Neutrophil-to-Lymphocyte Ratio and Outpatient Management of Low-Risk Acute Pulmonary Embolism

Abdolmohammad Ranjbar; Bahram Sohrabi; Reza Hajizadeh; Mahdi Karimi Shoar; Hadiseh Kavandi; Sahar Ghodratizadeh; Hanieh Sakha; Kamran Mohammadi

doi:10.4103/hm.hm_20_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 6 | Issue : 3 | Page : 183-186

Neutrophil-to-Lymphocyte Ratio and Outpatient Management of Low-Risk Acute Pulmonary Embolism

Abdolmohammad Ranjbar¹, Bahram Sohrabi², Reza Hajizadeh³, Mahdi Karimi Shoar², Hadiseh Kavandi², Sahar Ghodratizadeh⁴, Hanieh Sakha², Kamran Mohammadi²
¹ Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
² Cardiovascular Research Center, Tabriz University of Medical Science, Tabriz, Iran
³ Department of Cardiology, Urmia University of Medical Sciences, Urmia, Iran
⁴ Anesthesiology, Urmia University of Medical Sciences, Urmia, Iran, Iran

Date of Submission	13-Mar-2021
Date of Acceptance	02-Sep-2022
Date of Web Publication	30-Sep-2022

Correspondence Address:
Dr. Reza Hajizadeh
Department of Cardiology, Urmia University of Medical Sciences, Taleghani Hospital, Urmia
Iran

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/hm.hm_20_21

Abstract

Purpose: Low-risk pulmonary thromboembolism (PTE) outpatient management has been described recently. The blood neutrophil/lymphocyte ratio (NLR) has been shown to be a useful marker of cardiovascular disease and an independent predictor of cardiac mortality. The predictive value of NLR in predicting mortality of low-risk PTE was evaluated in this study. Materials and Methods: The total of 168 patients with definite pulmonary embolism diagnosed by computed tomography angiography whose on-admission simplified Pulmonary Embolism Severity Index (PESI) score was zero enrolled in this study. The survival rate of patients according to their NLR was evaluated. Results: During 12 months' follow-up period, eight patients (4.7%) died. None of the patients with an NLR of <3.2 died during the follow-up. The median values of NLR in the nonsurvivor and survivor groups were 9.2 ± 3.03 (2–29.5) and 4.69 ± 0.43 (0.8–24.5), respectively. NLR values were significantly higher in nonsurvivors compared to survivors (P = 0.043). Conclusion: This study suggests that patients with zero PESI score and NLR <3.2 could be managed patiently with good results.

Keywords: Low risk, neutrophil/lymphocyte ratio, outcome, pulmonary embolism, simplified pulmonary embolism severity index

How to cite this article:
Ranjbar A, Sohrabi B, Hajizadeh R, Shoar MK, Kavandi H, Ghodratizadeh S, Sakha H, Mohammadi K. Neutrophil-to-Lymphocyte Ratio and Outpatient Management of Low-Risk Acute Pulmonary Embolism. Heart Mind 2022;6:183-6

How to cite this URL:
Ranjbar A, Sohrabi B, Hajizadeh R, Shoar MK, Kavandi H, Ghodratizadeh S, Sakha H, Mohammadi K. Neutrophil-to-Lymphocyte Ratio and Outpatient Management of Low-Risk Acute Pulmonary Embolism. Heart Mind [serial online] 2022 [cited 2023 Mar 29];6:183-6. Available from: http://www.heartmindjournal.org/text.asp?2022/6/3/183/357544

Introduction

Pulmonary thromboembolism (PTE) is a life-threatening disease. After acute coronary artery disease and stroke, it is the third cause of cardiovascular death worldwide. Autopsy studies have shown that mortality due to PTE in the general population is higher than previous reports.^[1] Sudden pulmonary artery lumen obstruction in massive PTE, can result in acute right ventricular failure, hemodynamic instability, and even shock state, and sudden cardiac death which mostly occurs in the early hours.^[2]

Despite these findings, mortality of low-risk PTE is not high and recent researchers support outpatient management of low-risk PTE according to a simplified pulmonary embolism severity index (S-PESI) score.^[3] It seems that because clinicians are afraid of adverse events, they prefer inpatient treatment of low-risk PTE which is not cost-benefit in many cases.^[4],[5] Recently, some papers reported systemic inflammation as an important factor in PTE.^[6]

Leukocytosis is a known marker of inflammation. An increase in neutrophils and a decrease in the number of lymphocytes is a novel marker of inflammation.

