Journal of

Clinical Medicine

Article
Platelet-to-Lymphocyte Ratio (PLR) Is Not a Predicting Marker
of Severity but of Mortality in COVID-19 Patients Admitted to
the Emergency Department: A Retrospective Multicenter Study
Paul Simon 1,2 , Pierrick Le Borgne 1,3 , François Lefevbre 4 , Lauriane Cipolat 5 , Aline Remillon 5 , Camille Dib 5 ,
Mathieu Hoffmann 5 , Idalie Gardeur 5 , Jonathan Sabah 6 , Sabrina Kepka 1 , Pascal Bilbault 1,2,3 ,
Charles-Eric Lavoignet 7 and Laure Abensur Vuillaume 5, * on behalf of the CREMS Network
(Clinical Research in Emergency Medicine and Sepsis)

1 Emergency Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France

2 Medicine Faculty, Strasbourg University, 67000 Strasbourg, France
3 INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative
NanoMedicine (RNM), Fédération de Médecine Translationnelle (FMTS), 67000 Strasbourg, France
4 Department of Public Health, University Hospital of Strasbourg, 67000 Strasbourg, France
5 Emergency Department, Regional Hospital of Metz-Thionville, 57000 Metz, France
6 Department of Gynecologic Surgery, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
7 Emergency Department, Hôpital Nord Franche Comté, 90400 Trévenans, France
* Correspondence: [email protected]

Abstract: (1) Introduction: In the present study, we investigate the prognostic value of platelet-to-
Citation: Simon, P.; Le Borgne, P.;
lymphocyte ratio (PLR) as a marker of severity and mortality in COVID-19 infection. (2) Methods:
Lefevbre, F.; Cipolat, L.; Remillon, A.;
Dib, C.; Hoffmann, M.; Gardeur, I.;
Between 1 March and 30 April 2020, we conducted a multicenter, retrospective cohort study of patients
Sabah, J.; Kepka, S.; et al. with moderate to severe coronavirus 19 (COVID-19), all of whom were hospitalized after being
Platelet-to-Lymphocyte Ratio (PLR) admitted to the emergency department (ED). (3) Results: A total of 1035 patients were included in
Is Not a Predicting Marker of our study. Neither lymphocytes, platelets or PLR were associated with disease severity. Lymphocyte
Severity but of Mortality in count was significantly lower and PLR values were significantly higher in the group of patients
COVID-19 Patients Admitted to the who died, and both were associated with mortality in the univariate analysis (OR: 0.524, 95% CI:
Emergency Department: A (0.336–0.815), p = 0.004) and (OR: 1.001, 95% CI: (1.000–1.001), p = 0.042), respectively. However, the
Retrospective Multicenter Study. J.
only biological parameter significantly associated with mortality in the multivariate analysis was
Clin. Med. 2022, 11, 4903. https://
platelet count (OR: 0.996, 95% CI: (0.996–1.000), p = 0.027). The best PLR value for predicting mortality
doi.org/10.3390/jcm11164903
in COVID-19 was 356.6 (OR: 3.793, 95% CI: (1.946–7.394), p < 0.001). (4) Conclusion: A high PLR
Academic Editor: Alessandra value is however associated with excess mortality.
D’Abramo
Keywords: PLR; platelet-to-lymphocyte ratio; severity; mortality; COVID-19
Received: 30 July 2022
Accepted: 19 August 2022
Published: 21 August 2022

Publisher’s Note: MDPI stays neutral 1. Introduction

with regard to jurisdictional claims in
It has been over two years that the world has been facing an unprecedented health
published maps and institutional affil-
iations.
crisis that is straining health systems. Since the first cases were identified in December
2019 in Wuhan, China [1], this pandemic caused by a new virus of the coronavirus family
called SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) [2] has caused more
than 6 million deaths for more than 500 million cases worldwide [3]. In France, after
Copyright: © 2022 by the authors. five waves, taking account that the first one particularly affected the Grand-East region
Licensee MDPI, Basel, Switzerland. from which our database originates, there have been over 146,000 deaths for more than
This article is an open access article 28 million cases [4]. COVID-19 (Coronavirus Disease 2019), the disease caused by this
distributed under the terms and virus [2], is known mainly in its severe forms to be responsible for multi-organ failure
conditions of the Creative Commons and Acute Respiratory Distress Syndrome (ARDS). Pulmonary lesions are partly mediated
Attribution (CC BY) license (https:// by a dysregulation of the immune system leading to a “cytokine storm”, as evidenced by
creativecommons.org/licenses/by/ excessive secretion of pro-inflammatory cytokines, notably, GM-CSF, IL-6 and TNF-α [5].
4.0/).

J. Clin. Med. 2022, 11, 4903. https://doi.org/10.3390/jcm11164903 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2022, 11, 4903 2 of 11

