Comparison of the N-Terminal pro-Brain Natriuretic Peptide Levels,
Neutrophil-to-Lymphocyte, Lymphocyte-to-Monocyte and
Platelet-to-Lymphocyte Ratios Between the Patients with COVID-19 and
Healthy Subjects; Are the Patients with COVID-19 Under the Risk of
Cardiovascular Events?
Abstract
Backround: The ongoing pandemic of Coronavirus Disease 2019 (COVID-19)
infection has declared as a global emergency. Although the most people
had mild illness due to the infection, some patients were seriously
affected associated with complications especially including respiratory
and cardiovascular systems. In despite of the respiratory system
involvement is in the foreground, cardiovascular complications result in
worse clinical outcomes. The purpose of this study is to compare the
levels of the N-terminal pro-brain natriuretic peptide,
neutrophil-to-lymphocyte, lymphocyte-to-monocyte and
platelet-to-lymphocyte ratios -which are accepted as a marker of
negative outcomes in cardiovascular diseases- of the patients with
COVID-19 and healthy subjects and reveal the increased risk of
cardiovascular disease in patients with COVID-19.
Methods: This prospective study was designed in a single center and
included 33 patients with COVID-19 (Group 1) and 33 healthy subjects
consisted of health care professionals (Group 2). N-terminal pro-brain
natriuretic peptide levels, neutrophil-to-lymphocyte,
lymphocyte-to-monocyte and platelet-to-lymphocyte ratios were compared
between the groups.
Results: N-terminal pro-brain natriuretic peptide levels,
neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios were
statistically significantly higher in the patients with COVID-19
(p<0,0001) and lymphocyte-to-monocyte ratio was statistically
significantly lower in the same group (p<0,0001).
Conclusion: Cardiovascular manifestations result in worse outcomes in
patients with COVID-19 although the disease primarily affects the
respiratory system. Early detection of this clinical situation and
taking precautions have vital importance in the progress of the disease.
NT-proBNP levels, neutrophil-to-lymphocyte, lymphocyte-to-monocyte and
platelet-to-lymphocyte ratios are inexpensive, easy, fast and
reproducible parameters that can be used in determination of probabl
cardiovascular events that may develop during COVID-19 and enables early
optimal treatment strategies for patients.
Keywords: Cardiovascular disease, COVID-19, NT-proBNP,
lymphocyte-to-monocyte ratio, neutrophil-to-lymphocyte ratio,
platelet-to-lymphocyte ratio
What is already known about this topic?
. NT-proBNP levels, neutrophil-to-lymphocyte, lymphocyte-to-monocyte and
platelet-to-lymphocyte ratios are related with inflammation which cause
cardiac and vascular disorders in patients with COVID-19.
. NT-proBNP levels, neutrophil-to-lymphocyte, lymphocyte-to-monocyte and
platelet-to-lymphocyte ratios are studied in literature but separately
in patients with COVID-19.
What does this article add?
. This article is the unique in the literature in the subject of
comparison of NT-proBNP levels, neutrophil-to-lymphocyte,
lymphocyte-to-monocyte and platelet-to-lymphocyte ratios between the
patients with COVID-19 and healthy population in one study.
INTRODUCTION
Coronavirus Disease 2019 (COVID-19) was accepted as a public health
emergency situation and declared as a pandemic by the World Health
Organization (WHO) at the beginning of the March
2019.1 A large number of countries and territories
around the world were affected from the outbreak caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2).2COVID-19 is the third disease caused by coronavirus within last two
decades, after severe acute respiratory syndrome coronavirus (SARS-CoV)
and Middle East respiratory syndrome coronavirus
(MERS-CoV).3 Although lower case mortality rates of
SARS-CoV-2, it has greater infectivity and has killed more people than
those diseases.4
The clinical features of COVID-19 is mostly related with respiratory
tract symptoms including cough, fever, pharyngodynia and complications
related to pneumonia and acute respiratory distress
syndrome.5 Most of the patients with COVID-19 had a
good prognosis while critical patients might rapidly develop acute
respiratory failure, acute respiratory distress syndrome, multipl organ
failure and other mortal complications.6 These
complications include; neurological deficits, gastrointestinal
disorders, renal failure, myocarditis and acute coronary
syndromes.3
Effects of COVID-19 on cardiovascular system is associated with COVID-19
induced multiple cytokines and chemokines resulting in plaque
instability, vascular and myocardial inflammation.7Cardiac involvement was found up to 20% of hospitalised patients with
COVID-19 (1). Similarly, acute cardiac injury and arrhythmia were
reported 7.2 and 16.7% respectively, in a single-center study consist
of 138 COVID-19 patients.8 Huang et
al.9 declared in their study that acute myocardial
infarction was detected in 12% of patients with COVID-19.
