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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 68-75

Clinical Significance of Serial Measurements of Interleukin-6 and High-Sensitivity C-Reactive Protein as Early Predictor of Poor Neurological Outcome in Aneurysmal Subarachnoid Haemorrhage


1 Department of Neurosurgery, Govind Ballabh Pant Institute of Medical Education and Research, New Delhi, India
2 Department of Neurosciences, BLK-MAX Hospital, New Delhi, India
3 Department of Biochemistry, Govind Ballabh Pant Institute of Medical Education and Research, New Delhi, India

Date of Submission04-Jan-2022
Date of Decision10-Jan-2022
Date of Acceptance14-Jan-2022
Date of Web Publication5-Apr-2022

Correspondence Address:
Dr. Amit Kumar Sharma
Department of Neurosurgery, Govind Ballabh Pant Institute of Medical Education and Research, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcvs.jcvs_4_22

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  Abstract 


Introduction: The inflammatory events are implicated in the pathophysiology of subarachnoid haemorrhage (SAH) and secondary brain injury. The goal of this study was to determine the role of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) as an early predictor of the poor neurological outcome at 6 months in individuals with SAH.
Methods: In this prospective, observational study of consecutive patients with aneurysmal SAH included over 1 year. Peak IL-6 and hsCRP were used as an indicator of the inflammatory response. Initial IL-6 and hs-CRP levels were collected within 12 h from admission and then for the next consecutive 7 days. The primary outcome was neurological status at 6-month follow-up assessed with the Modified Rankin Scale (0–6) with a score with or higher than 3 labelled as poor outcome. Logistic regression analyses were used to evaluate the associations between the peak serum IL-6 and hs-CRP levels and the neurological outcome.
Results: The median peak levels of both markers were significantly higher in the poor outcome group on all 7 days. A significant correlation was seen between peak IL-6 and poor Hunt and Hess grade (P = 0.006), infarction (0.033) and systemic infection (0.03), whereas peak hsCRP had a correlation with rebleed (P = 0.017) and clipping (P = 0.032). Significant risk factors for the poor outcome were poor Hunt and Hess grade (P < 0.000) and high Fisher grades (P = 0.021) and peak IL-6 levels (P = 0.014) on regression analysis.
Conclusion: The serial measurements of inflammatory markers IL-6 and hsCRP may be used to predict the neurological outcome in aSAH patients. The peak IL-6 levels correlated significantly with poor neurological outcome. Although hsCRP was elevated in patients with the poor outcome, it was statistically non-significant, suggesting a non-specific inflammatory stress response.

Keywords: High-sensitivity C-reactive protein, interleukin-6, Modified Rankin Scale, subarachnoid haemorrhage


How to cite this article:
Sharma AK, Mamualiya R, Inganal R, Singh D, Mahajan B. Clinical Significance of Serial Measurements of Interleukin-6 and High-Sensitivity C-Reactive Protein as Early Predictor of Poor Neurological Outcome in Aneurysmal Subarachnoid Haemorrhage. J Cerebrovasc Sci 2021;9:68-75

How to cite this URL:
Sharma AK, Mamualiya R, Inganal R, Singh D, Mahajan B. Clinical Significance of Serial Measurements of Interleukin-6 and High-Sensitivity C-Reactive Protein as Early Predictor of Poor Neurological Outcome in Aneurysmal Subarachnoid Haemorrhage. J Cerebrovasc Sci [serial online] 2021 [cited 2022 May 22];9:68-75. Available from: http://www.jcvs.com/text.asp?2021/9/2/68/342562




  Introduction Top


Inflammatory events are crucial in subarachnoid haemorrhage (SAH) pathophysiology. The inflammatory events are implicated in the pathophysiology of SAH and secondary brain injury.[1] The outcome of aSAH is determined not only by the haemorrhage alone but also by complications that may arise soon after ictus, including rebleed, vasospasm, hydrocephalus, cardiomyopathy and infections. The outcome has improved over time due to advancements in aneurysm management techniques and the establishment of committed neurointensive care units.[2],[3],[4]