It has been observed that routine laboratory tests were affected by COVID-19 with
variable frequencies, such as depending on the series, 5–41.7% thrombocytopenia or up to
83% lymphopenia observed in infected patients [6,7]. Numerous studies have therefore
focused on the correlation between these biological abnormalities, especially biomarkers
reflecting inflammation, and the development of severe COVID-19. In addition to being
associated with the development of ARDS, some biological abnormalities are also correlated
with increased mortality from SARS-CoV-2: in a meta-analysis including 21 studies and
finding similar results to other papers [7–10], Brandon et al. showed that significantly lower
lymphocyte and platelet counts are associated with patient death compared to surviving
patients, as well as increased ALT, creatinine, LDH, PT and ferritin [11]. In addition,
other studies have looked more specifically at lymphopenia. Qin et al. showed in their
study a significant decrease in the total number of B, T and NK cells, this decrease being
even more pronounced in severe cases. T cells were shown to be more affected and they
noticed a significant decrease in the regulatory T-cells subpopulation (CD3+, CD4+, CD25+,
CD127low+) (9). Wang et al. obtained similar results, also finding a significant decrease in
the subpopulations of CD4+ and CD8+ T cells. Here, again, the decline was even greater in
severe forms, with the exception of LNK [12].
However, these biological parameters remain relatively nonspecific and the use of
a combined marker, such as the platelet-to-lymphocyte ratio (PLR), could provide an
additional argument to better discriminate patients at risk of developing a severe SARS-
CoV-2 infection. Indeed, the PLR seems to reflect changes in platelet and lymphocyte levels
related to inflammation and a pro-thrombotic state [13], which seems to be the lesioning
mechanism of SARS-CoV-2. This new biomarker, which reflects inflammatory processes,
is also being studied in several other types of pathologies where it provides prognostic
elements or activity monitoring. In oncology, in a meta-analysis, Templeton et al. showed
that a higher PLR, particularly a PLR > 185, was associated with poorer overall survival,
with a pooled HR of 1.70 (95% CI, 1.47–1.95; p < 0.001) [14]. In a review, Gasparyan et al.
summarized the research on PLR in rheumatic diseases and concluded that it can help
in the diagnosis and evaluation of the activity and severity of those diseases [15]. In
cardiovascular disease, Akboga et al. showed that PLR was an independent predictor of
severe coronary artery disease (OR 1.043 [1.036–1.049], p < 0.001) and determined that
an PLR > 109.5 had a sensitivity of 70%, specificity of 58% for predicting the presence of
severe coronary atherosclerosis (AUC: 0.708, 95% CI: (0.68–0.73), p < 0.001) [16]. Meng et al.
observed that in an acute non-ST-segment elevation myocardial infarction, a PLR ≥ 195.8
was significantly associated with increased 28-day mortality (HR 1.54; 95% CI: (1.09–2.18);
p = 0.013) [17].
This study aims to assess the prognostic value of PLR in the severity and mortality of
patients infected with SARS-CoV-2 on admission to the emergency department (ED).

2. Materials and Methods

2.1. Study Population and Settings
We conducted a multicentric retrospective study in six EDs in the North-East region of
France. We led our study in two university hospitals (CHRU of Strasbourg in Strasbourg
and CHU of Reims in Reims, France) and four general hospitals (Colmar Hospital in
Colmar, Nord Franche-Comté Hospital in Belfort, Metz-Thionville Hospital in Metz and
Thionville and Haguenau Hospital in Haguenau, France). These hospital centers, along
with the entire Greater-East region of France, were one of the outbreak’s epicenters in
Europe during the first wave.
We included all adult patients hospitalized for COVID-19 after being admitted to the
ED between 1 March and 30 April 2020. All patients included in our study had a laboratory-
confirmed diagnosis of COVID-19 by RT-PCR on nasopharyngeal swab (on admission).
Exclusion criteria were patients who had a non-confirmed diagnosis, or those who have
received outpatient care, and those who had received palliative therapy or limitation of
therapeutic effort upon admission to the ED. The exclusion criteria were also patients
J. Clin. Med. 2022, 11, 4903 3 of 11

with a medical background or treatment modifying their blood count and, therefore, their
circulating lymphocyte or platelet counts (e.g., chemotherapy, immunosuppressive therapy,
long- and short-term corticosteroid therapies, pre-admission antibiotic therapy, active
cancer or hematological malignancies).

2.2. Data Collection

We retrospectively collected epidemiological, clinical and biochemical data from
the patients’ electronic medical records, and standardized results in a report file. We
recorded symptom onset data along with the patient’s current treatment and medical
background (including cardiovascular disease, diabetes, pre-existing renal failure, cancer
and hematological diseases). The primary endpoint was the prognostic value of PLR on
COVID-19 mortality upon ED admission. The secondary endpoint was its prognostic value
on COVID-19 severity upon ED admission. The severity of COVID-19 disease was defined
by patient admission into the ICU (intensive care unit), which, during the first wave of
the pandemic, was mainly associated with invasive mechanical ventilation indication.
Moderate disease was defined by patient admission to conventional hospitalization units
and, in fine, the requirement for simple or high-flow oxygen therapy. Ambulatory patients
were excluded. Obesity was defined by a body mass index superior to 30 kg/m2 . Standard
biological parameters were collected, such as levels of creatinine, CRP, platelet count, total
leukocytes and lymphocytes. Lastly, we calculated PLR values at ED admission, the ratio
of platelets to circulating lymphocytes. All collected data are summarized in the Tables and
Results sections.

2.3. Ethics
This study was approved by the local ethics committee of the University of Strasbourg
in France (reference CE: 2020–39), which, in accordance with the French legislation, waived
the need for informed consent of patients whose data were entirely retrospectively studied.

2.4. Statistical Analysis

The statistical analyses included a descriptive and an analytical section. We performed
the descriptive analysis of the qualitative variables by providing the frequency of each value.
We compared them in a univariate analysis by using chi-squared or Fisher’s tests in case
the expected values in any of the cells of a contingency table was below 5. We performed
the descriptive analysis of the continuous variables by providing median, and first and
third quartiles of each value. We compared them in an univariate analysis by using a
non-parametric Mann–Whitney test or, in case the variables followed a normal distribution
by using a Welsh’s test. Using statistically significant results obtained from univariate
analyses and clinically relevant variables, a multivariate logistic model was performed
to assess disease severity, then the in-hospital mortality. A backward stepwise method
was performed. Receiver operating characteristic (ROC) curves were constructed and the
best cut-off value of PLR discriminating severe from moderate patients, and patients who
died during their stay from those who survived were determined by using the Yunden’s
index. p-values < 0.05 were considered significant and the confidence interval (CI) was
95%. Analyses were performed with the R software in version 4.0.2 (R Core Team 2020.
R: A language and environment for statistical computing. R Foundation for Statistical
Computing, Vienna, Austria), as well as with all the software packages required to conduct
the analysis.

