Pulmonary Embolism Severity Index Predicts Adverse Events in Hospitalized COVID-19 Patients: A Retrospective Observational Study.

OBJECTIVES: Pulmonary embolism is one of the leading causes of death in patients with COVID-19. Autopsy findings showed that the incidence of thromboembolic events was higher than clinically suspected. In this study, the authors investigated the relationship between pulmonary embolism severity index (PESI) and simplified PESI (sPESI) on admission to the hospital, as well as adverse events in hospitalized COVID-19 patients without clinically documented venous and/or pulmonary embolism. The adverse events investigated were the development of acute respiratory distress syndrome, the need for intensive care unit admission, invasive or noninvasive mechanical ventilation, and in-hospital mortality.
DESIGN: A retrospective and observational study.
SETTING: Two large-volume tertiary hospitals in the same city. PARTICIPANTS: A total of 720 hospitalized COVID-19 patients with a positive polymerase chain reaction were evaluated.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Of the study population, 48.6% (350) were women, and the median age was 66 years (19-96). The overall in-hospital mortality rate was 20.5%. In the multivariate logistic regression analysis, a significant relationship was found between the whole adverse events considered and PESI, as well as sPESI (p < 0.001). According to the results, sPESI ≥2 predicts in-hospital mortality with a sensitivity of 61.4% and specificity of 83.3% (area under the curve = 0.817, 95% confidence interval 0.787-0.845, p < 0.001). Similarly, PESI classes IV and V also were found as independent risk factors for in-hospital mortality (for PESI class IV, odds ratio = 2.81, p < 0.017; for PESI class V, odds ratio = 3.94, p < 0.001).
CONCLUSIONS: PESI and sPESI scoring systems were both found to be associated with adverse events, and they can be used to predict in-hospital mortality in hospitalized COVID-19 patients without documented venous and/or pulmonary embolism.

Introduction

The Coronavirus disease 2019 (COVID-19) pandemic, which started at the end of 2019, continues to affect people all around the world. COVID-19 has a wide clinical spectrum ranging from asymptomatic infection to life-threatening respiratory failure. The overall fatality rate in unvaccinated individuals is estimated to be between 0.15 to 1 percent 1.

Pneumonia is the most common manifestation of severe COVID-19. Acute respiratory distress syndrome (ARDS) occurs in symptomatic patients and can be associated with an exaggerated inflammatory response. ARDS is the leading cause of cardiac complications, need for mechanical ventilation (MV), secondary infections and death followed by sepsis 2. Similar to ARDS, “COVID-19 associated coagulopathy”, as a well-defined clinical condition, may lead to morbidity and mortality 3.

Predicting COVID-19 prognosis is critical to determine the progression of the disease and its treatment protocols. For this purpose, several comorbidity indices or scorings have been used in the previous studies. The pulmonary embolism severity index (PESI) is a score that has been most extensively validated to date and has been in use for the risk assessment of pulmonary embolism (PE) as well as to determine the severity of disease 4, 5. A simplified PESI (sPESI) was developed and validated to simplify the original version of PESI, by reducing 11 variables to 6 variables 6, 7. According to our literature review, the relationship between PESI or sPESI and the prognosis of the disease has not been investigated before in COVID- 19 patients without acute PE. Our first aim in this study was to investigate the relationship between PESI/sPESI and adverse events such as in-hospital mortality, the development of ARDS, the need for noninvasive/invasive MV and intensive care unit (ICU) in hospitalized COVID-19 patients without documented venous thromboembolism (VTE)/PE. Our secondary aim was to investigate the relationship between in-hospital mortality and comorbid clinical conditions.

Materials and Methods

Approval was obtained from the … before applying to the ethics committee. … University Non-Interventional Clinical Research Ethics Committee approved our study (dated … and protocol numbered …).

Data sources

This retrospective, cross-sectional study involved 762 consecutively hospitalized COVID-19 patients with (+) PCR, all above 18 years of age and applied to two hospitals in the same city, … Hospital and … Hospital (clinics of infectious diseases and ICUs of anesthesiology and reanimation) between May 2020 and November 2020.

We excluded 42 patients totally who had documented PE (n=19) and those were treated with hydroxychloroquine (n=23). Finally, the data of 720 hospitalized patients were analyzed.