Several markers can be used in the assessment of cardiac injury among
patients with COVID-19. One of these markers is N-terminal pro-brain
natriuretic peptide (NT-proBNP) which is relased as a response to
increased ventricular wall tension and shows reduced left ventricular
systolic function and poor prognosis in cardiac
invovement.10
Inflammation is one of the most important causes result in vascular
damage. Beside various markers that indicate inflammation,
neutrophil-to-lymphocyte (Neut/Lym), lymphocyte-to-monocyte (Lym/Mono)
and platelet-to-lymphocyte (Plt/Lym) ratios are recently introduced
biochemical markers for inflammation-associated diseases including
vascular injury.11-13
Our study is uniqe in terms of comparing NT-proBNP levels, Neut/Lym,
Lym/Mono and Plt/Lym ratios between the patients with COVID-19 and
healthy subjects in the same study and we aimed to reveal the incresed
risk of cardiovascular diseases among patients with COVID-19 by using
these parameters.
MATERIALS AND METHOD
Between October 2020 and January 2021, 33 adult patients diagnosed with
COVID-19 and 33 healthy subjects were included to this study. Diagnose
of the disease was performed via RNA detection from nasopharyngeal
secretions with real-time reverse transcriptase polymerase chain
reactions (PCR) and chest computed tomographic (CT) scan using the
diagnostic criteria defined in the World Health Organization (WHO)
interim guidance.Healthy subjects were consisted entirely of healthcare
professional volunteers without any chronical disease including
cardiovascular disease, cerebrovascular disease, hypertension, diabetes
mellitus, chronic obstructive pulmonary disease and any kind of
neoplasia, working in the institute in which the study was designed.
COVID-19 was excluded with the absence of viral RNA in PCR test results
in those group. Written informed consent was taken from all participants
and this single center prospective study was approved by the Clinical
Ethics Committee of the institution (decision no: 2020/369) and complies
with the declaration of Helsinki.
Data of the patients including demographic characteristics (age,
gender), comorbidities, laboratory findings, radiographic images,
electrocardiographic findings and treatments were collected from
hospital records. Laboratory tests were consist of blood count, liver
and renal function analyses, C-reactive protein (CRP), D-Dimer and
NT-proBNP which were measured within 24 hours of admission. Complete
blood cell counts and automated differential counts were determined via
an automated hematology analyzer (Cell-Dyn 3700, Abbott, Germany) which
provided total white blood cells count, platelet, neutrophil,
lymphocyte, monocyte, eosinophil, and basophils counts/ml. The baseline
Neut/Lym, Lym/Mono and Plt/Lym ratios were calculated by dividing the
absolute counts of these parameters. An electrochemiluminescence-based
immunoanalytical system, Elecsys 2010 (Roche Diagnostics Ltd, Manheim,
Germany) was used to determine plasma levels of NT-proBNP.Patients with
elevated NT-proBNP were hospitalized for close follow up to prevent and
do early intervention for probabl cardiac disorders that may develop and
all patients were performed transthoracic echocardiography. Favipiravir,
hydroxychloroquine sulfate, levofloxacin and enoxaparine sodium were
started after blood collection as an initial therapy to all patients
according to the Turkish Health Ministery Guideline for COVID-19
Therapy.
Exclusion criteria of the patients with COVID-19 were any diagnosed
cardiovascular and cerebrovascular diseases, hypertension, diabetes
mellitus, chronic obstructive pulmonary disease, neoplasia,younger than
18 years of age, pregnant women and the primary end point of the study
was the composite of death or the requirement of mechanical ventilation,
intensive care unit or extracorporeal membrane oxygenation (ECMO).
Participants were divided into two groups; Group 1 was consisted of the
patients with COVID-19 and the Group 2 was consisted of the healthy
subjects. NT-proBNP levels, neutrophil-to-lymphocyte,
lymphocyte-to-monocyte and platelet-to-lymphocyte ratios of the groups
were compared.
Statistical Analyse
All values were shown as the mean ± SD or percentage. The distribution
of all variables was checked with the Kolmogorov–Smirnov test.