3. Results
3.1. Characteristics of the Study Population
During the study period, a total of 49,326 patients were admitted to the EDs of all
six hospitals. Of these patients, 4470 had a laboratory-confirmed SARS-CoV-2 infection,
1685 received ambulatory care, 1750 met the exclusion criteria and, in fine, 1035 patients
were included in our study (flowchart: Figure 1).
 3. Results
3.1. Characteristics of the Study Population
During the study period, a total of 49,326 patients were admitted to the EDs of all six
hospitals. Of these patients, 4470 had a laboratory-confirmed SARS-CoV-2 infection, 1685
J. Clin. Med. 2022, 11, 4903 received ambulatory care, 1750 met the exclusion criteria and, in fine, 1035 patients 4were
of 11
included in our study (flowchart: Figure 1).

Figure 1.
Figure 1. Flowchart
Flowchart of
of the
the study.
study. Legend:
Legend: ED:
ED: emergency
emergency department,
department, ICU:
ICU: intensive
intensive care unit,
care unit,
COVID-19: coronavirus disease.
COVID-19: coronavirus disease.

Our cohort had a median age of 69 (58.0–79.0) years and was predominately male
(58.8%). Regarding the comorbidities, 1/3 of our study population was obese (36.9%) and
had coronary heart disease (34.5%), over 1/2 of the patients (56.7%) had hypertension,
over 1/4 of them (26.6%) had a history of diabetes and 23.2% of them presented chronic
kidney disease. Only 5.4% had chronic obstructive lung disease. At admission, even
if the median lymphocyte count was significantly lower in the group presenting severe
COVID-19 compared to that with moderate COVID-19 (0.780, 95% CI: (0.590–1.122)) vs.
0.900, 95% CI: (0.640–1.220), p = 0.003)), we did not find a significant difference between
these two groups for platelet count and PLR. The main clinical and biochemical patient
characteristics are summarized in Table 1.

Table 1. General characteristics, comorbidities and laboratory findings of study population with
moderate and severe COVID-19.

All Patients Moderate COVID-19 Severe COVID-19

p
(n = 1035) (n = 789) (n = 246)
Characteristics
Age (years) 69.0 (58.0–79.0) 70.0 (58.0–81.0) 66.0 (57.3–72.0) <0.001 *
Gender male 609 (58.8) 433 (54.9) 176 (71.5) <0.001 *
Current smoker 46 (4.4) 34 (4.3) 12 (4.9) 0.706
Comorbidities
Hypertension 587 (56.7) 453 (57.4) 134 (54.5) 0.416
Diabetes 275 (26.6) 202 (25.6) 73 (29.7) 0.207
BMI (kg/m2 ) (30, 40) 253 (33.2) 172 (31.2) 81 (38.6) 0.056
Obesity
BMI (kg/m2 ) ≥ 40 28 (3.7) 21 (3.8) 7 (3.3) 0.966
J. Clin. Med. 2022, 11, 4903 5 of 11

Table 1. Cont.

All Patients Moderate COVID-19 Severe COVID-19

p
(n = 1035) (n = 789) (n = 246)
COPD 56 (5.4) 44 (5.6) 12 (4.9) 0.672
Chronic kidney disease 237 (23.2) 199 (25.5) 38 (15.8) 0.002 *
Coronary heart disease 357 (34.5) 291 (36.9) 66 (26.8) 0.004 *
Laboratory findings
Lymphocyte count, ×109 per L 0.870 (0.630–1.200) 0.900 (0.640–1.220) 0.780. (0.590–1.122) 0.003 *
Platelet count, ×109 per L 194.5 (152.0–248.0) 196.0 (154.0–247.0) 192.0 (144.0–253.0) 0.518
PLR 223.3 (156.5–329.0) 219.9 (154.7–320.5) 238.5 (162.4–357.7) 0.061
Outcomes
Mortality 139 (13.6) 82 (10.4) 57 (24.1) <0.001 *
Length of hospital stay (days) 10.0 (7.0–17.3) 8.0 (6.0–12.0) 24.0 (17.0–38.0) <0.001 *
Data are all expressed in median (Q1–Q3) or n (%) where n is the total number of patients with available
data. * p < 0.05. Legend: BMI: body mass index, COPD: chronic obstructive pulmonary disease, PLR: platelet-to-
lymphocyte ratio.

We performed the analysis to observe if there was any interest in carrying on our
study and if there was a difference in PLR between living and dead patients. The median
PLR was significantly higher in the group of patients who died compared to those who
survived (242.3, 95% CI: (164.6–385.7) vs. 221.4, 95% CI: (154.7–319.4), p = 0.043)); Table 2.

Table 2. General characteristics, comorbidities and laboratory findings of the study population,
surviving and dying from COVID-19.

All Patients Survivor Non Survivor

p
(n = 1035) (n = 884) (n = 139)
Characteristics
Age (years) 69.0 (58.0–79.0) 67.0 (56.0–77.0) 78.0 (70.0–86.0) <0.001 *
Gender male 609 (58.8) 517 (58.5) 85 (61.2) 0.553
Current smoker 46 (4.4) 42 (4.8) 4 (2.9) 0.322
Comorbidities
Hypertension 587 (56.7) 477 (54.0) 103 (74.1) <0.001 *
Diabetes 275 (26.6) 227 (25.7) 42 (30.2) 0.259
BMI (30, 40) 253 (33.2) 222 (33.1) 30 (34.9) 0.889
Obesity
BMI ≥ 40 28 (3.7) 27 (4.0) 1 (1.2) 0.191
COPD 56 (5.4) 38 (4.3) 18 (13.0) <0.001 *
Chronic kidney disease 237 (23.2) 189 (21.6) 47 (35.3) <0.001 *
Coronary heart disease 357 (34.5) 283 (32.1) 72 (51.8) <0.001 *
Laboratory findings
Lymphocyte count, ×109 per L 0.870 (0.630–1.200) 0.890 (0.650–1.220) 0.720 (0.500–1.000) <0.001 *
Platelet count, ×109 per L 194.5 (152.0–248.0) 196.0 (153.3–248.0) 181.0 (138.3–246.0) 0.031 *
PLR 223.3 (156.5–329.0) 221.4 (154.7–319.4) 242.3 (164.6–385.7) 0.043 *
J. Clin. Med. 2022, 11, 4903 6 of 11

Table 2. Cont.

