal G. et al; Subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease. Towards a tailored diagnostic standard for future diagnostic studies in pulmonary embolism: communication from the SSC of the ISTH. J Thromb Haemost 2017; 15 (05) 1040-1043
  • 24 Thachil J, Cushman M, Srivastava A. A proposal for staging COVID-19 coagulopathy. Res Pract Thromb Haemost 2020; 4 (05) 731-736
  • 25 DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44 (03) 837-845
  • 26 Helms J, Tacquard C, Severac F. et al; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
  • 27 Jevnikar M, Sanchez O, Humbert M, Parent F. Prevalence of pulmonary embolism in patients with COVID-19 at the time of hospital admission and role for pre-test probability scores and home treatment. Eur Respir J 2021; 58 (02) 2101033
  • 28 Garcia-Olivé I, Sintes H, Radua J, Abad Capa J, Rosell A. D-dimer in patients infected with COVID-19 and suspected pulmonary embolism. Respir Med 2020; 169: 106023
  • 29 Espallargas I, Rodríguez Sevilla JJ, Rodríguez Chiaradía DA. et al. CT imaging of pulmonary embolism in patients with COVID-19 pneumonia: a retrospective analysis. Eur Radiol 2021; 31 (04) 1915-1922
  • 30 Choi JJ, Wehmeyer GT, Li HA. et al. D-dimer cut-off points and risk of venous thromboembolism in adult hospitalized patients with COVID-19. Thromb Res 2020; 196: 318-321
  • 31 Righini M, Robert-Ebadi H, Le Gal G. Diagnosis of acute pulmonary embolism. J Thromb Haemost 2017; 15 (07) 1251-1261
  • 32 Mouhat B, Besutti M, Bouiller K. et al. Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients. Eur Respir J 2020; 56 (04) 56
  • 33 Goudot G, Chocron R, Augy J-L. et al. Predictive factor for COVID-19 worsening: insights for high-sensitivity troponin and D-dimer and correlation with right ventricular afterload. Front Med (Lausanne) 2020; 7: 586307
  • 34 Chocron R, Duceau B, Gendron N. et al; Critical COVID-19 France investigators. D-dimer at hospital admission for COVID-19 are associated with in-hospital mortality, independent of venous thromboembolism: Insights from a French multicenter cohort study. Arch Cardiovasc Dis 2021; 114 (05) 381-393
  • 35 Kearon C, de Wit K, Parpia S. et al; PEGeD Study Investigators. Diagnosis of pulmonary embolism with D-dimer adjusted to clinical probability. N Engl J Med 2019; 381 (22) 2125-2134
  • 36 van Dam LF, Kroft LJM, van der Wal LI. et al. More on clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism. Thromb Res 2020; 196: 435-436
  • 37 Penaloza A, Verschuren F, Dambrine S, Zech F, Thys F, Roy PM. Performance of the pulmonary embolism rule-out criteria (the PERC rule) combined with low clinical probability in high prevalence population. Thromb Res 2012; 129 (05) e189-e193
  • 38 Freund Y, Cachanado M, Aubry A. et al; PROPER Investigator Group. Effect of the pulmonary embolism rule-out criteria on subsequent thromboembolic events among low-risk emergency department patients: the PROPER randomized clinical trial. JAMA 2018; 319 (06) 559-566
  • 39 Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. J Thromb Haemost 2004; 2 (08) 1247-1255
  • 40 Roy P-M, Colombet I, Durieux P, Chatellier G, Sors H, Meyer G. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ 2005; 331 (7511): 259
  • 41 Pan F, Ye T, Sun P. et al. Time course of lung changes at chest CT during recovery from coronavirus disease 2019 (COVID-19). Radiology 2020; 295 (03) 715-721
  • 42 Schwebel C, Clec'h C, Magne S. et al; OUTCOMEREA Study Group. Safety of intrahospital transport in ventilated critically ill patients: a multicenter cohort study*. Crit Care Med 2013; 41 (08) 1919-1928
  • 43 Collins GS, Ogundimu EO, Altman DG. Sample size considerations for the external validation of a multivariable prognostic model: a resampling study. Stat Med 2016; 35 (02) 214-226