Mann–Whitney U test was used for data with abnormal
distribution.Otherwise, the differences between mean values of two
groups were analyzed using the unpaired Student’s t test. Gender of the
two groups was analyzed using the chi-square test. The Pearson’s test
was used to assess the correlations, but Spearman correlation analysis
was performed in correlation analysis of data with abnormal
distribution. GraphPad Instat (version 3.05, GraphPad Software Inc., San
Diego, CA, USA) statistical software was employed. The statistical
significance was accepted at the level of 0.05.
RESULTS
Thirty three patients with COVID-19 and 33 healthy subjects were
included to the study. Participants were divided into two groups. The
demographic features and laboratory findings were summarized in Table
1.There were no statistically significant differences in terms of
demographic features including age and the gender between the groups.
There were also no marked differences in the subjects of leukocyte,
neutrophil, monocyte, platelet counts and liver and kidney function
tests. NT-pro BNP levels were markedly elevated in COVID-19 patients
(p<0,0001) as shown in Figure 1. NT-pro BNP levels were 8,5
times higher in patients with COVID-19 than in normal population.
D-Dimer (p=0,0135) and CRP (p<0,0001) levels and Neut/Lym
(p<0,0001), Plt/Lym (p<0,0001) ratios are
statistically significantly higher in Group 1. In contrast to these
results, Lym/Mono ratio was found to be statistically significantly
lower in Group 1 (p<0,001).
Correlations between ratios and biochemical parameters in patients with
COVID-19 were also compared and results were given in Table 2. We
detected that there was positive correlation only between NT-proBNP and
D-Dimer levels.
DISCUSSION
After the first cases describing pneumonia with unknown origin in Wuhan,
China, SARS-CoV-2 rapidly became pandemic.Current epidemiologic studies
suggest that about 80% of the patients with COVID-19 have mild symptoms
while 5% become critically ill, requiring mechanical
ventilation.14 Different type of responses are due to
the degree of viral load, age of the patients, host immune response and
prescence of comorbidities mainly hypertension, diabetes mellitus and
thrombotic events.15 Although the most common symptoms
including fever, dry cough, fatigue, headache, and shortness of breath
areassociated with respiratory system and the complications were usually
related to acute respiratory distress syndrome or pneumonia,
cardiovascular involvement is also an additional clinical problem to
deal with in COVID-19.16 Acute cardiac injury rates
during the illness range between 7% to 28% in different studies which
significantly increases the COVID-19 associated complications and
mortality.17 Especially, presence of pre-existing
cardiovascular disease and/or myocardial injury results in negative
outcomes in patients with COVID-19.7 Increased
affinity of the SARS-CoV-2 to angiotensin I converting enzyme 2 (ACE2)
receptor which is expressed mainly in the lung and other tissues
including vascular endothelial cells was shown in previous
studies.18 Directly infection ability of SARS-CoV-2 to
endothelial cells is one of the strange features of the virus and
distinguishes it from the most of the infectious
diseaes.19
Several mechanisms were suggested about the myocardial damage of
SARS-CoV-2 including direct damage by the virus, systemic inflammatory
responses, destabilized coronary plaque and aggravated
hypoxia.9 Viral entry into the myocardium and arteries
via ACE2 receptor induces ACE2 downregulation and
renin-angiotensin-aldosterone system dysfunction that leads to heart
dysfunction and pneumonia progression.20 The
activation and overproduction of inflammatory cytokines can also induce
necrosis and apoptosis of cardiomyocyte.6 Imbalance of
T helper 1 and T helper 2 responses triggered a cytokine storm in
patients with COVID-19 which may cause myocardial
injury.16 Vascular share stress of the coronary
arteries can be increased by systemic inflammation which leads to plaque
rupture and myocardial infarction.21 High oxygen
demand due to tachycardia and fever and insufficient oxygen supply due
to hypoxemia and respiratory failure are usually seen during the
infection which could result in a type 2 myocardial
infarction.22
Variety of cardiovascular involvement including heart failure,
myocarditis, pericarditis, acute coronary syndrome and arrhythmias were
described in previous studies.23 Although without a
history of heart failure, new onset of heart failure was observed in
hospitalized and intensive care required patients with COVID-19 was
observed in the rate of 25% and 30%, respectively.24Proinflammatory cytokines and recruitment of proinflammatory macrophages
and granulocytes in blood stream lead to severe inflammatory storm and
in combination with increased metabolic demand may cause cardiac
depression and either new onset heart failure or acute decompensation of
chronic heart failure.25 Viral infections have been
shown as one of the most common infectious causes of myocarditis and
pericarditis. In spite of widely reported myocarditis cases due to
SARS-CoV-2, limited data have been published on cases with COVID-19 who
developed pericarditis and pericardial effusion.26,27Directly affected myocardium and pericardium via replicated and
