Background
An interleukin-6 (IL-6) is a proinflammatory cytokine which plays an important role in COVID-19-associated hyperinflammation.
Aim. This study aimed to assess the predictive ability of serum IL-6 levels for the development of severe/critical clinical conditions, a hypoxemic state requiring supplemental oxygen, and lethal outcomes in patients with COVID-19-associated pneumonia and arterial hypertension (AH).
Materials and Methods
One hundred and thirty-five unvaccinated patients hospitalized for COVID-19-associated pneumonia were enrolled in the study. AH was diagnosed in 78.5% of cases. Pneumonia was confirmed radiologically. SARS-COV-2 as an etiological factor was confirmed by either PCR or ELISA. In addition to conventional laboratory tests, IL-6, ferritin, and soluble interleukin-2 levels were measured.
Results
Among AH patients, the median levels of IL-6 were higher in non-survivors (95.1 [37.8 - 158.8] pg/mL) as compared to survivors (39.5 [13.6 - 81.1] pg/mL) (p = 0.04). Among AH patients, the median serum level of IL-6 was 98.3 [37.8 - 158.8] pg/mL in critically ill patients, 41.7 [11.8 - 83.4] pg/mL in severely ill patients, 37.8 [13.6 - 74.4] pg/mL in moderately ill patients (p = 0.051). The median serum level of IL-6 was lower at the time of discharge (6.5 [2.0 - 21.5] pg/mL) as compared to that on admission (43.2 [16.1 - 92.0] pg/mL) (p< 0.001). IL-6 level failed to predict severe/critical condition (AUC=0.59, p = 0.13) and the need for supplemental oxygen (AUC=0.61, p = 0.06); however, it might be used for the prediction of the lethal outcome (AUC=0.69, p = 0.03). The cut-off value of IL-6 level for lethal outcome prediction of 91.0 pg/mL showed a sensitivity of 58.3% and a specificity of 78.7%. Patients with IL-6 levels > 91.0 pg/mL on admission had higher odds of lethal outcomes (OR = 4.87 [1.40 - 16.92], p = 0.01).
Conclusions
Serum IL-6 level on admission did not show significant predictive ability for severe/critical conditions and hypoxemic states requiring supplemental oxygen in AH patients. However, serum IL-6 levels on admission were higher in non-survivors and might be used for the prediction of lethal outcomes with a cut-off value of 91.0 pg/mL in AH patients.
Keywords:
COVID-19, Interleukin-6, Hypertension, Pneumonia, Predictive ValuePublication history
Copyright & License
Categories:
Research Article | Internal Medicine
Acknowledgments
Introduction
A novel coronavirus as a causal agent of severe acute respiratory syndrome was first described in December 2019 in China [1]. Afterwards this virus was named SARS-CoV-2 and spread rapidly worldwide causing a pandemic. According to the World Health Organization (WHO) reports, as of 23 June 2022, there were almost 540 million confirmed cases of COVID-19, including over 6.3 million deaths globally [2]. One of the most common manifestations of COVID-19 is pneumonia which may progress into acute respiratory distress syndrome [3, 4].
Severe COVID-19 cases are associated with hyperinflammation, leading to macrophage activation syndrome [5]. The devastating effect of immune dysregulation is considered to play a critical role in the deterioration of the patient’s condition [6]. In fatal cases, COVID-19 was found to lead to the hyperactivation of cytotoxic T-cells with high concentrations of cytotoxic granules [7]. An interleukin-6 (IL-6) is a proinflammatory cytokine that activates T- and B-cells [8]. IL-6 level rises in macrophage activation syndrome, as the cytokine is released by alveolar macrophages upon lung infection [9].
Lower IL-6 levels were found to be associated with a milder clinical course of COVID-19 [10]. Patients with complicated COVID-19 have 2.9-fold higher IL-6 levels than those with uncomplicated disease [11]. IL-6 level may predetermine the disease progression and is found to be significantly higher in non-survivors [12, 13]. An abrupt increase in the circulating IL-6 level was found in deceased patients [14].
IL-6 level as a predictor of severe disease and in-hospital death has been widely studied. IL-6 levels are higher in non-survivors as compared to survivors [15]. Furthermore, IL-6 level is found to be an independent prognostic factor for COVID-19 severity and mortality [16]. It should be noted that the presence of comorbidity or chronic diseases may potentially impact COVID-19 progression [17]. Thus, 49.7% of patients hospitalized for COVID-19 have arterial hypertension (AH) [18], which is associated with a 2-fold increase in mortality rate and incidence of severe COVID-19 [19]. The assessment of the association between IL-6 levels and lethal outcomes in AH patients is important, as an early intensive strategy may improve the patients’ prognosis. Thus, the assessment of the predictive value of IL-6 level for the prediction of the severe clinical condition and hypoxemic state requiring supplemental oxygen in AH patients is meaningful.
