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Fecal Calprotectin Is Increased in Stroke: Comparison
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Please note this is a comparison between Version 2 by Bruce Ren and Version 1 by Woo Jin Kim.

While there have been major advances in unveiling the mechanisms comprising the ischemic cascade of CNS, stroke continues to be a significant burden. There is a need to extend the focus toward peripheral changes, and the brain–gut axis has recently gained much attention. 

  • stroke
  • gut
  • leukocyte L1 antigen complex
  • ELISA

1. Introduction

According to a recent report from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), stroke continues to be a significant socioeconomic burden. In 2016, stroke was the second largest cause of death globally (5.5 million) and the second most common cause of global disability-adjusted life-years (DALYs) (116.4 million), an increase from 1990 (95.3 million). There were 13.7 million new strokes in 2016 [1].
Since rodent models of focal cerebral ischemia were first reported in the early 1980s [2], there have been major advances in the researchers knowledge regarding the complex biochemical and molecular mechanisms that comprise the ischemic cascade, and stroke mortality is gradually declining [3,4][3][4]. With more patients surviving stroke, there is a need for the focus of stroke research to turn its attention to post-stroke complications [5].
Following a stroke, gastrointestinal (GI) complications are common problems, including dysphagia, GI hemorrhage, delayed GI emptying, and colorectal dysfunction [6], and the communication between the central nervous system (CNS) and the gut in animal models has recently gained attention in stroke research [7]. While fecal calprotectin (FC) is a relatively new marker not yet explored in stroke research, it has been a useful marker of gastrointestinal inflammation predominantly released by neutrophils in the gut [8].

2. Results

2.1. FC Concentrations in Healthy Controls and Stroke Patients

Mean FC concentration for the healthy CON (n = 27) was 23.0 µg/g (range 0.0–166.1 µg/g). In comparison, the mean FC concentration for STR patients (n = 27) was 335.3 µg/g (range 0.0–1206.5 µg/g). The Mann–Whitney test showed there was a statistically significant difference between the FC concentrations of the CON and STR groups (Table 1).
Table 1. Fecal calprotectin concentrations of healthy controls and stroke patients.
  CON

(		n = 27) KS Normality Test STR (T1)

(		n = 27)
Variable Variable VariableKS Normality Test p
Analysis r p
FC (µg/g) 23.0 ± 39.7 no 335.3 ± 367.6
GCS Lymphocyteno <0.0001

2.2. Association among FC Concentration and GCS and Blood Variables in Stroke

Mean levels of blood variables in STR were 10,303/µL white blood cells (WBC), 7759/µL neutrophils, 1378/µL lymphocytes, 235,000/µL platelets, 4.6 mg/dL CRP, 11.3 g/dL hemoglobin, 24.3 mm/h ESR, 46.4 U/L AST, 41.0 U/L ALT, 6.1 g/dLTP, 3.5 g/dL albumin, 151.4 mg/dL glucose, and 0.6 mg/dL creatinine. Mean levels of GCS were 9.8. The blood variables with a significant correlation with GCS included lymphocyte count (positive), CRP (inverse), albumin (positive), and ESR (inverse). GCS showed a negative correlation with FC. The blood variables with a significant correlation with FC included lymphocyte count (inverse), CRP (positive), albumin (inverse), hemoglobin (inverse), and total protein (inverse) (Table 2).
Table 2. Correlations among FC, GCS, and blood variables in stroke patients.
  Pearson 0.4187 0.0297
  CRP   Spearman −0.65402 0.0002
  Albumin   Spearman 0.5636 0.0022
  ESR   Pearson −0.4073 0.0350
GCS   FC Spearman −0.5567 0.0026
  Lymphocyte FC Pearson −0.4074 0.0349
  CRP   Spearman 0.5768 0.0016
  Albumin   Spearman −0.4558 0.0169
  Hemoglobin   Pearson −0.4403 0.0215
  Total protein   Pearson −0.5553 0.0026