All Patients Survivor Non Survivor

p
(n = 1035) (n = 884) (n = 139)
C-reactive protein, mg/L 81.0 (39.0–142.0) 78.5 (37.0–139.0) 100.0 (56.0–158.0) 0.008 *
Creatinine, µmol/L 78.0 (64.0–98.0) 76.0 [62.0–94.0) 96.0 (77.5–144.5) <0.001 *
Lactate, mmol/l 1.2 (0.9–1.6) 1.2 (0.9–1.5) 1.4 (1.1–1.9) <0.001 *
Data are all expressed in median (Q1–Q3) or n (%) where n is the total number of patients with available
data. * p < 0.05. Legend: BMI: body mass index, COPD: chronic obstructive pulmonary disease, PLR: platelet-to-
lymphocyte ratio.

3.2. Biochemical Factors Associated and Factors Predicting COVID-19 Severity

Of the entire study population, 789 patients (76.2%) had moderate disease, whereas
246 (23.8%) had severe disease requiring ICU management. When comparing these two
subgroups, age (70 vs. 66 years, p < 0.001) and gender (p < 0.001) differed significantly.
Patients admitted to the ICU had fewer cardiovascular (p = 0.004) and renal (p = 0.002)
comorbidities. In the multivariate analysis, adjusted for age, gender, complications, and
laboratory findings following a backward stepwise selection, none of the parameters
studied were associated with the severity of infection. The results are summarized in
Table 3.

Table 3. Univariate and multivariate analyses for risk factor for COVID-19 severity.

Moderate Univariate Analysis Multivariate Analysis

All Patients Severe COVID-19
COVID-19 OR (95% CI) p OR (95% CI) p
Lymphocyte
0.870 (0.630–1.200) 0.900 (0.640–1.220) 0.780. (0.590–1.122) 0.827 (0.616–1.110) 0.206 0.937 (0.647–1.357) 0.729
count, 109 per L
Platelet count,
194.5 (152.0–248.0) 196.0 (154.0–247.0) 192.0 (144.0–253.0) 1.000 (0.998–1.002) 0.979 1.000 (0.998–1.003) 0.765
109 per L
PLR 223.3 (156.5–329.0) 219.9 (154.7–320.5) 238.5 (162.4–357.7) 1.000 (1.000–1.001) 0.107 1.001 (1.000–1.001) 0.107
Data are all expressed in median (Q1–Q3) or n (%) where n is the total number of patients with available data.
Legend: OR: odds ratio, CI: confidence interval, PLR: platelet-to-lymphocyte ratio.

We made a receiver operating characteristics (ROC) curve to predict the risk of disease
severity. Regarding the PLR during admission, the area under the curve (AUC) was 0.54
(95% CI: (0.497–0.582)). The best cut-off for predicting the risk of infection severity was
369.7; it yielded a sensitivity of 23.8% (95% CI: (18.6–29.7)) and specificity of 83.8% (95% CI:
(81.0–86.3)). In the multivariate analysis, if PLR was greater than 369.7, the OR was valued
at 1.884 (95% CI: (1.130–140), p = 0.015) (Figure 2).

3.3. Biochemical Factors Associated and Factors Predicting COVID-19 Mortality

Mortality analysis included 1023 patients, as 12 patients (1.2%) were lost to follow-up.
A total of 139 patients died during their hospital stay, representing 13.6% of our cohort,
while 884 (86.4%) survived. Non-surviving patients were significantly older (78 versus
67 years, p < 0.001). They were more likely to have a medical history of hypertension
(p < 0.001), chronic obstructive lung disease (p < 0.001), chronic kidney disease (p < 0.001)
and coronary heart disease (p < 0.001). Biochemically, higher levels of creatinine (96.0, 95%
CI: (77.5–144.5) vs. 76.0, 95% CI: (62.0–94.0), p < 0.001), CRP (100.0, 95% CI: (56.0–158.0)
vs. 78.5, 95% CI: (37.0–139.0), p = 0.008) and lactate (1.4, 95% CI: (1.1–1.9) vs. 1.2, 95%
CI: (0.9–1.5), p < 0.001) were observed in the non-surviving subgroup. Regarding the cell
blood count, lymphopenia was more profound (0.720, 95% CI: (0.500–1.000) vs. 0.890,
95% CI: (0.650–1.220), p < 0.001), and platelet count was significantly lower (181.0, 95% CI:
(138.3–246.0) vs. 196.0, 95% CI: (153.3–248.0), p = 0.031) in the non-surviving subgroup.
Upon admission to the ED, the lymphocyte count was significantly lower and PLR values
were significantly higher, and both were associated with mortality in univariate analysis
J. Clin. Med. 2022, 11, 4903 7 of 11

(respectively, p = 0.004 and p = 0.042). However, the only biochemical parameter signifi-
J. Clin. Med. 2022, 11, 4903 cantly associated with mortality in multivariate analysis was the platelet count (OR:8 0.996,
of 13
95% CI: (0.996–1.000), p = 0.027). These results are summarized in Table 4.

