First of all, this current study supported that a high NLR level was an independent predictor of SAP in stroke patients, and had better predictive validity than established biomarkers like leukocyte counts, which was in agreement with findings of previous research [14, 15, 21]. Furthermore, a high NLR level also is an independent risk factor for poor short- and long-term outcomes, as well as for mortality, further highlighting the clinical implications of this easily obtained ratio for everyday practice.
Moreover, our research showed that NLR measured before IVT, as well as within 12–24 h after IVT, can both predict the onset of SAP, functional dependence, and mortality after stroke. However, NLR measured within 12–24 h after IVT had a higher predictive value. As indicated in this study, the area under the ROC curve of NLR measured within 12–24 h after IVT was larger compared with that before thrombolytic treatment. The calculated cut-off therefore further showed adequate sensitivity and specificity (sens.: 80%, spec.: 70%). Intriguingly, NLR measured within 12–24 h after IVT was similar in AUROC of SAP to the widely accepted A2SD2 score (0.80, p < 0.001 vs 0.80, p < 0.001). Since stroke patients undergoing IVT are often admitted as an emergency and may lack a clear history, monitoring NLR is a more effective and simple method compared to the A2SD2 score in predicting SAP.
A possible explanation for the above result might be that the dynamic development of neuroinflammation after a stroke takes several hours and the immune activity changes after taking thrombolytic treatment. Ischemic stroke causes cell death by blocking blood flow to the brain and depriving cells of nutrients. This, in turn, activates immune cells to produce pro-inflammatory factors and produces a hierarchical biological effect of systemic inflammation in acute stroke patients, with an increase in peripheral blood neutrophils count. Subsequent increased activity of the adrenal medulla and hypothalamic axis leads to stroke-induced immunosuppression syndrome, which can lead to lymphocyte apoptosis and T cell inactivation, with resulting infectious complications. Indeed, while leukocyte numbers increase, lymphopenia occurs within 6 h and lasts for at least 6 days after stroke in patients . Furthermore, the number of circulating lymphocytes recovered one day after stroke in uninfected patients, while infected patients showed persistent lymphopenia . In this study, the blood collection time of NLR after IVT was about 12–24 hours after stroke, which gave sufficient time for the inflammatory response to development.
In addition, after reperfusion therapy, the recovery of cerebral blood flow further induces the production of ROS and the destruction of the blood-brain barrier, which makes it easier for immune cells in the peripheral circulation to penetrate the brain, promoting brain cell swelling and exacerbating tissue damage in the injury site and the ischemic penumbra [24, 25]. Therefore, reperfusion injury caused by thrombolytic therapy should be given special consideration in inflammatory events after AIS.
Previous studies have proved that early thrombolytic therapy can save the penumbra and reduce the development of inflammation [26, 27]. Therefore, if inflammation indicators such as NLR are still high after thrombolytic therapy, it may be an indicator of irreversible injury in the edema penumbra. In addition, in our cohort, the low NLR group had a better effect on IVT, as shown by a lower rate of END and lower incidence of hemorrhagic transformation. This is consistent with a previous study that has shown that higher NLR is associated with reperfusion failure after endovascular treatment . Therefore, although NLR can effectively predict the occurrence of SAP and is a relatively easily available indicator, the optimal time to detect NLR must be considered.
For the relevant baseline variables, we found that NLR measured within 12–24 h after IVT was closely related to the severity of the stroke and early neurological outcomes, as indicated by remaining significant correlation with initial NIHSS scores and early NIHSS changes after correction for possible confounders in a multivariate linear regression model. Previous studies have also shown that the severity of stroke is an important risk factor for SAP, and NLR is closely related to infarct volume and may have the ability to predict post-thrombolysis END [28, 29]. Another unexpected finding was that the OTT time was only significantly associated with NLR before IVT. It may suggest that with the increase in OTT time, the potential inflammatory response in patients of AIS before IVT may be more intense. On the other hand, our study also showed that OTT time had no significant effect on NLR measured within 12–24 h after IVT when thrombolytic therapy was actively administered within the time range of 4.5 hours. Therefore, NLR measured within 12–24 h after IVT may be a relatively stable marker for predicting SAP and functional outcome of patients with AIS because it is not affected by OTT time. However, several studies have shown that ultra-early thrombolysis contributes to functional recovery and lower mortality after cerebral infarction [30–32]. Indeed, it should be noted that, in our whole group, the median OTT was 2.93 h, and ultra-early thrombolysis of fewer than 90 mins accounted for only 8% of the total number, which is a relatively small number and may cause deviation. Meanwhile, it is worth noting that the OTT time has a confounding bias with the severity of stroke. Patients with more severe strokes are often found earlier, thus shortening the OTT time. In this study, there was no significant association between DNT and SAP, as well as NLR, so the extension of OTT was mainly related to the time from onset to arrival at the hospital.
This study has some potential limitations. First, the sample size is relatively small mainly because the participants were selected from a single institution. Second, Even if we have formulated strict exclusion criteria, we can not guarantee that patients with latent infection before admission can be completely excluded. However, in this study, the incidence rate of SAP was 15%, which is similar to the incidence reported in previous studies[6, 33–35]. Thus, this bias was within acceptable ranges. Third, it is also a pity that we did not record the specific onset time of pneumonia, nor did we record the severity of pneumonia. Finally, we did not develop an independent validation cohort to provide more credibility. Therefore, the clinical implications of these correlations need to be investigated further in future studies. Despite these limitations mentioned above, our study considered the impact of the thrombolytic treatment on NLR in predicting SAP, indicating that increased systemic inflammation after thrombolysis, expressed by increased NLR measured within 12–24 h after IVT, is more tightly associated with the occurrence of SAP and poor prognosis. Our results complement the role of NLR in cerebrovascular disease and provide a new idea for clinical practice.