“ High Neutrophil-to-Lymphocyte Ratio Predicts Stroke-Associated Pneumonia ”

In Response: We thank Drs Tao, Li, and Buonacera for their interest in our study and for the insightful comments on the correlation between the neutrophil-to-lymphocyte ratio (NLR) and stroke-associated pneumonia (SAP). We appreciatively have responded to each of the comments as follows. Dr Tao expressed concern about the inclusion of participants with community-acquired pneumonia or other types of infection in the study among patients with ischemic stroke within 7 days from symptoms’ onset. However, as described in the Methods section, we excluded patients with active infection within the 2 weeks’ period before admission. Although the patients’ age in the SAP group was significantly higher than that in the non-SAP group (75 versus 66 years, P<0.001), the effect of other types of infection on our results may be minimal. According to Dr Tao’s recommendation, we reevaluated 112 SAP patients using microbiological tests. In agreement with previous studies, the majority of the SAP patients (n=68, 61%) obtained negative culture results, and patients with positive culture results included: 13 with (12%) Staphylococcus aureus, 5 (4%) Streptococcus pneumoniae, 17 (15%) Klebsiella pneumoniae, and 9 (8%) others. The median time to SAP occurrence was 2 (1–3.75) days from admission, with no difference among the subgroups based on the results of microbiology tests (P=0.422). Dr Li recommended the use of erythrocyte sedimentation rate (ESR) for predicting SAP. Among the 1317 participants, ESR data was available for 555 patients, with a median ESR value of 16 (8–33) mm/h. In addition, ESR showed a high predictive power in the prediction of SAP (crude odds ratio, 2.521; 95% CI, 1.824–3.483; P<0.001), even after adjusting for confounders (adjusted odds ratio, 2.493; 95% CI, 1.636–3.797; P<0.001). However, with regard to the diagnosis of SAP, the area under the curve of ESR was 0.753 (0.667–0.802), which was lower than that of NLR (0.876 [0.855–0.895]). Moreover, prediction models using both the multiple inflammatory markers (eg, NLR, high-sensitivity C-reactive protein, and ESR: area under the curve, 0.735 [0.673–0.797]) or the clinical markers (eg, A2DS2 score+ESR: area under the curve, 0.860 [0.813– 0.907]) showed no significant difference compared with the model with A2DS2 score and NLR (area under the curve, 0.838 [0.816–0.859]). In our study, the results indicated that the SAP group had worse clinical outcomes in terms of the longer hospitalization duration, higher discharge National Institutes of Health Stroke Scale score, and high frequencies of the 30-day mortality and severe 3-months modified Rankin Scale scores.1 However, the SAP group additionally had higher initial National Institutes of Health Stroke Scale scores. We agree with Dr Li’s comment that the worse clinical outcomes could simply be because of more severe index stroke: hence, we conducted additional multivariate analyses, including the hospitalization duration, discharge National Institutes of Health Stroke Scale score, and severe 3-months modified Rankin Scale scores (modified Rankin Scale score, 3–6). In the multivariate logistic regression analysis, SAP remained an independent predictor of severe 3-months modified Rankin Scale (adjusted odds ratio, 4.533; 95% CI, 2.255–9.110; P<0.001] after adjusting for confounders. In addition, SAP was also independently associated with both discharge National Institutes of Health Stroke Scale score (B, 4.434; 95% CI, 3.516–5.353; P<0.001) and hospitalization duration (B, 10.775; 95% CI, 8.300–13.250; P<0.001) in the multivariate linear regression analyses. Thus, despite considering the effect of the initial National Institutes of Health Stroke Scale score, age, and other risk factors, the SAP group showed worse outcomes than the non-SAP group. Dr Buonacera recommended us to divide our cohort into the older (age >75 years) and younger (age ≤75 years) groups. In our cohort, the older group had 364 participants and showed significantly high rate of SAP occurrence (17%, 62/364 versus 5%, 50/953; P<0.001). However, being contrary to the study of Buonacera et al, NLR did not have significant interaction with age (NLR×age variable: adjusted odds ratio, 0.982; 95% CI, 0.953–1.011; P=0.226) in the multivariate analysis. We thought that it may result from the different characteristics of included participants between 2 studies. In Buonacera et al, they included participants who were diagnosed with community-acquired pneumonia without acute ischemic stroke events. Unlike community-acquired pneumonia, the burden of index stroke and subsequent comorbidities have a major role in the development of SAP. Dr Buonacera also suggested us to evaluate the relationship between NLR and carotid atherosclerosis. The carotid atherosclerosis seems to have no significant role in the development of SAP; thus, we did not include the assessment on carotid atherosclerosis (eg, carotid sonography, magnetic resonance angiography). In addition, our retrospective study design could not involve additional information about it. Further studies are needed to confirm that relationship.