Viruses | Free Full-Text | Prognostic Value of D-dimer to Lymphocyte Ratio (DLR) in Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Validation Study in a National Cohort

Infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), which has become the worst pandemic worldwide in the last few decades, with officially reported deaths exceeding 6.8 million, which are likely underestimated [1,2,3,4,5]. Although the SARS-CoV-2 virus presents a substantial pulmonary burden producing hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS), extrapulmonary complications have also been reported [6]. Pathophysiology seems to be complex; however, some clues have been elucidated. This virus appears to enter the epithelial cells of the respiratory tract by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is widespread in various organs including the respiratory system. Thus, the virus and the down-regulation of ACE2 leads to direct cytotoxic damage and a pro-inflammatory state, commonly misnamed as a “cytokine storm” [4,7]. Broadly, 14–20% of patients required admission to the intensive care unit (ICU), with an overall mortality of around 2%. In addition, among those admitted to an ICU, the mortality dramatically increases up to nearly 50% [1,2,3,8]. In this setting, it has been described that the presence of previous comorbidities and laboratory biomarkers, such as low lymphocyte count, high levels of D-dimer, C-reactive protein (CRP), and other inflammatory biomarkers, alongside some laboratory indices (or ratios), is associated with poor prognosis in SARS-CoV-2 infection [1,4,9,10,11,12]. Previous works have proposed that combining two different biomarkers in ratios might improve their prognostic capacity when compared to the biomarkers themselves. Previously, we hypothesized that SARS-CoV-2 might induce endothelial damage (vascular dysfunction) and activate the immune system, and those factors provoked a disbalance, provoking a pro-inflammatory (low lymphocyte count) and pro-coagulant state (elevation of D-dimer serum levels) [8,11,12,13,14,15,16]; taking into account the same theoretical basis, our working group evaluated, in a single-center cohort of 1113 hospitalized COVID-19 patients, the role of 10 laboratory indices as prognostic biomarkers, including both well-known ratios described previously in the literature (neutrophil to lymphocyte ratio (NLR), derived neutrophil to white blood cells minus neutrophile ratio (d-NLR), platelet to lymphocyte ratio (PLR), CRP to lymphocyte ratio, and CRP to albumin ratio) and proposed new laboratory indices. After multivariate regression logistic analysis, only the new proposed ratio, the D-dimer to lymphocyte ratio (DLR), showed an independent association in terms of mortality (adjusted OR 2.33; p 12].

A total of 10,575 COVID-19 patients were included in this study. The mean age of participants was 66.9 (±16) years, and 58.6% (6202 patients) of them were male. Among the comorbidities observed, arterial hypertension was the most common, affecting 51.8% of the patients (n = 5474), followed by dyslipidemia in 40.3% (n = 4259 patients), diabetes in 22.9% (n = 1098 patients), atrial fibrillation in 10.3% (n = 1089 patients), and dementia in 7.8% (n = 815 patients). The overall mortality rate was 16.3% (n = 1654 patients). In addition, ICU admission was needed in 10.5% (n = 1106 patients), non-invasive mechanical ventilation was required in 8.8% (n = 923 patients), and orotracheal intubation was required in 7.5% (789 patients). The median length of hospitalization was 9 days (6–15). Table 1 describes and summarizes the baseline characteristics of the total sample, while a comparison of distribution frequency between survivors and non-survivors is shown.

The predictive capacity of the D-dimer to lymphocyte ratio demonstrated an AUC of 0.69 (95% CI, 0.68–0.71) for in-hospital mortality (Figure 2, panel A). DLR > 1 was identified as the optimal cut-off point for mortality, with a negative predictive value (NPV) of 90%. NLR exhibited an AUC of 0.67 (95% CI, 0.65–0.68) for in-hospital mortality, with an optimal cut-off above 6.5 for predicting mortality (NPV 88%). The predictive capacity of d-NLR revealed an AUC of 0.66 (95% CI, 0.65–0.68) for in-hospital mortality. d-NLR > 4 was the optimal cut-off for mortality (NPV 89%). PLR showed an AUC of 0.58 (95% CI, 0.57–0.6) for in-hospital mortality, with an optimal cut-off above 290. The predictive capacity of the CPR to lymphocyte ratio showed an AUC of 0.67 (95% CI, 0.66–0.69) for in-hospital mortality, with an optimal cut-off above 0.1 for mortality (NPV 89%). The CPR to serum albumin ratio showed an AUC of 0.67 (95% CI, 0.65–0.68) for in-hospital mortality (Figure 2a), with an optimal cut-off above 25 for mortality (NPV 90%).