The demographic data, risk factors, medications and clinical and electrocardiographic findings on admission to the hospital were recorded in patients’ files. Routine laboratory analysis results were also recorded.

The adverse events that were investigated in our study were the development of ARDS, the need for ICU, invasive or noninvasive MV and in-hospital mortality. The diagnosis of ARDS was made according to the Berlin Definition and no classification was made according to clinical severity. PESI and sPESI were calculated for each study patient to evaluate adverse events.

Calculation of PESI and sPESI on admission to hospital

The original PESI, which includes 11 differently weighted variables, is calculated by scoring the following variables; age, male sex, cancer, chronic heart failure, chronic pulmonary disease, pulse rate ≥110 beat per minute, systolic blood pressure <100 mmHg, respiratory rate more than 30 breaths per minute, temperature <36°C, altered mental status, arterial oxyhemoglobin saturation <90% (Table 1 ). According to the PESI, patients with acute PE are divided into 5 categories; class 1: ≤65 points, class II: 66–85 points, class III: 86–105 points, class IV: 106–125 points, and class V >125 points. The 30-day mortality is low for patients in PESI classes I and II (1.7%-3.5%) and moderate-very high for patients in PESI classes III, IV and V (3.2%-24.5%) 8.

Table 1

Original and simplified Pulmonary Embolism Severity Index

Parameter	Original version	Simplified version
Age	Age in years	1 point (if age >80 years)
Male sex	+10 points	-
Cancer	+30 points	1 point
Chronic heart failure	+10 points	-
Chronic pulmonary disease	+10 points	1 point
Pulse rate ≥ 110 b.p.m.	+20 points	1 point
Systolic BP <100 mmHg	+30 points	1 point
Respiratory rate >30 breaths per min	+20 points	-
Temperature <36°C	+20 points	-
Altered mental status	+60 points	-
Arterial oxyhaemoglobin saturation <90%	+20 points	1 point

As mentioned before, sPESI is a simplified version of the original PESI. Each variable in the sPESI receives one point (Table 1). The variables are age>80 years, cancer, chronic heart failure/chronic pulmonary disease, pulse rate ≥110 beat per minute, systolic blood pressure <100 mmHg, and arterial oxyhemoglobin saturation <90%. If sPESI is 0 point, this indicates a low mortality rate (30-day mortality rate 1%) in patients with acute pulmonary thromboembolism. Also, sPESI≥1 point indicates high mortality rate (30-day mortality rate 10.9%) in the same patient group.

Testing for COVID-19

Nasopharyngeal specimens were obtained via FLOQSwabs (COPAN Diagnostics Inc, Italy) and were sent to the microbiology laboratory in a viral transport medium (Bioeksen, Turkey). The detection of SARS-CoV-2 RNA was done with SARS-Cov-2-Double Gene RT-qPCR amplification kit targeted the ORF1ab and N genes (Bio-Speedy, Bioeksen, Turkey). The lower detection limit (LoD) reported by the Ministry of Health's General Directorate of Public Health was 200 genom/mL, analytical sensitivity and specificity were 99.4% and 99.0%, respectively. Real-time RT-qPCR was performed using Rotor-Gene 5r Plex Real Time PCR Systems (Qiagen, Germany). A cycle threshold value (Ct-value) less than 38 was defined as a positive test result, and a Ct-value of 38 or more was defined as a negative test result.

Statistical analysis

SPSS software version 21.0 for Windows (SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. The normal distribution of the data was determined using visual and analytic methods. The study groups were compared using independent sample T-Test/One-way ANOVA for continuous variables with a normal distribution and by using Mann-Whitney U/Kruskal-Wallis H test for continuous variables without normal distribution. Categorical data were compared using the chi-square test. Receiver operating characteristic (ROC) analysis was drawn for the ability of sPESI to predict in-hospital mortality. Logistic regression analysis was performed to determine the independent predictors of adverse events. Traditional risk factors for adverse events were adjusted in all models. To investigate the relationship of PESI with mortality, the PESI was divided into 5 classes as previously validated. Class 1 was accepted as the baseline value and the ability of other classes to predict mortality was examined. MedCalc 19.6.4 was used to calculate ROC analyses to determine the cut-off value of sPESI to predict mortality. A p-value of less than 0.05 was considered as statistically significant.