Substantial evidence suggests the role of inflammatory mediators in the development of complications such as vasospasm, delayed cerebral ischaemia (DCI) and hydrocephalus, all of which have a negative effect on the outcome.[5],[6],[7],[8],[9] Numerous potential serum biomarkers have been investigated, including oxidative stress molecules such as nitric oxide, inflammatory cytokines such as Interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha, brain injury biomarkers like S100B and endothelial injury factor-like endothelin-1. A major objective has been to identify biomarkers that can classify the disease course, predict the possible complications, and serve as possible therapeutic targets.[10]

In SAH, mononuclear leucocytes release inside the blood clot in the subarachnoid space release IL-6.[11],[12] The increased cerebrospinal fluid (CSF) IL-6 levels are found to be associated with vasospasm following the rupture of an intracranial aneurysm.[13],[14],[15]

C-reactive protein (CRP) is another valuable marker of systemic inflammation in general.[16],[17] Recent research indicates that there is a correlation between increased CRP levels with vasospasm and DCI following SAH.[18],[19],[20],[21] As a result, measuring CRP concentrations can aid in the prediction of clinical outcomes in patients with SAH. As a result, measuring CRP concentrations can aid in the prediction of clinical outcomes in patients with SAH.[18],[22] It is unknown, however, whether initial/maximal CRP levels or changes in their levels, accurately predict neurological outcomes in patients with SAH. When compared to other acute-phase reactants, high-sensitivity CRP (hsCRP) is the preferred analyte for cardiovascular risk assessment due to its superior assay precision, accuracy, availability and the presence of standards for proper calibration. hsCRP measures trace amounts of CRP in the blood.

It would be beneficial to provide a biochemical marker to aid in the early stages of SAH in predicting clinical outcomes. The CSF space with blood triggers a sequence of inflammatory cascades in patients with SAH. It would be beneficial to provide a biochemical marker to aid in the early stages of SAH in predicting clinical outcomes. Numerous studies have shown an increasing understanding that inflammation, both local and systemic, can be a significant symptom of a deteriorating clinical path.[23],[24]

This study aimed to determine whether IL-6 and CRP levels or changes in their levels could be used to predict neurological outcomes in patients with SAH. This study aimed to determine the associations between IL-6 and hs-CRP levels and clinical neurological severity and outcome.


  Methods Top


The study was done at GIPMER over 1 year after obtaining valid informed consent and institutional ethical clearance. All patients with spontaneous, aneurysmal SAH without previous history of any cardiac disease included. In addition, patients with an acute infectious disease were excluded. Finally, this study analysed 69 consecutive patients diagnosed with SAH [Flowchart 1]. After admission, the modified Hunt and Hess Scale used for SAH grading and quantitative measurement of IL-6 and hsCRP were done daily for seven consecutive days.



In this study, Hunt and Hess grade of more than 3 was used to define poor-grade SAH. The primary endpoint was the poor neurological outcome 6 months after the admission. The modified Rankin Scale (mRS) was used to assess the neurological status on a scale from 0 to 6, and poor outcome was defined as >3. Within 12 h of admission, baseline IL-6 and hs-CRP levels were determined. The day of admission was labelled as day 1 and thereafter daily for 7 days serum levels were measured.

Definitions

Vasospasm

  1. A new focal neurological deficit and/or a decrease in Glasgow Coma Scale that was not caused by a new haemorrhage or hydrocephalus that required pharmacological intervention
  2. Ischaemic changes detected in imaging.


Infection

Patients were classified as infected only after positive bacterial cultures were confirmed.