Univariate logistic regression analysis for in-hospital mortality showed the following: DLR > 1 (crude OR 3.54; 95% CI 2.34–5.47), NLR > 6.5 (crude OR 3.58; 95% CI 2.39–5.44), d-NLR > 4 (crude OR 3.58, 2.40–5.39), CRP to lymphocyte ratio > 0.1 (crude OR 3.41, 95% CI 2.26–5.25), and CRP to serum albumin ratio > 25 (crude OR 2.93; 95% CI 1.96–4.43). On the other hand, the multivariate analysis presented an independent association with in-hospital mortality for DLR > 1 (adjusted OR 2.12, 95% CI 1.119–4.08; p = 0.02), age over 70 (adjusted OR 2.63; 95% CI 1.60–4.41; p =p Table 2 summarizes the association for univariate and multivariate analysis related to mortality.

Survival analysis for in-hospital mortality showed DLR > 1 (HR 2.24; 95% CI 2.03–2.47; p 6.5 (HR 1.92; 95% CI 1.74–2.11; p 4 (HR 1.98; 95% CI 1.80–2.18; p 0.1 (HR 1.97; 95% CI 1.78–2.17; p 25 (HR 1.89; 95% CI 1.71–2.09; p Figure 2b.

Since the presence of a low lymphocyte count and elevated D-dimer levels seems to be associated with poor prognosis in SARS-CoV-2 infection, searching for laboratory biomarkers presents a great clinical interest [15,16,17]. In this setting, Zhang H et al. [18] conducted a meta-analysis with 3337 patients and found that patients with severe COVID-19 had lower levels of lymphocytes, with a weight mean difference (WMD) of −0.468 (×109/L) (95% CI; −0.543 to −0.394), but higher levels of NLR, with a WMD of 6.939 (95% CI 4.581–9.297) and D-dimer levels with a WMD of 1.217 mg/L (95% CI 0.788–1.646), when compared with non-severe COVID-19. Another meta-analysis on 61 studies (15,522 patients) found that higher levels of NLR were associated with all-cause mortality in hospitalized COVID-19 patients in the univariate analysis but not in the multivariate analysis (crude OR 12.6; 95% CI 6.88–23.06), showing a high degree of heterogeneity (I2 = 98%) [19]. Contrarily, our working group found no association between NLR and 30-day mortality (crude OR 1.03; 95% CI 0.99–1.05) in a prospective cohort of 95 critically ill patients admitted to the ICU [17]. Further, some other laboratory indices were also evaluated. Sarkar et al. [20] evaluated the role of PLR in COVID-19 patients upon admission (14 studies; 2768 patients) for mortality, showing a WMD of 66.10 (95% CI: 47.75–84.44) with high heterogeneity (I2 = 89%) and low-quality evidence; a meta-analysis of 71 studies found no association for PLR with a poor prognosis in terms of mortality [21]. Moreover, a retrospective study evaluated the role of the CRP to serum albumin ratio in 272 COVID-19 patients in terms of mortality, finding an optimal cut-off above 21.5 (c-statistic of 0.72; 95% CI 0.66–0.77) [22], whereas another study that involved 3471 patients showed an optimal cut-off above 25 to be associated with mortality (OR, 1.47; 95% CI 1.19–1.82) [23]. A meta-analysis conducted by Zavalaga-Zegarra et al. [24] evaluated the potential association of the CPR to albumin ratio in terms of mortality in 17 studies (7164 COVID-19 patients), finding higher values in non-survivors (MD: 2.59; 95% CI: 1.95–3.23) with severe heterogeneity (I2 = 92%). A sensitivity analysis that included studies with a low risk of bias (5 studies) showed a significant association (MD: 2.99; 95% CI: 2.47–3.51; I2 = 0%), where cut-off values were only stated in two studies without specifying units of measure.

Formerly, our working group evaluated different laboratory indices published in the literature and a new index called the D-dimer to lymphocyte ratio as a potential prognostic biomarker in a single-center cohort of 1113 hospitalized COVID-19 patients. DLR > 0.6 showed an independent association for 30-day mortality (adjusted OR 2.33; 95% CI 1.01–5.38), but no other laboratory indices showed any association in multivariate analysis, including NLR, d-NLR, PLR, CRP to lymphocyte ratio, and CRP to albumin ratio [12]. The present study involved a large national multicenter cohort of 10,575 hospitalized COVID-19 patients, aiming to validate the potential association between DLR and short-term mortality. In this national cohort, 10.5% of patients were admitted to the ICU, while in other series, this may reach up to 5–17%. In addition, in this study, ICU mortality was 24.7% compared to up to 40–50% previously published in the literature. Thus, new biomarkers such as DLR might be helpful for a better prognosis prediction [2,3,4,9]. Among all laboratory biomarkers evaluated in this retrospective national cohort that involved 10,575 COVID-19 patients, we found that DLR showed an independent association for in-hospital mortality, proving its potential usefulness as a biomarker of poor prognosis with an optimal cut-off above 1 (adjusted OR 2.12, 95% CI 1.119–4.08) regarding age, ARDS, lymphopenia ⁻¹, D-dimer > 1000 ng/mL, among others (Table 2), with the worst survival rate for DLR > 1 (HR 2.24; 95% CI 2.03–2.47). In this large multicenter cohort, no other laboratory indices showed an independent association in multivariate analysis.