3. Fecal Calprotectin Is Increased in Stroke

The researchers studied calprotectin levels in fecal samples of stroke patients and showed that FC was significantly increased in stroke patients. According to the available literature on the determinants of FC levels, associated drugs with FC levels include proton pump inhibitors (PPI) (elevation), non-steroidal anti-inflammatory drugs (NSAID) (elevation) [11][9], or antibiotics (depression) [12][10]. The patients in this study took neither PPI nor NSAI but did take intravenous antibiotics around the collection time of fecal samples. Considering the available literature and medication profiles of patients, it seems less likely that the medication affected the increase in FC.
Calprotectin is a small acidic protein isolated from leukocytes in 1983 [13][11], which is involved in inflammatory processes. Since the late 1980s, when calprotectin was described from stool extracts using ELISA [14][12], related research has increased every year. Numerous studies have shown that FC is significantly elevated in patients with IBD and such increased levels correlate well with both endoscopic and histologic assessment of disease activity. Lee et al. recently reported that a cutoff value of 201.3 μg/g for FC predicted endoscopic inflammation in the ulcerative colitis with a sensitivity of 81.8% and a specificity of 100% [15][13]. Gastrointestinal complications after stroke are common and are often associated with an increased hospital stay, development of further complications, and even increased mortality [16][14]. The mean FC of stroke patients in the researchers study was higher than 201.3 μg/g. Furthermore, objective non-invasive markers of gastrointestinal inflammation in stroke are rarely found. Therefore, furtherer investigation is warranted to find the role of FC in detecting gastrointestinal inflammation in patients with acute stroke.
The researchers correlation study showed that FC had a positive association with CRP and a negative association with lymphocytes and albumin. On the other hand, GCS had a negative association with CRP and a positive association with lymphocytes and albumin. These findings are consistent with the finding that FC is negatively associated with GCS. Many studies have been conducted regarding the association between those markers and acute stroke. CRP is a marker of inflammation, and its elevation in acute stroke is reportedly a poor prognostic factor [17][15]. GCS is widely used in assessing level of consciousness, and low levels of GCS are reportedly associated with higher mortality [18][16]. Lymphocytes are a subset of leukocytes, and their depletion in acute stroke is associated with poor neurologic outcome [19][17]. Albumin serves as a biochemical marker of nutritional status, and hypoalbuminemia is associated with poor functional outcome [20][18]. In an IBD study, Lee et al. showed that FC had a positive correlation with CRP levels (r = 0.379, p < 0.001) and a negative correlation with serum albumin levels (r = −0.426, p < 0.001) in patients with ulcerative colitis [15][13]. Other studies showed that low serum albumin and high CRP levels are associated with severe disease activity in patients with ulcerative colitis [21][19]. Furthermore, a correlation was found between fecal calprotectin and clinical outcome in patients with ulcerative colitis [22][20]. These findings warrant further study to find the role of FC as a prognostic marker in patients with acute stroke.
The brain controls the researchers body through complex neurohumoral mechanisms. Severe cerebral insults, such as acute stroke, can induce changes in neurosensory or neuromotor pathways, thereby enhancing systemic immune response and causing secondary peripheral organ damage [23,24][21][22]. To evaluate and monitor acute stroke, clinical scales, such as GCS and the aforementioned laboratory tests, are performed at the patient’s bedside. Though FC is rarely ordered in acute stroke patients, it has been used as one of the most reliable, non-invasive tools for managing inflammatory bowel disease (IBD) in clinical practice [25][23]. Here, the researchers explored the method of measuring fecal calprotectin and its association with patient variables in stroke. The researchers found that FC is significantly elevated in patients with stroke and is correlated with laboratory variables, which are performed to evaluate and monitor acute stroke in the clinical field. the researchers findings may help clinicians be more attentive to gut response in parallel with systemic response in stroke and warrant further studies to elucidate the usefulness of FC in stroke management.

References

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