disseminated virus through the blood or the lymphatic system from the
respiratory tract may be the probabl mechanism of these
complications.5 In patients infected with SARS-CoV-2,
increased interleukin-6 and D-Dimer levels which indicates the augmented
coagulation response, are linked with plaque instability and occurrence
of acute coronary syndrome.28 According to the study
designed by Bangalore et al29, 9 of the 18 patients
with COVID-19 and had ST-segment elevation on electrocardiogram were
performed coronary angiography. Three of them were found to be any
obstructive disease which indicates hypoxic injury, coronary spasm,
microthrombi and endothelial injury may also result in acute coronary
syndrome without any occlusion in patients with COVID-19. According to a
study designed in Wuhan it was revealed that acute coronary syndrome
rates were significantly higher in 36 of the 138 patients with COVID-19
who were required intensive care.30 Cardiac
arrhythmias and cardiac arrest are another common manifestation observed
in COVID-19 patients but spesific types of arrhythmia were not
described. High-grade atrioventricular tachycardia, atrial fibrillation,
polymorphic ventricular tachycardia and pulseless electrical activity
arrest are the common disorders mentioned in the literature. Hypoxemia
and electrolyte disturbances are thought to be responsible from
arrhythmogenicity.31,32
Several markers can be used in the detection of heart injury including
hs-cTnI, NT-proBNP, CK-MB, myoglobin and lactate
dehydrogenase.33 B-type natriuretic peptide (BNP) was
first isolated from porcine brain, however it was soon found to
originate mainly from the heart, representing a cardiac
hormone.34 BNP is synthesized as a prehormone (proBNP)
consists of 108 aminoacids and on secretion this propeptide is split
into its biologically active form BNP and the remaining NT-proBNP.
Although plasma concentration and cardiac production of NT-proBNP is
very low in the normal status, increased ventricular wall stretch,
neurohormonal activation and hypoxia stimulate the secretion of this
hormone.35
Increased levels of NT-proBNP and its association with worse outcomes in
patients with COVID-19 were reported in several studies. In a study
designed by Gao et al8, higher levels of NT-proBNP in
patients with COVID-19 was found to be related with lower cumulative
survival rate and its prognostic effect might be a specific index of
reflecting the overall state of SARS-CoV-2 infection.Guo et
al9 demonstrated a high positive correlation between
troponin and NT-proBNP levels in COVID-19 patients in their study.
Sorrentiono et al2 revealed that elevated NT-proBNP
levels were associated with worse prognosis in COVID-19 patients, in
their meta-analysis consisted of 2248 patients. Similarly, in an
analysis including 416 hospitalized patients with COVID-19, NT-proBNP
was significantly higher among patinets with myocardial injury than
those without36. Han et al4indicated that NT-proBNP levels were significantly higher in severe and
critical cases infected with SARS-CoV-2 than mild cases and can be used
to predict the severity of the COVID-19. Zhou et al37suggested that increased levels of NT-proBNP were associated with more
severe symptoms and disease progression among patients with COVID-19.
Mahajan et al14 advocated that NT-proBNP has a
critical role in estimating cardiac risk stratification and
prognostication of patients with severe COVID-19. A meta-analysis by Li
et al38, cardiac biomarkers included troponin, CK-MB
and NT-proBNP were significantly higher in severe cases compared to
milder cases.Abnormalities in NT-proBNP were found to be similar to the
inflammatory markers in the subject of in-hospital mortality according
to death risk analysis.39 Jin et
al40 compared the NT-proBNP levels in patients with
COVID-19 who developed cardiac injury and not, and demonstrated that
patients with cardiac injury were more likely have elevation of
NT-proBNP in comparison 66.7% to 10%. Aladag and
Atabey3 reported higher NT-proBNP levels in patients
diagnosed with COVID-19 on the admission in correlation with our study.
Our results demonstrated statistically significant increase in NT-proBNP
levels in patients with COVID-19 when compared to the healthy
population.
The role of the inflammation at every phase of atherosclerotic process
was revealed in the literature.Immunoglobulin molecules, T lymphocytes,
presence of antigen-antibody complex, and plasma cells that found in the
structure of the atheroma plaque indicate the importance of the
inflammation in the development and progression of atherosclerosis
according to the histological studies.41
Different type of markers were defined as predictors of inflammation and
cardiovascular risk in several studies such as; proinflammatory
cytokines, adhesion molecules, oxidized low-density lipoproteins, acute
phase reactants, white blood cells and erythrocyte sedimentation
rate.42 In addition to these markers Neut/Lym,
Lym/Mono and Plt/Lym ratios are novel biomarkers which are used as
indicators of inflammation.11-13
Relationship between the white blood cells and its subtypes and presence
and prognosis of atherosclerotic process was shown in several studies.