Results

Patients Characteristics

A total of 720 consecutive hospitalized COVID-19 patients were enrolled in our study. Of the study population, 48.6% (350) were female, and the median age was 66 [19-96]. The first hospitalization place of 13.8% of study patients was ICU, the rest was non-ICU hospitalization. A total of 115 of the non-ICU patients needed intensive care during the follow-up. A total of 148 (20.5%) patients died during their hospitalization period. All of the demographic data and comorbid risk factors of the patients are shown in Table 2 .

Table 2

Comparison of baseline clinical parameters according to in-hospital mortality

	Mortality (+) N=148	Mortality (-) N=572	P value
Age, years, mean±SD	74.5 [35-95]	64 [19-96]	0.001
Sex (male), n(%)	88 (59.5)	283 (49.4)	0.029
Diabetes Mellitus, n(%)	59 (39.9)	186 (32.5)	0.093
Hypertension, n(%)	97 (65.5)	298 (52.1)	0.003
Chronic Pulmonary Disease, n(%)	40 (27.0)	70 (12.2)	<0.001
Coronary Artery Disease, n(%)	44 (29.7)	78 (13.6)	<0.001
Peripheral Artery Disease, n(%)	5 (3.4)	9 (1.6)	0.156
Chronic Heart Failure, n(%)	23 (15.5)	23 (4.0)	<0.001
Cerebrovascular disease, n(%)	20 (13.5)	19 (3.3)	<0.001
Cancer, n(%)	23 (15.5)	28 (4.9)	<0.001

SD: Standard deviation

Outcomes

We found that PESI and sPESI scores were independent predictors of all investigated adverse events in patients with COVID-19 PCR (+) and no VTE. Additionally, we found that in-hospital mortality was higher in patients with advanced age, male gender, hypertension, chronic lung disease, coronary artery disease, heart failure, cerebrovascular disease and cancer.

PESI and sPESI calculated by using the clinical parameters obtained when the patient was admitted to the hospital, were compared in terms of in-hospital mortality. Heart rate >100, respiratory rate more than 30 breaths per minute, arterial oxyhemoglobin- saturation <90% and temperature <36°C was found to be statistically significantly elevated in the mortality group (p<0.001). When the patients were examined according to their first hospitalization place after admission, the mortality rate was increased in the ICU patients (70 (65.5%) vs 30 (5.4%), p<0.001). Mortality related comparison of baseline electrocardiogram parameters, drug usage and clinical manifestations are shown in Table 3 . The comparison of each sPESI score and PESI class according to in-hospital mortality is shown in Table 4 . We also compared the sPESI score among each other's in terms of in-hospital mortality. The difference was found to be statistically significant among sPESI score (p<0.001). However, in subgroup analyses the difference between the sPESI scores was not significant when sPESI was 4 or above (p=0.343).

Table 3

Comparison of baseline electrocardiogram parameters, drug usage, clinical manifestations and PESI scores according to in-hospital mortality

	Mortality (+) N=148	Mortality (-) N=572	P value
Electrocardiogram
Atrial fibrillation	29 (19.6)	28 (4.9)	0.001
ST segment depression	17 (12.0)	27 (6.3)	0.027
T wave inversion	18 (12.7)	50 (11.6)	0.834
QRS fragmentation	9 (6.3)	30 (7.0)	0.798
LBBB	11 (7.7)	10 (2.3)	0.003
RBBB	7 (4.9)	23 (5.3)	0.850
Drug useage
Antiplatelet	60 (40.5)	158 (27.6)	0.002
Beta-blocker	45 (30.4)	145 (25.3)	0.214
Calcium channel blocker	34 (23.0)	136 (23.5)	0.872
Alfa blocker	7 (4.7)	25 (4.4)	0.850
ACEI	20 (13.5)	86 (15.0)	0.641
ARB	33 (22.3)	122 (21.3)	0.798
Diuretic	49 (33.1)	153 (26.7)	0.125
Oral anticoagulant	29 (19.6)	37 (6.5)	<0.001
Clinical manifestations, PESI scoring
Pulse rate ≥110 bpm	32 (22)	52 (9)	<0.001
Respiratory rate >30 breaths per minute	35 (24)	28 (5)	<0.001
Arterial oxyhaemoglobin- saturation <90%	22 (15)	18 (3)	<0.001
Temperature <36°C	43 (29)	65 (11)	<0.001
ICU hospitalization at admissionPESI, pointsPESI, point	70 (65.4)231 [136-303]3 [1-6]	30 (5.4)94 [35-246]1 [0-4]	<0.001<0.001<0.001