To Predict Multivariate Analysis

COVID-19 AUC Cut-Off Sensitivity Specificity with Cut-Off
Severity OR (95% CI) p

PLR 54.0 (49.7–58.2) 369.7 0.24 (0.19–0.30) 0.84 (0.81–0.86) 1.884 (1.130–3.140) 0.015 *
Legend—AUC: area under curve; PLR: platelet-to-lymphocyte ratio; OR: odds ratio; CI:
confidence interval, * p < 0.005.

Figure2.2.Receiver
Figure Receiveroperating
operatingcharacteristics (ROC)
characteristics curve
(ROC) for PLR
curve as a predictive
for PLR factor factor
as a predictive of severe
of
COVID-19.
severe COVID-19.

3.3. Biochemical
Table 4. UnivariateFactors Associated analyses
and multivariate and Factors Predicting
for risk factors COVID-19 Mortality
for COVID-19 mortality.
Mortality analysis included 1023 patients, as 12 patients (1.2%) were lost to follow-
Univariate Analysis Multivariate Analysis
All Patients up. A total Survivor
of 139 patients Nondied
Survivor
during their hospital stay, representing 13.6% of our co-
OR (95% CI) p OR (95% CI) p
hort, while 884 (86.4%) survived. Non-surviving patients were significantly older (78 ver-
Lymphocyte
0.870 (0.630–1.200) sus 670.890 (0.650–1.220)
years, p < 0.001).0.720
They (0.500–1.000)
were more0.524 (0.336–0.815)
likely 0.004 *
to have a medical 0.756 (0.393–1.456)
history 0.403
of hypertension
count, 109 per L
Platelet count, (p < 0.001), chronic obstructive lung disease (p < 0.001), chronic kidney disease (p < 0.001)
194.5 (152.0–248.0) 196.0 (153.3–248.0) 181.0 (138.3–246.0) 0.998 (0.995–1.000) 0.078 0.996 (0.992–1.000) 0.027 *
×109 per L and coronary heart disease (p < 0.001). Biochemically, higher levels of creatinine (96.0, 95%
PLR 223.3 (156.5–329.0) CI: (77.5–144.5)
221.4 (154.7–319.4)
vs. 76.0,242.3
95% (164.6–385.7) 1.001p(1.000–1.001)
CI: (62.0–94.0), < 0.001), CRP 0.042 *
(100.0, 1.000
95%(0.999–1.002)
CI: (56.0–158.0) 0.444
vs.
Data are95%
78.5, all expressed in median p
CI: (37.0–139.0), (Q1–Q3)
= 0.008) n (%)lactate
or and where n(1.4,
is the95%
totalCI:
number of patients
(1.1–1.9) with
vs. 1.2, available
95% data.
CI: (0.9–
* p < 0.05. Legend: OR: odds ratio, CI: confidence interval, PLR: platelet-to-lymphocyte ratio.
1.5), p < 0.001) were observed in the non-surviving subgroup. Regarding the cell blood
count, lymphopenia was more profound (0.720, 95% CI: (0.500–1.000) vs. 0.890, 95% CI:
We createdpreceiver
(0.650–1.220), < 0.001),operating
and platelet characteristics (ROC) curveslower
count was significantly to predict
(181.0,the riskCI:
95% of (138.3–
disease
mortality.
246.0) vs.Regarding
196.0, 95%the CI:PLR at admission,
(153.3–248.0), p =the areainunder
0.031) the curve (AUC)
the non-surviving was 0.55Upon
subgroup. (95%
CI: (0.498–0.611)). The best cut-off for predicting the risk of
admission to the ED, the lymphocyte count was significantly lower and PLR values wereinfection severity was 356.6:
itsignificantly
yielded a sensibility
higher, andof 34.3%
both were(95%associated
CI: (26.3–43.0)) and a specificity
with mortality in univariateof 82.4% (95%(re-
analysis CI:
(79.7–84.9)). In the multivariate analysis, if the PLR was greater
spectively, p = 0.004 and p = 0.042). However, the only biochemical parameter significantly than 356.6, the OR was
valued at 3.793
associated with(95% CI: (1.946–7.394),
mortality in multivariate p < 0.001)
analysis (Figure
was the3). platelet count (OR: 0.996, 95%
CI: (0.996–1.000), p = 0.027). These results are summarized in Table 4.
 We created receiver operating characteristics (ROC) curves to predict the risk of dis-
ease mortality. Regarding the PLR at admission, the area under the curve (AUC) was 0.55
(95% CI: (0.498–0.611)). The best cut-off for predicting the risk of infection severity was
J. Clin. Med. 2022, 11, 4903
356.6: it yielded a sensibility of 34.3% (95% CI: (26.3–43.0)) and a specificity of 82.4% (95%
8 of 11
CI: (79.7–84.9)). In the multivariate analysis, if the PLR was greater than 356.6, the OR was
valued at 3.793 (95% CI: (1.946–7.394), p < 0.001) (Figure 3).

To Predict Multivariate Analysis with Cut-Off

COVID-19 AUC Cut-Off Sensitivity Specificity
Severity OR (95% CI) p

PLR 55.4 (49.8–61.1) 356.6 0.3433 (0.26–0.43) 0.8243 (0.80–0.85) 3.793 (1.946–7.394) <0.001 *

Legend—AUC: area under curve; PLR: platelet-to-lymphocyte ratio; OR: odds ratio; CI:
confidence interval, * p < 0.005.
3. Receiver
Figure 3.
Figure Receiveroperating
operatingcharacteristics
characteristics (ROC)
(ROC) curve
curve for
for PLR
PLR as
asa apredictive
predictivefactor
factorofof
COVID-19 mortality.
COVID-19 mortality.