This study aimed to assess the predictive ability of serum IL-6 levels for severe/critical clinical condition development, a hypoxemic state requiring supplemental oxygen, and lethal outcomes in patients with COVID-19-associated pneumonia and AH.
Materials and Methods
Study Design
This was a single-centre, prospective clinical study conducted in the Ivano-Frankivsk Central City Hospital and the Ivano-Frankivsk City Hospital No. 1. The patients were enrolled between March and June 2021.
Study Population
One hundred and thirty-five adult patients hospitalized for COVID-19-associated pneumonia were enrolled in the study. All patients were not vaccinated for COVID-19. A total of 106 (78.5%) patients had AH.
The main characteristics of patients enrolled in the study are shown in Table 1.
Diagnostic Statements
Pneumonia was confirmed by chest computed tomography or chest X-ray. Coronavirus SARS-CoV-2 as an etiological agent of pneumonia was confirmed with either polymerase chain reaction (PCR) or ELISA test, with the assessment of immunoglobulin M (IgM) level.
The diagnosis of AH was made in accordance with the criteria of the 2018 European Society of Cardiology guidelines [20]. Pneumonia severity was assessed in accordance with the CURB-65 score [21, 22].
The severity of COVID-19-associated pneumonia was assessed according to the Protocol of Medical Care for Treatment of Coronavirus Disease (COVID-19) [23]. A severe clinical condition was defined in the presence of at least one of the following characteristics: respiratory rate ≥ 30 breaths per minute; oxygen saturation ≤ 93%; pulmonary infiltrates involving > 50% of the lung area. The critical condition was defined in the presence of at least one of the following signs: acute respiratory distress syndrome; sepsis; altered consciousness; multiple organ dysfunction syndrome.
Disease severity of all enrolled patients is shown in Fig. 1.
In addition to conventional laboratory tests (complete blood count, urinalysis, fasting glucose, biochemical profile), levels of IL-6 (IL E-3200 Interleukin-6, “Novamedline”, ELISA test), soluble IL-2 receptors (30166211, sInterleukin-2-Receptor, “IVSet”, ELISA test), and ferritin (L2KFE2, Immulite 2000 Ferritin, “Siemens”, ELISA test) were measured. A PCR test and ELISA test with the assessment of IgM level (in patients with negative PCR test) were performed as well.
Patient Management
All patients were treated in accordance with the Protocol of Medical Care for Treatment of Coronavirus Disease (COVID-19) [23]. All patients received corticosteroids and either low-molecular-weight heparin or unfractionated heparin.
Statistical Analysis
Statistical processing of the study results was performed using the software Statistica 10, MedCalc, and MS Excel. The Shapiro-Wilk test was used to evaluate the distribution of variables. Descriptive statistics for data with non-normal distribution are presented as the median and interquartile range (Me [Q1 - Q3]). Mean with standard deviation (Mean ± SD) was calculated for descriptive statistics for data with normal distribution. The Mann-Whitney U test, the Kruskal-Wallis test with the post-hoc Dunn’s test, the Wilcoxon signed-rank test, the Chi-square test, the Odds ratio (OR), and the Spearman’s rank correlation analysis were used. A p-value < 0.05 was considered significant.
Results
The median level of IL-6 at the time of admission in AH patients did not significantly differ from that in patients without AH (Table 2). However, serum soluble interleukin-2 receptor (sIL-2R) level was higher in AH patients. Among AH patients, there was no statistically significant difference in IL-6 serum levels in terms of clinical condition (moderate - 37.8 [13.6 - 74.4] pg/mL, severe - 41.7 [11.8 - 83.4] pg/mL, critical - 98.3 [37.8 - 158.8] pg/mL; p = 0.051).
There was no statistically significant difference in IL-6 levels among AH patients in terms of gender (males - 30.7 [12.7 - 83.9] pg/mL, females - 50.6 [20.0 - 93.6] pg/mL; p = 0.24) and hypoxemic state (the need for supplemental oxygen - 63.5 [20.0 - 110.8] pg/mL, no need for supplemental oxygen - 37.0 [10.8 - 68.4] pg/mL; p = 0.06).
The lethal outcome was observed in 12 (11.3%) AH patients. Fig. 2 presents serum IL-6 levels in survivors and non-survivors with AH and all enrolled patients on admission.
Fig. 2
Serum IL-6 levels in survivors and non-survivors with arterial hypertension (a) and all enrolled patients (b) on admission.
At the time of discharge, in survivors, the median level of IL-6 was 6.5 [2.0 - 21.5] pg/mL in patients with AH and 18.2 [2.0 - 37.2] pg/mL in patients without AH (p = 0.39). Serum IL-6 level was significantly lower in AH patients at the time of discharge as compared to that on admission (p < 0.001); however, this was not statistically significant in patients without AH (p = 0.07).