Variables are expressed as n (%) and median [minimum-maximum]. Abbrreviations: ACEI; Angiotensin Converting Enzyme Inhibitors, ARB; Angiotensin Receptor Blockers, ICU; Intensive Care Unit, LBBB; Left Bundle Branch Block, PESI; Pulmonary Embolism Severity Index, sPESI; simplified Pulmonary Embolism Severity Index, RBBB; Right Bundle Branch Block.

Table 4

Comparison of each sPESI and PESI score group according to in-hospital mortality

	Mortality (+)	Mortality (-)	P value
sPESI			<0.001
0	(0)0	259 (45.4)
1	6 (4.1)	172 (29.6)
2	36 (24.3)	95 (16.6)
3	41 (27.7)	41 (7.2)
4	55 (37.2)	5 (0.9)
5	8 (5.4)	0 (0)
6	2 (1.4)	0 (0)
PESI			<0.001
0-65	0 (0)	61 (10.7)
66-85	0 (0)	141 (24.7)
86-105	5 (3.4)	184 (32.2)
>105	143 (96.6)	186 (32.5)

Variables are expressed as n (%).

Abbrreviations: PESI; Pulmonary Embolism Severity Index, sPESI; simplified Pulmonary Embolism Severity Index.

Multivariate logistic regression analysis was performed to determine the relationship between PESI/sPESI and adverse events in hospitalized COVID-19 patients. Adverse events, such as the development of ARDS, the need for ICU, invasive or noninvasive MV and in-hospital mortality, were significantly associated with PESI and sPESI (Table 5 ). ROC curve analysis was performed to examine the power and cut-off value of sPESI in predicting in-hospital mortality (Figure 1 ). We concluded that sPESI≥2 predicts in-hospital mortality with a sensitivity of 61.4% and a specificity of 83.3% (AUC=0.817, 95% CI= 0.787–0.845, p<0.001). The patients were divided into five classes according to their PESI scores. Patients in PESI Class 1 were accepted as baseline. Regression analysis was used to detect whether the other four PESI classes were independent risk factors for in-hospital mortality or not. It was concluded that PESI Class 4 and 5 were independent risk factors for in-hospital mortality, Figure 2 (for PESI class 4; OR= 2.81, 95% CI= 1.53–5.84, p<0.017, for PESI class 5; OR= 3.94, % 95CI= 2.13–11.18, p<0.001).

Table 5

Multivariate logistic regression analysis to determine the relation of PESI and sPESI with adverse events in hospitalized COVID-19 patients

	OR	P value
sPESI
Non-invasive MV need	2.304 (1.925±2.733)	<0.001
ICU need	3.214 (2.625±3.927)	<0.001
ARDS	3.183 (2.570-3.944)	<0.001
Invasive MV need	3.104 (2.520- 3.823)	<0.001
Mortality	3.323 (2.666-4.141)	<0.001
PESI
Non-invasive MV need	1.031 (1.027±1.036)	<0.001
ICU need	1.066 (1.054±1.078)	<0.001
ARDS	1.085 (1.066-1.105)	<0.001
Invasive MV need	1.086 (1.067- 1.106)	<0.001
Mortality	1.080 (1.062-1.098)	<0.001

Abbrreviations: ARDS; Acute Respiratory Distress Syndrome, ICU; Intensive care unit, OR: Odds ratio, MV; mechanical ventilation, PESI; Pulmonary Embolism Severity Index, sPESI; simplified Pulmonary Embolism Severity Index.

Figure 1

ROC curve showing the distinguishing ability of sPESI for mortality.

