Table 1.
Characteristics of clinical patient studies investigating the role of extracellular vesicles (EV) in sepsis.
| Study | Diagnosis | Mortality | Time to first sample | Sampling time points | Anticoagulant | Cohort size | EV sources | Summary of findings |
|---|---|---|---|---|---|---|---|---|
| 1. Larsson (1996) 151 | Gram-negative sepsis on ICU | Unknown | At day of ICU admission | Day 1, 2, 4 and 6 | Citrate | Sepsis (n=4) | Platelets | 3 out of 4 septic patients showed high PEV count (no statistics). |
| 2. Lundahl (1996) 152 | Mixed ICU population | Unknown | Unknown | Once | Citrate | ICU patients (n=19), healthy (n=20) | Platelets | Increased PEV (no statistics) in 2 out of 8 patients who died shortly after sampling. |
| 3. Nieuwland (2000) 53 | Meningococcal septic shock | 5 survivor, 2 non-survivors | <24 h | At 0, 4, 10, 16, 24, 36 h | ethylene diamine tetraacetic acid | Septic shock (n=7), healthy (n=5) | Platelets, ECs, granulocytes, monocytes, erythrocytes | Only PEV and GEV increased in septic vs. healthy on admission. Only GEV decreased within 10h of admission. |
| 4. Joop (2001) 28 | Mixed severe sepsis | 4 survivors, 5 non-survivors at day 28 | Unknown | Once | Citrate | Severe sepsis (n=9), healthy (n=14) | Platelets, erythrocytes, ECs, granulocytes, TF+ cells | AnnV+/CD61+ higher, AnnV-/CD61+ lower, AnnV-/glycophorinA+ higher, AnnV-/ CD62E+ lower, AnnV+/ CD66b+ and AnnV-/ CD66b+ higher, AnnV+/CD142+ lower in sepsis vs. healthy. |
| 5. Ogura (2001) 92 | Mixed sepsis, trauma + SIRS, all with C-reactive protein >10 mg/dl | Unknown | 2-7 d post trauma | Once | Citrate | Sepsis (n=14), SIRS (n=12) healthy (n=12) | Platelets | PEV/platelet count higher in sepsis vs. healthy, no difference trauma vs. sepsis. |
| 6. Fujimi (2002) 153 | Mixed sepsis with CRP>10 mg/dL | Unknown | <24 h | Once | Heparin | Sepsis (n=21), healthy (n=21) | Granulocytes | GEV counts higher in septic vs. healthy. Enhanced expression of CD11b in sepsis vs. healthy on GEV < 1 µm but not GEV > 1 µm. |
| 7. Janiszewski (2004) 154 | Septic shock | Unknown | <24 h post diagnosis | Once | Heparin | Septic shock (n=16), healthy (n=6) | Platelets, leukocytes, monocytes, granulocytes, ECs | PEVs exposed p22phox and gp91phox, exhibited intrinsic ROS production and enhanced apoptosis (vs. healthy volunteers) after incubation with ECs or vascular smooth muscle cells. Effects reversible by addition of ROS antagonists. |
| 8. Soriano (2005) 30 | Mixed severe sepsis | 51.4% at day 28 | 24-48 h after organ failure | At admission, day 1 and day 2 | Citrate | Severe sepsis (n=35), healthy (n=45) | ECs, platelets | EEV, not PEV and EEV-monocyte conjugate count was higher in septic patients on day 1 vs. healthy controls. EEV-monocyte conjugates at all time points were higher in non-survivors vs. survivors. |
| 9. Gambim (2007) 155 | Mixed septic shock | Unknown | <24 h after diagnosis | Once | Citrate | Septic shock (n=12), healthy (n=10)) | Platelets | EV from human platelets were similar to septic patients-derived PEV after in vitro exposure to NONOate and LPS, but not to TNF-alpha or thrombin, generated superoxide and nitric oxide. ECs incubated with EVs underwent caspase-3 activation/apoptosis, inhibited by ROS antagonists. |
| 10. Azevedo (2007) 156 | Septic shock | Unknown | <48 h after diagnosis | Once | Heparin | Septic shock (n=55), healthy (n=12) | Platelets | Exosomes from septic patients decreased maximal DT and positive dT/dt in rat papillary muscle preparations and positive dT/dtmax in isolated rabbit hearts pre-exposed to LPS. Exosomes from septic patients showed intrinsic NO production and induced myocardial NO content. No effects of exosomes from septic patients on isolated rabbit heart not pre-exposed to LPS and rat aortic ring contractility. |
| 11. Huisse (2008) 157 | Severe sepsis | 14% in-hospital mortality | Unknown | Once | Citrate | Severe sepsis (n=14), heat-stroke (n=18), healthy (n=18) | Total EVs, platelets, monocytes, granulocytes, ECs | Severely septic patients showed lower PEVs, increased GEVs and MEVs and similar EEVs vs. healthy volunteers. |
| 12. Mostefai (2008) 105 | Mixed septic shock | 28% at day 28 | 10 h post ICU admission | Once | Citrate | Septic shock (n=36), ICU non-septic (n=18) | Total EVs, platelets, ECs, leukocytes, granulocytes, monocytes, erythrocytes | Total EVs, PEVs, EEVs, L-Selectin+EVs and P-Selectin+EVs were increased, LEVs were decreased, and GEVs, MEVs, EryEVs and AnnV+ EVs were not different in septic vs. non-septic ICU patients. |