There was a moderate positive correlation between IL-6 and ferritin levels (r = 0.35, p<0.001) in AH patients. In AH patients, there was no correlation between the levels of IL-6 and sIL-2R (r = 0.18, p = 0.07). In patients without AH, IL-6 level did not correlate with ferritin level (r = -0.17, p = 0.39) and sIL-2Rs (r = -0.26, p = 0.18).
The predictive abilities of IL-6 level for the development of severe and critical clinical conditions, supplemental oxygen requirement, and in-hospital lethal outcomes in AH patients on admission are shown in Table 3 and receiver operating characteristic (ROC) curves are presented in Fig. 3-5.
Table 3.
Predictive ability of serum IL-6 level for the development of severe/critical clinical conditions, a hypoxemic state requiring supplemental oxygen, and lethal outcomes in patients with arterial hypertension.
Fig. 3
ROC curve of IL-6 serum level on admission for prediction of severe/critical clinical condition in patients with arterial hypertension.
Fig. 4
ROC curve of IL-6 serum level on admission for prediction of hypoxemic state requiring supplemental oxygen in patients with arterial hypertension.
Fig. 5
ROC curve of IL-6 serum level on admission for prediction of in-hospital lethal outcome in patients with arterial hypertension.
IL-6 serum level failed to predict severe/critical clinical condition (Area Under the Curve (AUC) = 0.585, p = 0.13) and hypoxemic state requiring supplemental oxygen (AUC=0.606, p = 0.06). There was acceptable discrimination (AUC = 0.688, p = 0.03) of IL-6 serum levels in the prediction of lethal outcomes. However, the Youden index was 0.37 indicating the inability of serum IL-6 level to predict the lethal outcome. The cut-off value of IL-6 level of > 91.0 pg/mL showed a sensitivity of 58.3% and a specificity of 78.7%. Patients with such IL-6 levels at the time of admission had higher odds of lethal outcomes (OR = 4.87 [1.40 - 16.92], p = 0.01).
Discussion
Our study showed that IL-6 level was higher in non-survivors. Multiple studies showed similar results. In a study of Guirao et al., higher levels of IL-6 were associated with severe COVID-19 course, mechanical ventilation requirements in the intensive care unit (ICU), and mortality [24]. The cut-off value of serum IL-6 levels of 35 pg/mL was proposed; both the risk of mortality (OR = 20.00, p = 0.0001) and ICU admission (OR = 12.75, p = 0.005) increased in patients with IL-6 level above this cut-off point [24]. Another study showed that non-survivors had higher IL-6 levels than survivors; the optimal cut-off value of IL-6 level was considered as 30.95 pg/mL [25]. Population with elevated IL-6 had a higher mortality rate (28.2% vs 5%; p = 0.0001, OR = 7.47) [26].
A study by Zhou et al. showed that elevated IL-6 levels were associated with an increase in the incidence of critical cases, acute respiratory distress syndrome, mechanical ventilation rate, and mortality [27]. Serum IL-6 concentration is an independent predictor of the lethal outcome; the optimal cut-off value for predicting the lethal outcome is 26.09 pg/mL [27].
Our study showed some tendency towards an increase in serum IL-6 level on admission with clinical condition worsening in AH patients, although statistical significance was not achieved. According to Zhou et al. a higher level of IL-6 predicted a more severe clinical condition [28]. In a study by Sun et al., IL-6 levels were higher in patients with severe COVID-19 and non-severe disease [29]. A meta-analysis conducted by Mojtabavi et al. showed that patients with severe COVID-19 had 23.1 pg/mL higher IL-6 as compared to patients with non-severe COVID-19 [30].
Liu et al. reported that IL-6 level might be an independent risk factor for disease severity and in-hospital mortality [31]. However, among ICU patients, IL-6 failed to predict clinical outcomes in terms of survivors vs. non-survivors [32].
Sabaka et al. reported a significant predictive ability of IL-6 level (AUC = 0.911, p = 0.0001), with high sensitivity (100.0%), specificity (88.9%), positive predictive value (76.9%), and negative predictive value (100.0%) of the cut-off value > 24 pg/mL in the prediction of the development of hypoxemia requiring supplemental oxygen [33]. In our study, the values for the development of severe or critical clinical conditions (AUC = 0.585, p = 0.13) and hypoxemia requiring supplemental oxygen (AUC = 0.606, p = 0.06) were significantly lower. These differences may be explained by differences in disease severity at the time of recruitment in these studies. Our study studied the predictive ability of IL-6 level in AH patients only, while a study by Sabaka et al. included ambulatory patients, among whom, 54.2% of patients were hospitalized [33].
