The blood-brain barrier dysfunction in sepsis

Figures & data

Figure 1. Sepsis pathophysiology on the BBB. The BBB junctions have transmembrane proteins, such as claudin (CLND), occluding (OCLN), and junctional adhesion molecules (JAMs) that interact with each other and seal the spaces that exist between neighboring cells. Adherens junctions have vascular endothelial cadherin (VE-cadherin), which facilitates the adhesion of endothelial cells to each other. The BBB assists in interacting with other glial cells including astrocytes end-foot protecting the CNS against the invasion of pathogens, toxins, and inflammation. During sepsis, infection and the host immune response promote the release of inflammatory molecules that can damage the vascular endothelium cells, interrupt tight junction proteins, and lead to BBB dysfunction, allowing peripheral immune cells to enter the CNS by altering their homeostasis with consequent neuronal damage. CLDN: claudin; IL: interleukin; JAM: junction adhesion molecule; MMPs: matrix metalloproteinases; OCLN: occludin; ROS: reactive oxygen species; TNF-α: tumor necrosis factor-alpha; VE-cadherin: vascular endothelial-cadherin

Table 1. Endothelial cells and BBB biomarkers to predict mortality, MODS, and organ dysfunction in septic patients

Biomarkers	Sample	Demographic	Specificity (%)	Sensitivity (%)	Cutoff	R-squared (R^2)	AUC	Clinical relevance	Ref.
Prognostic values of tight-junction proteins levels for in-hospital mortality in septic patients
Ang-1	Plasma	SIRS, n = 943	-	-	5719 pg/ml	-	-	↑ Ang-1 was associated with low 28-day mortality OR = 0.71.	^Citation1
Ang-2	Plasma Serum	SIRS, n = 943 Severe sepsis, n = 48 Sepsis shock, n = 54	--	--	42063 pg/ml-	--	--	↑ Ang-2 was associated with ↑ high 28-day mortality OR = 2.06. ↑ Ang-2/Ang-1 ratio increased from day 1 to day 7 in non-survivors (B = 1.965 and p = .000).	^Citation1,Citation2
CLDN-5	Plasma	Sepsis, n = 51	-	-	-	-	0.534	CLDN-5 levels did not present a correlation with APACHE II score. No, predict mortality.	^Citation3
OCLN	Plasma Brain tissue	Sepsis, n = 51 Sepsis, n = 47	80.49%-	70.00%-	509.06 pg/ml-	--	0.773-	↑ OCLN correlated positively with APACHE II. Predict mortality. ↑ Sepsis severity. The deceased patients with BBB damage, less OCLN, had higher SOFA scores.	^Citation3,Citation4
PAI-1	Plasma	Sepsis, n = 166	-	-	-	-	0.85	↑ Sepsis severity. Predict mortality.	^Citation5
S100B	Serum	SAE, n = 59 non-SAE, n = 45	80.0% 84,44%	66.1% 69,49%	0.226 μg/l 0.144 μg/l	--	0.611 0.731	S100B, on day-1 to predict 180-day mortality. S100B, on day-3 to predict 180-day mortality.	^Citation6
sE-selectin	Plasma	Sepsis, n = 166	-	-	-	-	0.77	Predict mortality.	^Citation5
sFlt-1	Plasma	Sepsis, n = 166	-	-	-	-	0.85	↑ Sepsis severity. Predict mortality.	^Citation5
sICAM	Plasma Serum	Sepsis, n = 166 Severe sepsis, n = 48 Sepsis shock, n = 54	--	--	-Day-1 1599 ng/ml Day-7 2058 ng/ml	--	0.71-	Predict mortality. ↑ ICAMs levels on day-1 and on day-7 were associated with 90-day mortality.	^Citation5,Citation2
sVCAM-1	Plasma Plasma Plasma	Sepsis, n = 166 SIRS, n = 943 Severe sepsis, n = 48 Sepsis shock, n = 54	---	---	-819 pg/ml Day-1 416 ng/ml Day-7 495 ng/ml	---	0.78--	Predict mortality. ↑ sVCAM-1 was associated with increased 28-day mortality, OR = 2.71. ↑ sVCAM-1 levels on day-1 and on day-7 were associated with 90-day mortality.	^Citation5,Citation1,Citation2
ZO-1	Plasma	Sepsis, n = 51	87.80%	90%	354.3 pg/ml	-	0.856	↑ Sepsis severity. ↑ ZO-1 correlated positively with APACHE II. Predict mortality.	^Citation3
Prognostic values of tight-junction proteins levels for MODS diagnostic in septic patients
CLDN-5	Plasma	Sepsis, n = 51	-	-	-	-	0.625	CLDN-5 was not associated with MODS.	^Citation3
OCLN	Plasma	Sepsis, n = 51	-	-	-	-	0.633	OCLN was not associated with MODS.	^Citation3
ZO-1	Plasma	Sepsis, n = 51	79.31%	63.64%	272.36 pg/ml	-	0.748	↑ ZO-1 levels were higher in patients for MODS diagnostic.	^Citation3
Prognostic values of tight-junction proteins levels for organ dysfunction in septic patients
Ang-1	Plasma	Shock, n = 206	-	-	-	−0.67	-	↑ Ang-1 was associated with low organ dysfunction.	^Citation1
Ang-2	Plasma Serum	Shock, n = 206 Severe sepsis, n = 48 Sepsis shock, n = 54	--	--	--	0.97-	--	↑ Ang-2 was associated with high organ dysfunction. ↑ Ang-2/Ang-1 ratio ↑ SOFA score.	^Citation1,Citation2
OCLN	Plasma	Sepsis, n = 51	80.49%	70%	509.06 pg/ml	-	0.773	↑ OCLN correlated positively with SOFA scores.	^Citation3
	Brain tissue	Sepsis, n = 47	-	-	-	-	-	OCLN absence was associated with the maximum SOFA score. OCLN absence was associated with ↑ blood PCT (> 10 μg/l).	^Citation4
PAI-1	Plasma	Sepsis, n = 166	-	-	-	0.15	-	↑ PAI-1 correlated with the SOFA score.	^Citation5
S100B	Serum Serum	Severe sepsis, n = 21 Shock, n = 22 Delirium, 45% MOF, 50%	--	--	-0.15 μg/l	--	0.124-	S100B levels did not correlate with the SOFA score. Patients with delirium had elevated S‐100B levels and more severe organ dysfunction.	^Citation7,Citation8
sE-selectin	Plasma	Sepsis, n = 166	-	-	-	0.18	-	↑ sE-selectin correlated with SOFA score.	^Citation5
sICAM	Plasma	Sepsis, n = 166	-	-	-	0.10	-	↑ ICAM correlated with the SOFA score.	^Citation5
sVCAM-1	Plasma Plasma Serum	Sepsis, n = 166 Shock, n = 206 Severe sepsis, n = 48 Sepsis shock, n = 54	---	---	---	0.24 1.51-	---	↑ sVCAM-1 correlated with the SOFA score. ↑ sVCAM-1 associated with SOFA score. The sVCAM-1 levels, B = 0.008 p = .001, was a predictor of Δ SOFA score in septic patients.	^Citation5,Citation1,Citation2
sFlt-1	Plasma	Sepsis, n = 166	-	-	-	0.36	-	↑ sFlt-1 had a higher association with organ dysfunction.	^Citation5
ZO-1	Plasma	Sepsis, n = 51	87.80%	90%	354.3 pg/ml	-	0.856	↑ ZO-1 correlated positively with SOFA scores.	^Citation3