Figure 2

Logistic regression analysis to determine the relation of PESI (Pulmonary Embolism Severity Index) class with in-hospital mortality in COVID-19 patients.

When the electrocardiographies (ECGs) of all patients were evaluated, the frequency of atrial fibrillation (AF), left bundle branch block (LBBB) and ST segment depression were found to be significantly high in the mortality group. The frequency of antiplatelet and anticoagulant drug usage was also high in the mortality group. There were no significant differences between the two groups in terms of the frequency of the usage of other medications.

Discussion

This study hypothesized that there may be a relationship between PESI/sPESI scores and poor outcomes as well as survival in hospitalized COVID-19 patients. The major implications of a high PESI/sPESI score from our study were found to be: (1) worsening of the clinical outcomes, (2) ICU requirement, and (3) in-hospital death.

The COVID-19 pandemic still affects many people all around the world. The overall mortality rate from COVID-19 in hospitalized patients ranges from 15% to 20%, but it may be up to 40% for patients requiring admission to the ICU 9. Various laboratory markers, clinical factors and risk scores can be used to determine the need for ICU and in-hospital mortality rate in COVID-19 patients 10. Among them, advanced age is the most important predictor of mortality 11.

COVID-19 infection has been associated with a hypercoagulable state that may lead to increased risk of VTE and pulmonary thrombosis/thromboembolism 12. Although the actual rate of VTE in patients hospitalized with COVID-19 is elusive, it varies from 4.8% to 85% according to the recent studies 13-15. Jimenez et al. evaluated meta-analysis of 36 studies with more than 11,000 patients and found that the rate of VTE in COVID-19 patients was 17% (12% for DVT, 7.1% PE) 14. However, postmortem studies reported high rate of VTE 16, 17.

PESI is a proven risk scoring system used in acute thromboembolism risk classification. According to the study of Xu et al., 101 hospitalized COVID-19 patients with PE confirmed by pulmonary CT angiography were evaluated and found that the patients with intermediate to high-risk PESI (Class 3, 4 and 5) had worse outcomes than the patients with low-risk PESI (Class 1 and 2), resulting in high percentage of ICU admission (29% vs 11%; p = 0.038) and high mortality rate (27% vs 6%; p = 0.007) 18. In this study, most patients (65%) had intermediate to high-risk PESI (>85), which portended a worse prognosis with high mortality rate and prolonged length of stay. However, unlike our study, the hospitalized COVID-19 patients with PE were also enrolled into this study.

In another study, a new score (modified-sPESI (m-sPESI)) was developed in COVID-19 patients, by changing the age limit from >80 to >65. In this study, the relationship between ICU requirement and m-sPESI was detected 19. Patients who had a history of DVT/PE were not included. However, it was not investigated whether the patients were diagnosed with PE during their hospitalization. As a result of this study, it was found that the modified-sPESI predicted the need for intensive care with high specificity and sensitivity (AUC=0.948; 84.6% sensitivity and 94.6% specificity, p < 0.001).

To our knowledge, there has been no published study on the prognostic effects of PESI or sPESI in hospitalized COVID-19 patients without documented VTE/PE. As a result of our study, we concluded that the PESI and sPESI measured at diagnosis are independent risk factors for in-hospital adverse events in hospitalized COVID-19 patients without documented VTE/PE. We also found that a PESI class of 4 and 5 at the time of diagnosis and sPESI ≥2 can be used as a strong predictor of in-hospital mortality in this patient population. As we mentioned before, predicting COVID-19 prognosis is critical to determining the progression of the disease and treatment protocols. According to our findings, PESI and sPESI on admission to the hospital are useful in determining adverse events in hospitalized COVID-19 patients. In other words, we can determine the risk status of hospitalized COVID-19 patients according to PESI and sPESI values on admission to the hospital, and we may be more courageous in applying anticoagulant and specific treatments.

The reason why the PESI/sPESI are related to adverse events may be the presence of undiagnosed VTE/PE in hospitalized COVID-19 patients. It is difficult to diagnose PE in COVID-19 patients by virtue of the similarity of symptoms and laboratory findings for both conditions. Additionally, the fact that the histopathologically diagnosed VTE diagnosis rates were much higher than the clinical rates may have caused these results.