In addition, a study conducted by Gao et al. showed acceptable discrimination of IL-6 levels for severe COVID-19 (AUC = 0.795, p < 0.001) [34]. Broman et al. supported these results and concluded that IL-6 was one of the strongest predictors of severity in patients hospitalized for COVID-19 [35]. Gorham et al. demonstrated the predictive ability of IL-6 level for ICU mortality (AUC = 0.73, p = 0.01) similar to data from our study [36]. A study conducted by Aykal et al. showed an important role of this marker as a predictor of severe clinical condition in patients with COVID-19 [37]. This study showed that patients with severe condition had higher IL-6 levels than patients with moderate and mild conditions. The AUC for IL-6 level as a predictor of severe clinical condition was 0.864 (p < 0.001) [37].
A model using both IL-6 and IL-10 suggested by Dhar et al. showed high predictive ability for severe COVID-19 (AUC = 0.957; accuracy 91.7%), whereas IL-6 (AUC = 0.821; accuracy 77.8%) and IL-10 (AUC = 0.878; accuracy 80.6%) taken individually showed far lower predictive ability [38].
Yamamoto et al. found that IL-6 level on day 3 after admission had satisfactory discrimination ability for mortality in critically ill patients (AUC = 0.766; p < 0.001) [39]. IL-6 level showed somewhat lover discriminative ability in hospitalized patients (AUC = 0.74, p < 0.0001), according to a study by Laguna-Goya et al. [40]. However, a meta-analysis conducted by Liu et al. showed no predictive ability of IL-6 level for mortality (AUC = 0.531 with a sensitivity of 0.15 and a specificity of 0.73) [41]. Our study showed a lower discriminative ability of IL-6 level for the prediction of lethal outcomes (AUC = 0.688, p = 0.03, Youden index = 0.37).
There is a wide range of optimal cut-off values for lethal outcome prediction. Avila-Nava et al. reported that the optimal cut-off value was 30.95 pg/mL with a Youden index of 0.57 and for each 100 pg/mL the probability of lethal outcomes increased by 10% [25], whereas according to the research by Mandel et al., the optimal cut-off value was 163.4 pg/mL with a sensitivity of 91.7% and a specificity of 57.6% [42]. Milenkovic et al. reported that the optimal cut-off value of IL-6 for lethal outcome prediction was 74.98 pg/mL [43]. Our study showed the optimal cut-off point of 91.0 pg/mL for the prediction of in-hospital mortality in AH patients.
Dynamic IL-6 changes may predict lung injury in COVID-19 and guide future treatment of patients [31]. Serum levels of post-tocilizumab IL-6 showed a good predictive ability to discriminate survivors from non-survivors (AUC = 0.815, p = 0.02) [44]. Galván-Román et al. showed that early administration of tocilizumab for patients with high IL-6 levels is associated with improved oxygenation [45]. Targeting IL-6 levels with tocilizumab reduces the mortality rate in patients with COVID-19 [46]. Anti-IL-6 signaling agents in addition to standard care reduced the mortality rate in COVID-19 [47].
There was a correlation between serum levels of IL-6 and ferritin (r = 0.64, p = 0.0001) [48]. Chen at el. reported no correlation between IL-6 level and sIL-2Rs [49]. Our correlation analysis demonstrated similar results.
Our research study significantly differs from the studies listed above as we studied the predictive ability of serum IL-6 levels in AH patients, while other studies included the general population. The results of our research may be extrapolated on patients hospitalized for COVID-19-associated pneumonia suffering from AH only. Measurement of IL-6 level on admission is important as high levels predict in-hospital lethal outcome. This enables categorizing patients with high IL-6 levels as a high-risk group requiring meticulous monitoring of clinical condition.
Limitations
Our study has some limitations; therefore, the findings need to be interpreted carefully: firstly, our study was limited by the number of participants; secondly, our study included unvaccinated patients only, which means that the results of the study cannot be extrapolated to the general population; thirdly, no patient with mild condition was included in this study as all enrolled patients were hospitalized with COVID-19-associated pneumonia.
Conclusions
Serum IL-6 level on admission did not show significant predictive ability for severe/critical conditions and hypoxemic states requiring supplemental oxygen in AH patients. However, serum IL-6 levels on admission were higher in non-survivors and might be used for the prediction of lethal outcomes with a cut-off value of 91.0 pg/mL in AH patients.
Ethical Statement & Informed Consent
The research was approved by the Bioethical Committee of Ivano-Frankivsk National Medical University. A consent form was signed by each prospective participant before recruitment into the study. All the procedures in the study met bioethical standards according to the Helsinki Declaration.
Acknowledgments
Conflict of interest: The authors declare that no conflicts exist.
Financial Disclosure: The authors declared no financial support.
Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Appendices
Appendix 1
Comorbidities and drugs received by hypertensive and non-hypertensive patients before hospitalization (Table).