Abbreviation: Ang-1 (angiopoietin-1), Ang-2 (angiopoietin-2), APACHE II (acute physiology and chronic health evaluation II), BBB (blood-brain barrier), CLDN-5 (claudin-5); MODS (multiple organ dysfunction syndrome), MOF (multiple organ failure), OCLN (occluding), OR (odds ratio), PAI-1 (plasminogen activator inhibitor 1), qSOFA (quick sequential organ failure assessment), S100B (calcium-binding protein B), SAE (sepsis-associated encephalopathy), sE-Selectin (soluble E-selectin), sFlt-1 (soluble fms-like tyrosine kinase 1), sICAM-1 (soluble intercellular adhesion molecule 1), SIRS (systemic inflammatory response syndrome), SOFA (sequential organ failure assessment), sVCAM-1 (soluble vascular cell adhesion molecule 1), ZO-1 (zonula occluden 1).

Fang Y, et al. 2018; Piazza O, et al. 2007.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J-D, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. 2016;315(8):1–10. Epub 2016/02/24. doi:10.1001/jama.2016.0287.

 Web of Science ®Google Scholar

CDC. Data & Reports. 2020 [updated August 20, 2020]; Available from: cdc.gov/sepsis/datareports/index.html.

 Google Scholar

Prescott HC, Angus DC. Enhancing recovery from sepsis: a review. Jama. 2018;319(1):62–75. doi:10.1001/jama.2017.17687.

 PubMed Web of Science ®Google Scholar

Prescott HC, Carmichael AG, Langa KM, Gonzalez R, Iwashyna TJ. Paths into sepsis: trajectories of presepsis healthcare use. Ann Am Thorac Soc. 2019;16(1):116–123. Epub 2018/09/14. doi:10.1513/AnnalsATS.201806-391OC.

 PubMed Web of Science ®Google Scholar

Prescott HC, Osterholzer JJ, Langa KM, Angus DC, Iwashyna TJ. Late mortality after sepsis: propensity matched cohort study. BMJ (Clinical Research Ed). 2016;353:i2375. Epub 2016/05/18

 PubMedGoogle Scholar

Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. Jama. 2010;304(16):1787–1794. doi:10.1001/jama.2010.1553.

 PubMed Web of Science ®Google Scholar

 Kumar S, Ingle H, Prasad DV, Kumar H. Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol. 2013;39(3):229–246. doi:10.3109/1040841X.2012.706249.

 PubMed Web of Science ®Google Scholar

Heckenberg SG, Brouwer MC, van de Beek D. Bacterial meningitis. Handb Clin Neurol. 2014;121:1361–1375. Epub 2013/12/25.

 PubMedGoogle Scholar