As in previous COVID-19 studies, mortality was found to be elevated in patients with hypertension, diabetes mellitus, cerebrovascular disease, heart failure, chronic obstructive pulmonary disease, and coronary artery disease, as well as in male sex and older age groups 20, 21. In our study, patients with diabetes mellitus were also significantly high in the mortality group in consistent with previous studies. However, this difference was not statistically significant (39.9 % vs 32.5%, p=0.093). Cancer patients have an increased risk of COVID-19 infection due to their immunosuppressive state and cancer treatment, and their prognosis is poorer than the general population 22. COVID-19 is more fatal, especially in cancer patients above the age of 70 years 23, 24. In our study, 7% of the patients hospitalized with COVID-19 were diagnosed with cancer. The incidence of cancer was significantly high in the mortality group (15.5% vs. 4.9%, p<0.001).

The frequency of peripheral artery disease (PAD) was found to be 1.9% in our study, and no significant correlation was found with in-hospital mortality. Smolderen et al. found a significant relationship between PAD and overall mortality and major cardiac events in their study 25. This difference may be related to the retrospective design of our study, as well as the presence of undiagnosed patients with PAD. Additionally, while in-hospital mortality was evaluated in our study, overall mortality was evaluated in the study by Smolderen et al.

In our study, ECG features of the patients were also examined. The ECG abnormalities in COVID-19 may be due to cytokine storm, electrolyte abnormalities, hypoxic injury, plaque rupture, microthrombi, coronary spasm and/or myocardial injury 26. The frequency of AF was found to be higher in the mortality group (19.6% vs. 4.9%, p=0.001). According to meta-analysis by Romiti et al., the prevalence of AF was found as 8% in patients with COVID-19 and the risk of all-cause mortality was high in patients with AF than non-AF patients with a high degree of heterogeneity (OR: 3.97, 95% CI: 2.76–5.71) 27. Left bundle branch block (LBBB) has previously been associated with mortality in COVID-19 patients. In our study, the frequency of LBBB was found to be higher in the mortality group (7.7% vs 2.3% p=0.003). However, we did not find a relationship between ST segment depression and T wave inversion and mortality. In the study by Lanza et al., AF, LBBB, and ST segment depression were associated with mortality 28. They also concluded that LBBB is an independent risk factor for mortality (HR=9.48, 95%CI= 3.37–26.6, p<0.001). In the same study, no relationship was found between right bundle branch block (RBBB) and mortality. Also in our study, no significant relationship was found between the presence of RBBB and mortality (4.9% vs 5.3, p=0.850).

Limitations

The major limitations of our study are its retrospective design and a short time participation period. Another limitation of our study was that all patients did not undergo routinely any imaging method to rule out VTE and PE. Only patients with clinical suspicion were screened for VTE and/or PE by imaging methods. As a result, we excluded patients with confirmed PE and/or VTE. However, among the included patients, there may have been many patients who had undiagnosed VTE and/ or PE. This imparts bias to the findings.

In addition to these, the patient population included in our study reflects the pre-vaccination era of the COVID-19 Pandemic. The management of hospitalized COVID-19 patients has changed over time with the invention of the COVID-19 vaccines, the changes in treatment protocols, and prophylactic anticoagulant therapies. New studies may be planned in the future to examine how the PESI and sPESI scoring systems predict the risk of adverse events in vaccinated patients or different variants. Nevertheless, this study provides precious prognostic information regarding the COVID-19 clinical course and it will shed light on future studies.

Conclusion

Our study demonstrates that PESI and sPESI scores can successfully determine clinical deterioration, need for ICU admission, and in-hospital mortality of hospitalized COVID-19 patients without clinically documented venous or pulmonary thromboembolism.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Approval was obtained from the Turkish Republic Ministry of Health, General Directorate of Health Services, COVID-19 Scientific Research Evaluation Commission (No: 2020-11-11T14_36_01) before applying to the ethics committee. Zonguldak Bulent Ecevit University Non-Interventional Clinical Research Ethics Committee approved our study (dated 02/12/2020 and protocol numbered 2020/23).

Declaration of conflicting of interest

The author(s) declared no potential conflicts of interest for this article.