  Results Top


Demographic and clinical data

In this prospective study, 69 patients were studied. Twenty-five (36.2%) patients had poor Hunt and Hess grades,(3–5), whereas 8 (11.6%) had WFNS grade 3–5. Sixteen (23%) of patients had poor neurological functional outcome (mRS grade ≥3) at 30 days' follow-up. Nine (13%) patients died during the hospital stay. The 30-day outcome was significantly associated with severe Hunt and Hess grade, severe Fischer grade and peak IL-6. The clinical parameters of included patients are described in [Table 1].
Table 1: Patient characteristics

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Outcome and inflammatory markers trends

To analyse the systemic inflammatory response following aSAH, we determined the 7 days consecutive levels of IL-6 and hsCRP [Figure 1]. The median serum IL-6 and hs-CRP levels remained elevated over 7 days indicating persistent systemic inflammatory response syndrome (SIRS) with a gradual decline in levels [Figure 2]. Peak IL-6 and hs-CRP levels were used as an indicator of the intensity of the SIRS. The peak levels of IL-6 had a significant positive correlation with poor Hunt and Hess grade at admission (P = 0.006), systemic infection (P = 0.000) and infarction (P = 0.033), whereas a similar correlation was not noted with hsCRP.
Figure 1: Serum levels of Interleukin-6 and high-sensitivity C-reactive protein of all 69 patients for consecutive 7 days

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Figure 2: Median levels of all 69 patients over 7 days

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Sixteen (23.2%) patients had poor neurological functional outcome (mRS score 3–6) including 9 patients (13%) died during hospital stay. The patients having poor functional outcome was found to have a significant positive correlation with Hunt and Hess grade 3–5 (P < 0.000), and modified Fischer grade (P = 0.021). The median peak IL-6 and hs-CRP levels were found to be significantly higher in patients with poor outcomes on all 7 days as compared to good outcomes [Figure 3]. Patients with poor outcome had significant higher levels of peak IL-6 (P = < 0.014; median = 131.0 ng/ml; interquartile range = 53.0–198.7 ng/ml) but similar significance was not observed with hsCRP (P = 0.477) [Figure 4].
Figure 3: Levels of Interleukin-6 and high-sensitivity C-reactive protein over 7 days in patients with good and poor functional outcomes

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Figure 4: Box plot showing median levels of interleukin-6 and high-sensitivity C-reactive protein inpatient with good and poor outcomes

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The peak levels of IL-6 and hsCRP were used to assess the inflammatory response following SAH. The median peak levels for each subgroup are compared, as shown in [Table 2]. A significant high peak serum levels of IL-6 were observed in the patients with poor Hunt and Hess grade, unfavourable outcome, with cerebral infarction and systemic infection. In comparison, only patients with rebleed had significantly higher peak serum levels of hsCRP.
Table 2: Peak IL-6 values and hsCRP in dichotomised clinical groups

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Receiver-operating characteristic analysis

[Figure 5] shows the receiver-operating characteristic analyses of the peak levels of inflammatory markers for predicting 30-day neurological outcomes. The peak IL-6 with cutoff levels >78.5 pg/ml had a sensitivity of 75% and a specificity of 34%, whereas peak hsCRP >mg/dL had a sensitivity of 57% and specificity of 77% to predict the poor functional outcome. The area under the curve for IL-6 and hsCRP was 0.702 (95% confidence interval [CI]: 0.544–0.861) and 0.584 (95% CI: 0.409-0.760), respectively [Figure 5].
Figure 5: Receiver-operating characteristic analyses of the inflammatory markers for predicting 30-day outcome

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  Discussion Top


The study aimed to assess the time course and correlation of systemic inflammatory response with the neurological outcome in patients with aSAH. We evaluated whether IL-6 and hs-CRP levels over seven consecutive days can be used to predict the neurological outcome in aSAH patients. The critical observations are following: 23.2% of patients had poor outcomes and positively correlated with severe SAH grade and severe modified Fischer grade. O admission, both markers were significantly raised and remained so throughout 7 days. The IL-6 levels progressively declined by day 7 in comparison to hsCRP. The serum peak levels were higher in patients with poor outcomes as compared to good outcome.

We observed higher hsCRP levels in patients who underwent clipping, suggesting a non-specific stress response. The transient global ischaemia may occur in the early stages of brain injury as a result of decreased cerebral blood flow, increased intracranial pressure, metabolic and oxidative disturbances associated with an acute vascular reaction. This transient global ischemia may account for the elevated IL-6 levels observed upon admission.