The blood neutrophil/lymphocyte ratio (NLR) is a useful marker of cardiovascular disease and an independent predictor of cardiac mortality.^[7],[8]

Since NLR is a part of routine blood analysis, can be obtained easily by the whole blood count, and is quite easy to calculate, we investigated the prognostic value of NLR in patients with low-risk PTE in an outpatient survey.

Materials and Methods

A total of 168 patients with definite pulmonary embolism were diagnosed by computed tomography angiography whose on-admission S-PESI score was zero enrolled in this study.^[9] On admission, a 1 cc blood sample was taken for complete blood count analysis.

Exclusion criteria were active infection, recent surgery during the past 3 months, using a corticosteroid, active inflammation, and, any recent tissue injury such as burning and cancer. Patients' demographic data and laboratory data were gathered from patients' files. All patients were admitted at least for 3 days, followed up for 12 months after admission for mortality was done by telephone call and routine visits monthly. The association between on-admission NLR and midterm mortality was analyzed to reach a cutoff point in which patients could be managed safely in outpatient type management. S-PESI score uses six variables for risk stratification of patients with pulmonary embolism. These variables include chronic cardiopulmonary disease, heart rate >110 beats per minute, systolic blood pressure <100 mm Hg, arterial oxygen saturation <90%, previous cancer, and the age of the patient more than 80 years. Each variable gets 1 point and if the sum is zero patient is defined as low risk. Any patient with a score 0–1 is defined as high risk.^[3] A zero S-PESI score shows that a patient with pulmonary embolism has a good prognosis and low probability for death.

Statistical analysis

Continuous data were expressed as mean ± standard deviation for normal variables; categorical data were expressed as percentage. The predictive value of NLR was assessed by receiver operating characteristic (ROC) analysis, estimating the area under the curve (AUC). SPSS software, version 23.0 (SPSS Inc, Chicago, Illinois, USA) was used for data analysis. Independent t-test, Fisher's exact test, and one Mann–Whitney U-test were used for data analysis.

Ethical Statement

This research was approved by ethics committee of Tabriz University of Medical Sciences with approval code of 93/1-5/13.

Results

Two cardiologists evaluated 210 patients with a definitive diagnosis of PTE based on the S-PESI.^[9] Finally, 184 patients had zero scores according to the S-PESI score and were defined as low-risk patients. Sixteen patients with low-risk PTE, including eight patients who had undergone a recent surgical procedure or missing follow-up due to death related to a car accident, four patients with cancer, two with chronic inflammatory disease and, two with a history of corticosteroid consumption were excluded from the study. Finally, 168 patients enrolled in the study. The characteristics of patients are described in [Table 1]. The mean age of patients was 59.17 ± 1.87, according to the gender of patients, 69 patients (41.0%) were female and 99 patients (58.9%) were male, 25 patients (14.9%) have a history of smoking, 57 patients (33.9%) have hypertension, 16 patients (9.5%) had hyperlipidemia, 20 patients (11.9%) had a history of heart failure, 20 patients (11.9%) had chronic obstructive pulmonary disease (COPD), 25 patients (14.9) had a history of immobilization, and 3 patients (1.8%) had recent long travel. Treatment started in the emergency room, 16 patients (9.5%) took fibrinolytic therapy following unfractionated heparin (UFH) therapy, and other patients (90.5%) took only UFH following warfarin therapy with a goal of international normalizing ratio (INR) = 2–3. INR during the hospital course, two patients developed hypotension and took vasopressor therapy, one patient went under mechanical ventilation.

Table 1: Association of age and complete blood count parameters on low-risk pulmonary thromboembolism mortality

Click here to view

During 12 months' follow-up, eight patients (4.7%) died. Four patients developed low blood pressure or decreasing O2 saturation during their hospital course, two patients developed severe pulmonary hypertension, one patient developed sudden death and one patient developed paradoxical embolization. The mean value of NLR in the nonsurvivor and survivor groups was 9.2 ± 3.03 (2–29.5) and 4.69 ± 0.43 (0.8–24.5), respectively. NLR values were significantly higher in nonsurvivors compared to survivors (P = 0.043).

Although NLR values were significantly higher in nonsurvivors, an optimal cutoff value was achieved by ROC curve analysis [Figure 1]. According to the ROC curve, an NLR >3.2 with a sensitivity of 89.5% and specificity of 100% could predict 12 months' mortality in low-risk patients. There was no significant difference in neutrophil counts between nonsurvivors and survivors (AUC = 0.941, P < 0.001).