Lymphocytes are one of its subtypes and responsible for cellular and
humoral immunity. Lymphocyte apoptosis increases by the inflammation and
lower lymphocyte counts are in correlation with worse outcomes in terms
of vascular diseases.43
Neut/Lym ratio is a fast, easy and inexpensive method for assessment of
inflammatory status and has been recently introduced biomarker for
investigation of cardiovascular risk. Ratio of absolute neutrophil count
to absolute lymphocyte count is the calculation method of this
marker.44 The relation between atherosclerosis and
Neut/Lym ratio was investigated by Balta et al45 and
it was declared that Neut/Lym ratio can be affected by atherosclerotic
risk factors such as hypertension, diabetes mellitus,
hypercholesterolemia and metabolic syndrome; in addition it can also be
used in the prediction of mortality in cardiovascular diseases.
Similarly, correlation between Neut/Lym ratio and severity of coronary
artery disease was shown in a study designed by Kaya et
al46. Association between Neut/Lym ratio and COVID-19
studied in the literature and higher Neut/Lym ratio was found to be an
independent risk factor of the in-hospital mortality for COVID-19
patients.47 In a study consisted of 125 patients with
COVID-19 it was hypothesized that elevated Neut/Lym ratio would be a
prognostic indicator of mortality in a COVID-19 patient
population.48 In our study Neut/Lym values are also
statistically significant higher in patients with COVID-19 than in
control group.
Lym/Mono has been found to be a novel systemic inflammation marker which
could reproducible and widely available in clinical praxis. Ratio of
absolute lymphocyte count to absolute monocyte count is the calculation
method of this marker.12 Decreased Lym/Mono ratio is
found to be a risk factor for critical limb ischemia and other vascular
peripheral arterial occlusive diseases in a study conducted by Gary et
al.49 Demir et al50 suggested that
lower Lym/Mono ratios are useful indicators for metabolic syndrome that
includes atherosclerosis in vascular arterial structures. In a study
designed by Lissoni et al51, 71% of the patients with
COVID-19 had lower Lym/Mono ratio when compared with controls, and they
indicated that Lym/Mono is a simple and less expensive biomarker that
can be used in clinical evolution of COVID-19 infection. Shivakumar et
al52 compared the Lym/Mono ratios between the
survivors and nonsurvivors of the patients with COVID-19 and Lym/Mono
was lower in nonsurvivors group. Our study revealed statistically
significantly lower values of Lym/Mono ratios in patients with COVID-19
than control group.
Plt/Lym ratio is one of the fast, broadly available and cheap marker
that can be used in evaluation of inflammation and atherosclerosis.
Ratio of absolute platelet count to absolute lymphocyte count is the
calculation method of this marker. Its relation with severity and
complexity of coronary artery disease in patients with acute coronary
syndromes was studied and increased levels of Plt/Lym ratio was found in
association with worse outcomes in those patients53.
According to the study designed by Sari et al54 it was
declared that patients with abnormal coronary angiography results had
higher Plt/Lym ratios than patients with normal coronary angiography
results. Moreover, it is also correlated with severity of coronary
artery disease. Wang et al55 evaluated the Plt/Lym
ratio in a study consisted of 131 patients and explored the association
between higher Plt/Lym ratio and mortality in COVID-19 due to
aggregation disorders occur in vascular structures. Relationship between
Plt/Lym ratio and severity of COVID-19 was revealed in a meta-analysis
included 998 patients. Higher Plt/Lym ratio on admission was found to be
related with severe COVID-19.56 According to our study
Plt/Lym ratio is higher in the group of patients with COVID-19 than
control group.
In conclusion, the patients with COVID-19 are prone to develop cardiac
morbidities and mortalities with different mechanisms. NT-proBNP,
Neu/Plt, Lym/Mono and Plt/Lym ratios are the important cardiovascular
markers that can be used for close follow up in hospital patients who
were infected with SARS-CoV-2 and helps clinicians to adopt optimal
treatment strategies at an early stage to prevent probabl cardiovascular
events.
Conflicts of Interest: The authors declared no conflicts of interest.
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Table 1. Demographic features and laboratory findings of the groups