The initial events in brain injuries including SAH and cerebral ischemia can lead to secondary complications.[25] The necrotic cells of the ischemic core releases cytokines resulting in delayed brain injury in the penumbra.[1] Increased serum IL-6 levels occur in the majority of post-SAH complications as a result of a generalised inflammatory response rather than a specific post-SAH complication. Tissue damage in SAH may cause an unspecific upregulated inflammatory response, hence the SAH grade, higher the IL-6 levels. Numerous studies have demonstrated elevated IL-6 levels in the interstitial space and CSF of patients with SAH, as well as a positive correlation between this increased IL-6 and vasospasm. [15,26-30] Ischaemia itself may result in a delayed elevation of serum IL-6 levels. In patients with cerebral ischaemia.[31] The cerebral ischaemia usually develops within 2 weeks after bleeding in aSAH patients. The DCI also develops late, and a rise in IL-6 levels immediately before DCI have been reported.[32] In contrast to delayed rise in serum IL-6 in DCI, the heterogeneity in the initial intracranial pressure rise, severity and extend of transient global ischaemia and early brain injury may explain the lower serum IL-6 levels during the initial days of SAH. As in previous studies, an increased level of IL-6 was associated with a poor outcome.[33],[34] The IL-6 may serve as a proxy for the overall inflammatory burden. Due to its haemostatic basal regulation and rapid induction in response to various disease states, IL-6 is regarded as a more accurate predictor of disease activity and clinical outcome than CRP.[35],[36],[37] However, to diagnose infection or sepsis, hsCRP is the most common inflammatory marker used.[38],[39] The CRP, in acute inflammation and infection, is sensitive but not a specific marker.[16] After initial stimulus, the CRP level peaks within 48 h and returns to baseline within 7–12 days after inflammatory stimulus disappears.[16],[40],[41] It has been reported that elevated CRP is associated with poor neurological outcome ischaemic stroke patients.[17],[42],[43] Cerebral arterial occlusion leading to ischaemic injury manifests as acute local inflammation with changes in the levels of inflammatory markers.[42] Recent studies show that is raised CRP levels after SAH are associated with vasospasm and DCI.[18],[19],[20],[21] CRP synthesis is also strongly stimulated by increased soluble adhesion molecules and cytokines associated with the pathogenesis of cerebral vasospasm in DCI.[19] Due to similar pathophysiology of DCI, MI or ischaemic stroke, the severity and clinical outcome of SAH patients may be predicted by the measurement of serum CRP levels.[16],[17],[18],[19] The DCI is a complex, multifactorial syndrome associated with vasospasm, early brain injury and microthrombosis.[44],[45],[46],[47]

A cascade of reactions involving the release of vasoactive and pro-inflammatory factors is triggered by the extravasated blood and early activated inflammatory pathways post-aSAH.[45] Elevation of levels of circulating cytokines due to activation of systemic immune response which results in cerebrovascular vasospasm.[44] However, in our study, we did not observe a similar correlation with DCI. However, CRP levels were significantly high in patients who rebleed, pointing to a local inflammatory response. At a very early stage, a single absolute CRP level may not reflect the severity of the disease as the CRP levels can increase rapidly after aneurysm rupture. Therefore, for prognostic prediction at a single time point, a serial follow-up of CRP levels is required. Hence, after SAH, a daily CRP measurement at least for 7 days may help monitor the course of infection in patients and predict the outcome. In our study, the patient those underwent surgical clipping had significant high CRP levels thus acting as a confounding factor affecting the prediction of a neurological outcome as surgical stress/trauma also increases CRP levels.


  Conclusion Top


The serial measurements of inflammatory markers IL-6 and hsCRP may be used to predict the neurological outcome in aSAH patients. The peak IL-6 levels correlated significantly with poor neurological outcome. Although hsCRP was elevated in patients with the poor outcome, it was statistically non-significant, suggesting a non-specific inflammatory stress response.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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