4. Discussion
The aim of our study was to investigate the prognostic value of the PLR in a cohort of
SARS-CoV-2-infected patients from their admission to the ED. We selected our patients as
carefully as possible to limit confounding factors that could have altered the CBC. Our study
did not show significant results to recognize PLR as an efficient marker to discriminate
among hospitalized patients, those likely to develop a severe form and requiring ICU
management. Furthermore, in the univariate analysis, the PLR was significantly higher
in patients who died compared to those who survived, although this association was not
observed in the multivariate analysis.
The results of the studies investigating PLR in COVID-19 remain heterogeneous. Some
studies seem to indicate that the PLR would be an efficient predictive marker of the severity
and mortality of COVID-19, which slightly differs according to our results. In addition to
the limited number of subjects, which may be responsible for the lack of power presented in
these studies and explain the difference of results, it is important to notice that the inclusion
criteria were also different in other studies. Indeed, some authors used a control group of
COVID-19-negative patients as a comparison [18,19]. Others, including a majority of the
studies from China, had inclusion criteria that referred to the criteria met from the General
Office of the National Health Commission of China [20] and classified patients into two
subgroups: “mild” and “common", which, in our study, met the exclusion criteria [21–23].
Finally, the PLR was higher and appeared to be a valuable marker to discriminate non-
infected patients from infected patients, such as patients with pauci-symptomatic forms of
the disease from patients meeting the hospitalization criteria. However, the PLR did not
make it possible to discriminate between moderate and severe forms requiring intensive
care management. Wang R et al., in a study with a patient selection similar to ours, were
one of the few researchers to obtain results for the PLR that were similar to our study. The
J. Clin. Med. 2022, 11, 4903 9 of 11

PLR was significatively higher in the non-surviving group compared to the surviving group
(237.32, CI 95%: (160.15–400.96) vs. 173.29, CI 95%: (132.35–252.22), p < 0.001), and in the
univariate analysis there was an association between a high PLR and mortality (OR: 1.004,
CI 95%: (1.002–1.05), p < 0.001), which they did not observe in the multivariate analysis
(OR: 1.003, CI 95%: (0.999–1.007), p = 0.154) [24].
Another particularity of our study was its exclusion criteria. Indeed, we decided to
exclude patients with comorbidities or treatments that could alter the CBC and modify
the PLR. However, there were some situations where the PLR was often increased, with
a negative correlation with the underlying disease, and which had a poor prognosis in
the case of SARS-CoV-2 infection. Solid cancers, for example, have been described as a
risk factor for mortality in COVID-19 [10,25] cases and a high PLR was associated with
advanced disease and mortality [14,26]. Similarly, we excluded patients who received
corticosteroid therapy, which tends to increase the platelet count and to a lesser extent the
lymphocyte count [27], and thus increase the PLR. However, corticosteroid therapy is now
an integral part of the treatment used for COVID-19 [28].
From a pathophysiological point of view, several causes are put forward to explain
lymphopenia and thrombocytopenia. Lymphopenia could be linked to a cell-exhaustion
phenomenon, direct viral lymphocyte infection, bone marrow infection, apoptosis of lym-
phocytes led by inflammation and inhibition of lymphocytes by metabolic dysregula-
tion [29,30]. Thrombocytopenia is essentially linked to platelet consumption, but also to
lower levels of production due to bone marrow damage and to an immunological phe-
nomena leading to platelet destruction [31]. However, since those do not appear from
the same mechanism, the onset speed of these two biological anomalies differs. Studies
have analyzed the evolution of these biological abnormalities during infection. Indeed,
there is high variability over time concerning the number of platelets and lymphocytes,
particularly during the early onset of the disease [32–35]. This also raises the question
of PLR’s variability and its interpretation. According to our results, we can also ask our-
selves about the utility of this ratio and, more broadly, the contribution of biological ratios
that have emerged in recent years, such as the neutrophil-to-lymphocyte ratio (NLR), the
lymphocyte-to-monocyte ratio (LMR) or the systemic immune-inflammation index (SII).
In their study, Pierrakos et al. reviewed the emergence of numerous new inflammatory
markers and pointed out that the majority were evaluated by less than five studies and
even more were evaluated by studies with small numbers, or that these studies answered
a specific clinical question rather than addressing their general diagnostic or prognostic
properties [36]. A state of play seems to be necessary for these new ratios as biomarkers
of inflammation.

Limitations
Firstly, this was a retrospective study, which means that although we added a number
of exclusion criteria (including comorbidities that alter blood cell count and therefore
the number of circulating lymphocytes and platelets), the data were subject to further
confounding factors.
With the aim of keeping away the risk of confounding factors, we excluded patients
who were potentially more severe and more frequently hospitalized. Similarly, we did not
take into account patients who received ambulatory care. In fact, we probably minimized
the effects studied, the same way that we cannot, with our results, discriminate between
patients with “mild and common”, “moderate” and “severe” forms.
Finally, our patients were exclusively included in the first wave, which had several
implications. Firstly, many patients received non-recommended treatments before their
admission to the ED, such as antibiotics—which could modify the CBC and which we
excluded—or antimalarials. Secondly, patient management has evolved considerably since
the first wave, notably with the widespread use of anticoagulants to prevent thromboem-
bolic events and corticoids, which can alter the CBC. Finally, the disease itself has evolved
J. Clin. Med. 2022, 11, 4903 10 of 11

with the emergence of new variants, the most recent of which appear to be more contagious
but less virulent.

5. Conclusions
Although the PLR is an interesting marker of inflammation, it does not appear to be a
good prognostic marker to discriminate the most severe patients infected with SARS-CoV2
admitted to an ED. A high PLR could, however, be associated with excess mortality. Further
studies would be needed to confirm this.