Figure 1: ROC curve shows a cutoff point for NLR value according to 30 days' mortality. NLR = Neutrophil/lymphocyte ratio, ROC = Receiver operating characteristics, AUC = Area under the curve

Click here to view

Discussion

We evaluated the association between NLR and the prognosis of PTE based on the S-PESI score. The S-PESI score is a useful method for predicting the short-term mortality of patients with pulmonary embolism.^[3] Our findings suggest that NLR may be an independent predictor of mortality in low-risk PTE.

Elevated NLR implies a greater increase in neutrophils compared to lymphocytes count. Neutrophil plays a major role against infection and also regulates and links innate and adaptive immunity.^[10]

An increase in apoptosis or higher corticosteroid level may lead to lymphocytopenia in stressful conditions such as PTE and inflammatory disorders. Recently, it has been demonstrated that mortality increased with an increase in NLR in patients with acute coronary syndrome.^[11] One study showed that elevated NLR was significantly associated with heart failure and cancer.^[12] Neutrophils are important in different lung diseases especially COPD.^[13] COPD exacerbation can be predicted in the early stages by increased NLR.^[14] Dying neutrophils should be cleared from lung tissue, otherwise, they can aggravate lung disease by enhancing autoimmune damage by releasing various phlogistic cargoes.^[15]

By increasing chemokines secretion from epithelial cells, neutrophil elastase plays a major role in enhancing inflammation in COPD exacerbations.^[16] Cardiovascular events can be increased in lymphocytopenia.^[17]

Karataş et al. showed that PESI scores (P = 0.01) and elevated NLR (P = 0.01) were independently associated with mortality in PTE.^[18] A report by Cavuş et al. showed that NLR values >5.465 could predict higher mortality in PTE (P < 0.001).^[19] In this study, according to the ROC curve, an NLR >3.2 could predict 6 months' mortality in low-risk patients. Lower cutoff point in our study could be due to lower disease severity in our study and only low-risk patient enrollment.

C-reactive protein as an inflammatory marker is increased (P = 0.002) and albumin as an anti-inflammatory marker, is decreased in patients with higher NLR values (P = 0.001).^[7] In Soylu et al.'s study, 142 patients with PTE were included. They found that NLR may be used as an independent predictor of in-hospital mortality.^[20],[21] Hence, NLR can be an indicator of the adverse function of different systems and an effective tool in evaluating patients affected by PTE. Although previous studies have shown the prognostic value of NLR in PTE patients,^[22] our study showed that even in low-risk subgroup of patients NLR can be a reliable tool for differentiating patients at risk of mortality. To the best of our knowledge, this is the first study that shows that NLR can be helpful in predicting mortality in low-risk PTE.

Recently, some reports have suggested outpatient treatment for low-risk PTE. The outpatient management of PTE ranges from 4% to 50% in different studies which shows we do not have a definite strategy in this era of medicine. Outpatient management has some advantages for patients and the health-care system such as better quality of life and lower costs. Nowadays, we do not have strong evidence supporting outpatient management of low-risk PTE.^[23] Roy et al. showed that the overall risk of mortality in those with low-risk PTE according to PESI or S-PESI was <3% and they suggested that outpatient management in these patients is safe.^[4] Among patients with low-risk PTE, NLR may be helpful to differentiate those who can be treated at home and those who need hospital admission. There are few studies investigating the outcome of patients with pulmonary embolism taking an outpatient treatment. Although some authors believe that a zero S-PESI score alone could be used for selecting those patients who could receive outpatient treatment, more investigations could give more evidence for such treatment.

Our study has several limitations. First, our study was a single-center study. Second, because we did not have a large sample size, subgroup analysis especially according to the age of patients was not done.

