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Stroke. Author manuscript; available in PMC 2016 November 01. Published in final edited form as: Stroke. 2015 November ; 46(11): e244. doi:10.1161/STROKEAHA.115.011288.

Response to Letter Regarding Article, “Monocyte Count and 30Day Case Fatality in Intracerebral Hemorrhage” Kyle B. Walsh, MD1, Daniel Woo, MD, MS2,3, and Opeolu Adeoye, MD, MS.1,3,4 1Department

of Emergency Medicine, University of Cincinnati (UC), Cincinnati, OH

2Department

of Neurology and Rehabilitation Medicine, UC, Cincinnati, OH

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3UC

Neuroscience Institute, Cincinnati, OH

4Department

of Neurosurgery, UC, Cincinnati, OH

Keywords intracerebral hemorrhage; case-fatality; monocytes; inflammation

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We appreciate the letter from Hu et al. regarding our recent publication.1 Our response addresses two points raised in their letter: 1) evidence that infiltrating neutrophils (not monocytes) play a role in intracerebral hemorrhage (ICH)-induced brain injury; and, 2) their multivariate logistic regression analysis of 321 ICH patients which found (contrary to our analysis) that higher total white blood cell (WBC) and neutrophil count, but not monocyte count, were independently associated with mortality. We agree that there is a preponderance of evidence that neutrophils are present in and around the hematoma after ICH. However, we note that neutrophils facilitate monocyte recruitment to the injury site and recent experiments have found that monocytes were more numerous than other leukocytes at the site of injury early after ICH.2, 3 Fewer inflammatory monocytes at the ICH site was associated with improved motor function3 and reducing monocyte recruitment has been associated with less behavioral disability. Lastly, we note that until recently, phagocytic microglia (the first non-neuronal cells to react to brain injury) have been difficult to distinguish from infiltrating monocytes/macrophages.4 Thus, the early evidence for neutrophils may have reflected limitations of cell identification techniques.

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The patients enrolled by Hu et al. (n =321) and in our investigations (n=1865 and 2401) were similar with regards to age, gender, and time from symptom onset to blood draw. There were obvious racial/ethnic differences, including 100% Chinese in the analysis by Hu et al. compared to 78% white and 22% black in our first cohort,5 and 37% white, 33% black, and 30% Hispanic in the second.1 In addition, the patients enrolled by Hu et al. had larger median ICH volume [16.5 mL (IQR 6.8 to 36.2) vs. 12.8 mL (IQR 4.9 to 29.4)5 and 9.9 mL

Corresponding Author: Opeolu Adeoye, MD, MS, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0769, [email protected], Phone: 513-558-3117, Fax: 513-558-6434. Disclosures: None

Walsh et al.

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(IQR 4.4 to 26.7)1], and lower median Glasgow Coma Scale (GCS) [11 (IQR 6 to 13) vs. 14 in both of our publications (IQR 10 to 155 and IQR 11 to 151)].

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To achieve better linearity, ICH volume was log transformed in our regression models. A model without log transformation of ICH volume, particularly with larger hemorrhages and higher associated WBC and neutrophil counts, could result in predominance of those cell types in the model. It was not evident to us whether Hu et al. transformed variables and what impact that may have on their findings. Further, we note that neutrophils are the primary component of total WBC. As such, we posit that the ‘independent’ association of WBC identified by Hu et al. is driven primarily by neutrophils. Ultimately, sufficient preclinical and now clinical data exist implicating both neutrophils and monocytes as putative mediators of secondary injury after ICH. Additional research is needed to further characterize the role of specific leukocytes in the secondary inflammatory response after ICH.

Acknowledgments Funding Sources: The following grant from the National Institutes of Health: NS-069763

References

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1. Walsh KB, Sekar P, Langefeld CD, Moomaw CJ, Elkind MS, Boehme AK, et al. Monocyte count and 30-day case fatality in intracerebral hemorrhage. Stroke. 2015; 46:2302–2304. [PubMed: 26130090] 2. Taylor RA, Hammond MD, Ai Y, Sansing LH. Cx3cr1 signaling on monocytes is dispensable after intracerebral hemorrhage. PloS one. 2014; 9:e114472. [PubMed: 25469644] 3. Hammond MD, Taylor RA, Mullen MT, Ai Y, Aguila HL, Mack M, et al. Ccr2+ ly6c(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2014; 34:3901–3909. [PubMed: 24623768] 4. Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Progress in neurobiology. 2010; 92:463–477. [PubMed: 20713126] 5. Adeoye O, Walsh K, Woo JG, Haverbusch M, Moomaw CJ, Broderick JP, et al. Peripheral monocyte count is associated with case fatality after intracerebral hemorrhage. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2014; 23:e107–111. [PubMed: 24119622]

Author Manuscript Stroke. Author manuscript; available in PMC 2016 November 01.

Response to Letter Regarding Article, "Monocyte Count and 30-Day Case Fatality in Intracerebral Hemorrhage".

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