Author Contributions: Conceptualization, P.L.B., C.-E.L., L.A.V.; methodology, P.S., L.A.V., F.L.;
validation, L.A.V. formal analysis, P.S., L.A.V., F.L.; investigation, P.L.B., L.C., A.R., C.-E.L., L.A.V.;
writing—original draft preparation, P.S., L.A.V.; writing—review and editing, All authors; visual-
ization, L.A.V.; supervision, L.A.V. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: This study was approved by the institution’s (Strasbourg
University Hospital, France) Ethics Review Board (reference: CE-2020–39).
Informed Consent Statement: Patient consent was waived, in accordance with the French legislation,
who waived the need for informed consent of patients whose data were entirely retrospectively studied.
Data Availability Statement: All data analyzed as part of the study are included.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A Novel Coronavirus from
Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733. [CrossRef] [PubMed]
2. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory
syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020, 5, 536–544. [CrossRef]
[PubMed]
3. Tableau de Bord COVID-19. Tableau de Bord COVID-19. Available online: https://dashboard.covid19.data.gouv.fr/vue-d-
ensemble?location=FRA (accessed on 29 July 2022).
4. Ritchie, H.; Mathieu, E.; Rodés-Guirao, L.; Appel, C.; Giattino, C.; Ortiz-Ospina, E.; Hasell, J.; Macdonald, B.; Dattani, S.;
Roser, M.; et al. Our World Data 5 Mars 2020. Available online: https://ourworldindata.org/covid-deaths (accessed on 29 July
2022).
5. Hu, B.; Huang, S.; Yin, L. The cytokine storm and COVID-19. J. Med. Virol. 2021, 93, 250–256. [CrossRef]
6. Zhang, Y.; Zeng, X.; Jiao, Y.; Li, Z.; Liu, Q.; Ye, J.; Yang, M. Mechanisms involved in the development of thrombocytopenia in
patients with COVID-19. Thromb Res. 2020, 193, 110–115. [CrossRef] [PubMed]
7. Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Ou, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.; Hui, D.S.C.; et al. Clinical Characteristics of
Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720. [CrossRef]
8. Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of
150 patients from Wuhan, China. Intensive Care Med. 2020, 46, 846–848. [CrossRef]
9. Qin, C.; Zhou, L.; Hu, Z.; Zhang, S.; Yang, S.; Tao, Y.; Xie, C.; Ma, K.; Shang, K.; Wang, W.; et al. Dysregulation of Immune
Response in Patients with Coronavirus 2019 (COVID-19) in Wuhan, China. Clin. Infect. Dis. 2020, 71, 762–768. [CrossRef]
10. Wu, C.; Chen, X.; Cai, Y.; Xia, J.; Zhou, X.; Xu, S.; Huang, H.; Zhang, L.; Zhou, X.; Du, C.; et al. 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. [CrossRef]
11. Henry, B.M.; de Oliveira, M.H.S.; Benoit, S.; Plebani, M.; Lippi, G. Hematologic, biochemical and immune biomarker abnormalities
associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): A meta-analysis. Clin. Chem. Lab. Med.
2020, 58, 1021–1028. [CrossRef]
12. Wang, F.; Nie, J.; Wang, H.; Zhao, Q.; Xiong, Y.; Deng, L.; Song, S.; Ma, Z.; Mo, P.; Zhang, Y. Characteristics of Peripheral
Lymphocyte Subset Alteration in COVID-19 Pneumonia. J. Infect. Dis. 2020, 221, 1762–1769. [CrossRef]
13. Gong, P.; Liu, Y.; Gong, Y.; Chen, G.; Zhang, X.; Wang, S.; Zhou, F.; Duan, R.; Chen, W.; Huang, T.; et al. The association of
neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and lymphocyte to monocyte ratio with post-thrombolysis early
neurological outcomes in patients with acute ischemic stroke. J. Neuroinflamm. 2021, 18, 51. [CrossRef]
14. Templeton, A.J.; Ace, O.; McNamara, M.G.; Al-Mubarak, M.; Vera-Badillo, F.E.; Hermanns, T.; Šeruga, B.; Ocaña, A.; Tannock, I.F.;
Amir, E. Prognostic Role of Platelet to Lymphocyte Ratio in Solid Tumors: A Systematic Review and Meta-Analysis. Cancer
Epidemiol. Biomark. Prev. 2014, 23, 1204–1212. [CrossRef]
J. Clin. Med. 2022, 11, 4903 11 of 11