Conclusion

Increased NLR is a simple, nonspecific marker of inflammation that is associated with increased mortality in patients with low-risk PTE. We suggest outpatient management of low-risk patients with PTE with NLR <3.2.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Gimbel IA, Mulder FI, Bosch FT, Freund JE, Guman N, van Es N, et al. Pulmonary embolism at autopsy in cancer patients. J Thromb Haemost 2021;19:1228-35.
2.	Martin KA, Molsberry R, Cuttica MJ, Desai KR, Schimmel DR, Khan SS. Time trends in pulmonary embolism mortality rates in the United States, 1999 to 2018. J Am Heart Assoc 2020;9:e016784.
3.	Ostovan MA, Ghaffari S, Pourafkari L, Dehghani P, Hajizadeh R, Nadiri M, et al. Modification of simplified pulmonary embolism severity index and its prognostic value in patients with acute pulmonary embolism. Heart Lung Circ 2016;25:184-90.
4.	Roy PM, Moumneh T, Penaloza A, Sanchez O. Outpatient management of pulmonary embolism. Thromb Res 2017;155:92-100.
5.	Hajizadeh R, Ghaffari S, Habibzadeh A, Safaei N, Mohammadi K, Ranjbar A, et al. Outcome of surgical embolectomy in patients with massive pulmonary embolism with and without cardiopulmonary resuscitation. Kardiochir Torakochirurgia Pol 2017;14:241-4.
6.	Bontekoe E, Brailovsky Y, Hoppensteadt D, Bontekoe J, Siddiqui F, Newman J, et al. Upregulation of inflammatory cytokines in pulmonary embolism using biochip-array profiling. Clin Appl Thromb Hemost 2021;27:10760296211013107.
7.	Go SI, Lee A, Lee US, Choi HJ, Kang MH, Kang JH, et al. Clinical significance of the neutrophil-lymphocyte ratio in venous thromboembolism patients with lung cancer. Lung Cancer 2014;84:79-85.
8.	Kayrak M, Erdoğan HI, Solak Y, Akilli H, Gül EE, Yildirim O, et al. Prognostic value of neutrophil to lymphocyte ratio in patients with acute pulmonary embolism: A restrospective study. Heart Lung Circ 2014;23:56-62.
9.	Righini M, Roy PM, Meyer G, Verschuren F, Aujesky D, Le Gal G. The Simplified Pulmonary Embolism Severity Index (PESI): Validation of a clinical prognostic model for pulmonary embolism. J Thromb Haemost 2011;9:2115-7.
10.	Kaur BP, Secord E. Innate immunity. Pediatr Clin North Am 2019;66:905-11.
11.	Afari ME, Bhat T. Neutrophil to lymphocyte ratio (NLR) and cardiovascular diseases: An update. Expert Rev Cardiovasc Ther 2016;14:573-7.
12.	Venkatraghavan L, Tan TP, Mehta J, Arekapudi A, Govindarajulu A, Siu E. Neutrophil Lymphocyte Ratio as a predictor of systemic inflammation – A cross-sectional study in a pre-admission setting. F1000Res 2015;4:123.
13.	Liu J, Pang Z, Wang G, Guan X, Fang K, Wang Z, et al. Advanced role of neutrophils in common respiratory diseases. J Immunol Res 2017;2017:6710278.
14.	Meijer M, Rijkers GT, van Overveld FJ. Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease. Expert Rev Clin Immunol 2013;9:1055-68.
15.	Jasper AE, McIver WJ, Sapey E, Walton GM. Understanding the role of neutrophils in chronic inflammatory airway disease. F1000Res 2019;8:F1000 Faculty Rev-557.
16.	Victoni T, Gicquel T, Bodin A, Daude M, Tenor H, Valença S, et al. Roflumilast n-oxide associated with PGE2 prevents the neutrophil elastase-induced production of chemokines by epithelial cells. Int Immunopharmacol 2016;30:1-8.
17.	Zidar DA, Al-Kindi SG, Liu Y, Krieger NI, Perzynski AT, Osnard M, et al. Association of lymphopenia with risk of mortality among adults in the US general population. JAMA Netw Open 2019;2:e1916526.
18.	Karataş MB, İpek G, Onuk T, Güngör B, Durmuş G, Çanga Y, et al. Assessment of prognostic value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in patients with pulmonary embolism. Acta Cardiol Sin 2016;32:313-20.
19.	Cavuş UY, Yildirim S, Sönmez E, Ertan C, Ozeke O. Prognostic value of neutrophil/lymphocyte ratio in patients with pulmonary embolism. Turk J Med Sci 2014;44:50-5.
20.	Soylu K, Gedikli Ö, Ekşi A, Avcıoğlu Y, Soylu Aİ, Yüksel S, et al. Neutrophil-to-lymphocyte ratio for the assessment of hospital mortality in patients with acute pulmonary embolism. Arch Med Sci 2016;12:95-100.
21.	Ma Y, Mao Y, He X, Sun Y, Huang S, Qiu J. The values of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in predicting 30 day mortality in patients with acute pulmonary embolism. BMC Cardiovasc Disord 2016;16:123.
22.	Wang Q, Ma J, Jiang Z, Ming L. Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in acute pulmonary embolism: A systematic review and meta-analysis. Int Angiol 2018;37:4-11.
23.	Jiménez D, Yusen RD. Outpatient therapy for acute symptomatic pulmonary embolism diagnosed in the emergency department: Time to improve the evidence base. Thromb Res 2018;161:117-8.