The value of rapidly available blood markers as predictors for SAI has not been studied extensively, although WBC, CRP and Mcyt are routinely measured within the first hours of admission. Copeptin and PCT measured on admission were good predictors of any infection, pneumonia and UTI in the present cohort. They showed a similar predictive value for future infection compared to WBC and CRP. In a recent study neither WBC, CRP, Mcyt nor PCT measured on admission were sensitive enough to reliably be associated with SAI 
. In another study, WBC and Mcyt count on admission did not differ between infected and non-infected stroke patients 
. Only on day 1 after stroke onset, body temperature 
and WBC 
became significantly associated with infections after stroke. However, in these studies the time point of diagnosis in relation to biomarker measurements was not taken into account. Therefore, they could not really establish the predictive value of these markers but rather their diagnostic accuracy at the time of infection. Moreover the sample size was somewhat small and associations might have been missed due to lack of power. To our knowledge our study is the first to assess the predictive value of these markers taking into account the time point of measurements as well as diagnosis.
In the present study, each laboratory parameter remained a strong predictor after adjusting for NIHSS, age and CI and infarct localization. This is an unexpected finding because age and stroke severity may also contribute to SIS and thus infection after acute ischemic stroke 
. However, these biomarkers seem to add prognostic information beyond age, stroke severity and a higher CI as well as infarct localization.
Copeptin was a strong predictor for SAI on admission and during the acute phase of stroke. The predictive value of copeptin in respect of SAI was similar to that of established biomarkers of infection (i.e. WBC, CRP). This finding might be due to the association of copeptin with the activation of the HPAA: increased copeptin-levels probably indicate a high degree of stress and SIS, which means a higher susceptibility to develop an infection. The prognostic value of PCT was also in the range of WBC and CRP. In the literature PCT is a superior diagnostic marker in pneumonia and other bacterial infections when compared to WBC and CRP 
. However, the prognostic accuracy of a single PCT valueis limited 
. PCT might be rather a specific than a sensitive prognostic marker in predicting infections.
The combination of established inflammatory makers (WBC, CRP) combined with a biomarker of stress, i.e. copeptin or a biomarker of bacterial infection, i.e. PCT 
improves prediction of SAI compared to the strongest prognostic marker alone. The combination of biomarkers probably reflects better the complexity of an infection than one biomarker alone and may lead to a more accurate prediction of a beginning but not yet clinically apparent infection.
The investigated biomarkers seem to detect infections before clinical or paraclinical signs prompt further diagnostic work-up leading to the diagnosis of infection. Thus, these markers may help in risk stratification and may select high-risk patients for intervention studies.
We are aware of the following limitations: First, our results are based ona single cohort and our findings need to be validated in an independent and larger cohort. Second, the sample size was relatively small when assessing subgroups of infection. The bivariate analysis may have a limited statistical power and validity underestimating possible effects of biomarkers and other potential predictors. Third, although WBC and CRP was not a criterion for making the diagnosis of pneumonia, any infection and UTI, one must take into account that WBC was one of three criteria for the diagnosis of the subgroup of OI. Therefore, the good predictive value of WBC - in the case of OI - is most probably due to incorporation bias. This, on the other hand, strengthens the predictive value of copeptin that might be underestimated compared to WBC in this study. Fourth, we are not able to proof causalities or provide more insights into pathomechanisms, to explain why these markers are good predictors of infections even before clinical signs occur. But even if these markers are only surrogates of underlying processes which predispose patients for infections, from a clinical standpoint we belief that the observed associations are very interesting since we identified accurate prognostic markers for risk stratification. Finally, the distinction between prediction and early diagnosis of infection is difficult. We are not able to differentiate whether the biomarkers investigated in this study might rather detect infections at an early state or predict vulnerability for future post-stroke infections, although we excluded patients with possible infection prior to the onset of stroke.
In summary, copeptin, PCT, WBC and CRP were good predictors of the development of any infection, pneumonia and UTI. The combination of the 3 biomarkers even improved the prognostic value by accurately separating patients with and without future infections already on admission. If validated in larger prospective studies the combination of these 3 biomarkers with best AUC values may add significant information for the early identification of high-risk patients. Future intervention studies could select patients with high-risk profiles according to these biomarker levels and these high-risk patients may proof to benefit from prophylactic antibiotic treatment.