15. Gasparyan, A.Y.; Ayvazyan, L.; Mukanova, U.; Yessirkepov, M.; Kitas, G.D. The Platelet-to-Lymphocyte Ratio as an In-flammatory
Marker in Rheumatic Diseases. Ann. Lab. Med. 2019, 39, 345–357. [CrossRef]
16. Akboga, M.K.; Canpolat, U.; Yayla, C.; Ozcan, F.; Ozeke, O.; Topaloglu, S.; Aras, D. Association of Platelet to Lymphocyte Ratio
With Inflammation and Severity of Coronary Atherosclerosis in Patients With Stable Coronary Artery Disease. Angiology. 2016,
67, 89–95. [CrossRef]
17. Meng, Z.; Yang, J.; Wu, J.; Zheng, X.; Zhao, Y.; He, Y. Association between the platelet-lymphocyte ratio and short-term mortality
in patients with non-ST -segment elevation myocardial infarction. Clin. Cardiol. 2021, 44, 994–1001. [CrossRef]
18. Sun, S.; Cai, X.; Wang, H.; He, G.; Lin, Y.; Lu, B.; Chen, C.; Pan, Y.; Hu, X. Abnormalities of peripheral blood system in patients
with COVID-19 in Wenzhou, China. Clin. Chim. Acta 2020, 507, 174–180. [CrossRef]
19. Seyit, M.; Avci, E.; Nar, R.; Senol, H.; Yilmaz, A.; Ozen, M.; Oskay, A.; Aybek, H. Neutrophil to lymphocyte ratio, lymphocyte
to monocyte ratio and platelet to lymphocyte ratio to predict the severity of COVID-19. Am. J. Emerg. Med. 2021, 40, 110–114.
[CrossRef]
20. Wei, P.F. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). Chin. Med. J. (Engl.) 2020, 133,
1087–1095.
21. Wang, H.; Xing, Y.; Yao, X.; Li, Y.; Huang, J.; Tang, J.; Zhu, S.; Zhang, Y.; Xiao, J. Retrospective Study of Clinical Features of
COVID-19 in Inpatients and Their Association with Disease Severity. Med. Sci. Monit. 2020, 26, e927674-1–e927674-9. Available
online: https://www.medscimonit.com/abstract/index/idArt/927674 (accessed on 29 July 2022). [CrossRef]
22. Wang, W.; Zhao, Z.; Liu, X.; Liu, G.; Xie, D.; Xu, Z.; Zhao, J.; Zhang, J. Clinical features and potential risk factors for discerning
the critical cases and predicting the outcome of patients with COVID-19. J. Clin. Lab. Anal. 2020, 34, e23547. Available online:
https://onlinelibrary.wiley.com/doi/10.1002/jcla.23547 (accessed on 29 July 2022). [CrossRef]
23. Wang, X.; Li, X.; Shang, Y.; Wang, J.; Zhang, X.; Su, D.; Zhao, S.; Wang, Q.; Liu, L.; Li, Y.; et al. Ratios of neutrophil-to-lymphocyte
and platelet-to-lymphocyte predict all-cause mortality in inpatients with coronavirus disease 2019 (COVID-19): A retrospective
cohort study in a single medical centre. Epidemiol. Infect. 2020, 148, e211. [CrossRef] [PubMed]
24. Wang, R.; He, M.; Yin, W.; Liao, X.; Wang, B.; Jin, X.; Ma, Y.; Yue, J.; Bai, L.; Liu, D.; et al. The Prognostic Nutritional Index
is associated with mortality of COVID-19 patients in Wuhan, China. J. Clin. Lab. Anal. 2020, 34, e23566. Available online:
https://onlinelibrary.wiley.com/doi/10.1002/jcla.23566 (accessed on 29 July 2022). [CrossRef] [PubMed]
25. Dessie, Z.G.; Zewotir, T. Mortality-related risk factors of COVID-19: A systematic review and meta-analysis of 42 studies and
423,117 patients. BMC Infect. Dis. 2021, 21, 855. [CrossRef]
26. You, J.; Zhu, G.-Q.; Xie, L.; Liu, W.-Y.; Shi, L.; Wang, O.-C.; Huang, Z.-H.; Braddock, M.; Guo, G.-L.; Zheng, M.-H. Preoperative
platelet to lymphocyte ratio is a valuable prognostic biomarker in patients with colorectal cancer. Oncotarget 2016, 7, 25516–25527.
[CrossRef]
27. Info Cancer, La Corticothérapie. Available online: http://www.arcagy.org/infocancer/traitement-du-cancer/traitements-
systemiques/hormonotherapie/la-corticotherapie.html/ (accessed on 29 July 2022).
28. Covid-19: Conditions D’utilisation de la Dexaméthasone ou D’autres Corticoïdes de Substitution chez les Patients Hospitalisés. 2020.
34p. Available online: https://www.hcsp.fr/Explore.cgi/Telecharger?NomFichier=hcspa20201019_utideladexetdautcordanlecov.
pdf (accessed on 29 July 2022).
29. Fathi, N.; Rezaei, N. Lymphopenia in COVID-19: Therapeutic opportunities. Cell Biol. Int. 2020, 44, 1792–1797. [CrossRef]
30. Tan, L.; Wang, Q.; Zhang, D.; Ding, J.; Huang, Q.; Tang, Y.Q.; Wang, Q.; Miao, H. Lymphopenia predicts disease severity of
COVID-19: A descriptive and predictive study. Signal Transduct. Target. Ther. 2020, 5, 33. [CrossRef]
31. Barale, C.; Melchionda, E.; Morotti, A.; Russo, I. Prothrombotic Phenotype in COVID-19: Focus on Platelets. Int. J. Mol. Sci. 2021,
22, 13638. [CrossRef]
32. Zhang, J.; Cao, Y.; Tan, G.; Dong, X.; Wang, B.; Lin, J.; Yan, Y.Q.; Liu, G.H.; Akdis, M.; Akdis, C.A.; et al. Clinical, radiological,
and laboratory characteristics and risk factors for severity and mortality of 289 hospitalized COVID-19 patients. Allergy 2021, 76,
533–550. [CrossRef]
33. Liu, J.; Li, S.; Liu, J.; Liang, B.; Wang, X.; Wang, H.; Li, W.; Tong, Q.; Yi, J.; Zhao, L.; et al. Longitudinal characteristics of
lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020, 55,
102763. [CrossRef]
34. Li, Q.; Cao, Y.; Chen, L.; Wu, D.; Yu, J.; Wang, H.; He, W.; Dong, F.; Chen, W.; Chen, W.; et al. Hematological features of persons
with COVID-19. Leukemia 2020, 34, 2163–2172. [CrossRef]
35. Yang, X.; Yang, Q.; Wang, Y.; Wu, Y.; Xu, J.; Yu, Y.; Shang, Y. Thrombocytopenia and its association with mortality in patients with
COVID-19. J. Thromb. Haemost. 2020, 18, 1469–1472. [CrossRef]
36. Pierrakos, C.; Velissaris, D.; Bisdorff, M.; Marshall, J.C.; Vincent, J.L. Biomarkers of sepsis: Time for a reappraisal. Crit. Care 2020,
24, 287. [CrossRef]