| 13. Pérez-Casal (2009) 158 | Severe sepsis, rhAPC treatment | Unknown | At start of rhAPC infusion | Days 0, 1 and 4 of rhAPC infusion | Citrate | Severe sepsis with rhAPC (n=4), severe sepsis without rhAPC (n=4) | EPCR+ EVs | Co-localization of EPCR and APC on EVs from septic patients during, but not before, rhAPC infusion. APC on EPCR+ EVs was higher during vs. before (individual controls) rhAPC treatment and vs. non-rhAPC-treated controls. |
| 14. Forest (2010) 159 | SIRS, mixed sepsis or septic shock | 0% in all SIRS patients, 0% in <50 y sepsis, 26% in ≥75 y sepsis | Within 1 h of hospital admission | Once | Citrate | <50y SIRS (n=26), <50y sepsis (n=27), ≥75y SIRS (n=31), ≥75y sepsis (n=27) | ECs, erythrocytes, platelets | Lower EEVs, but the same EV procoagulant activity in older vs. younger patients. Lower EEVs in sepsis vs. SIRS in young patients. Lower EV procoagulant activity in sepsis vs. SIRS in both old and young patients. Elderly sepsis non-survivors had higher EEVs vs. elderly survivors. |
| 15. Rank (2011) 160 | Sepsis | Unknown | Before conditioning | Twice a week for 30 days, thereafter once a week until discharge | Citrate | hematopoietic stem-cell transplantation (n=19), incl. infection/sepsis (n=15) | Erythrocytes | EryEVs level was affected only by development of graft-versus-host-disease but not conditioning therapy, total body irradiation, high-dose chemotherapy, in vivo T-cell depletion, aplasia or engraftment in uncomplicated patients, infectious complications and/or sepsis. |
| 16. Pérez-Casal (2011) 70 | Severe sepsis (Pneumonia or intraabdominal infection), rhAPC indication | 36% at day 28 | Start of RhAPC | Before RhAPC infusion and at day 2, 3, 4, 5 and 6 | Citrate | Severe sepsis with rhAPC (n=25) or without rhAPC (n=25), healthy (n=6) | EPCR+EV, APC+EV, myeloid cell line | Increased circulating EV carrying EPCR and APC expression after rhAPC. Decrease of endothelial permeability by APC+EVs via PAR-1. |
| 17. Prakash (2012) 101 | Septic peritonitis, mixed ICU with suspected ventilator-associated pneumonia or lung donors | Unknown | Unknown | Once | N/A (abdominal lavage fluid or BAL fluid within 2h of collection) | Septic peritonitis (n=3), control abdominal lavage fluid from non-septic laparotomy (n=4), ICU suspected pneumonia BAL (n=33), control BAL from lung donor (n=2) | Granulocytes, platelets, ECs, erythrocytes | GEV only present in inflamed foci. THP-1 cells were activated by phagocytosis of GEV. |
| 18. Woth (2012) 55 | Mixed severe sepsis | 21% | At admission to the ICU | At admission, day 3 and day 5 | Citrate | Severe sepsis (n=33), healthy (n=20) | Platelets | Elevated AnnV+ EV and PEV in septic vs. healthy on admission. Higher AnnV+ EV and PEV in fungal vs. non-fungal septic patients on day 1. CD42+ EV increased in fungal vs. non-fungal sepsis at all times and PAC1+ EVs at day 1 and day 5. |
| 19. Timár (2013) 103 | S. aureus bacteremia and fever | Unknown | Within 24 h after fever | Once | Unknown | Bacteremia (n=12), healthy (n=6) | Granulocytes | GEV 5-6 fold higher in serum and bacterial-EV aggregates larger with serum of bacteremic patients vs. healthy. |
| 20. Tőkés-Füzesi (2013) 22 | Severe sepsis | 15% at day 28 | Within 24 h of diagnosis of severe sepsis | At admission, day 3 and day 5 | Citrate | Severe sepsis (n=37) or non-septic ophthalmic patients (n=20) | Platelets, monocytes, myeloid cell line | Increased total, CD41+, CD42a+, and PAC1+ EVs in septic vs. healthy. Increased total, CD41+, and CD13+ EVs on admission in septic patients with renal dysfunction. Negative correlation of CD42a+ PEVs with blood urea nitrogen and creatinine concentrations in sepsis. |
| 21. Mostefai (2013) 161 | Septic shock | 12.5% at day 28 | 10±4 h after ICU admission | Once | Unknown | Septic shock (n=16) | Unknown | Septic EVs augmented histamine-induced contraction in human tissue-engineered vascular media. Septic EV treatment increased cyclo-oxygenase-1 and IL-10 expression of IL-10 (but not IL-1α, IL-1β, IL-6). |
| 22. Van Ierssel (2013) 162 | Mixed severe sepsis or septic shock | 14% at day 28 | At admission (<72 h of sepsis diagnosis) | Once | Citrate | Severe Sepsis (n=30), healthy (n=15) | ECs | EEV not different between septic and healthy. |
| 23. Delabranche (2013) 122 | Mixed septic shock with DIC | 29.3% at day 28 | At diagnosis of septic shock | At admission (day 1), day 2, day 3 and day 7 | Unknown | Septic shock (n=92) incl. (n=40) with DIC | Procoagulant EVs (prothrombinase assay), ECs, leukocytes | CD11a+ and CD105+ EVs were increased in DIC at admission. Increased CD105+ EVs had higher and CD31+ EVs lower odds ratios for DIC. |
| 24. Dalli (2014) 106 | Sepsis caused by CAP | Unknown | <24h from admission | Once | Unknown | Sepsis survivor (n=25), sepsis non-survivor (n=25), healthy (n=15) | Granulocytes | Alpha-2-macroglobulin+ EVs were higher in sepsis survivors vs. non-survivors and healthy volunteers. High alpha-2-macroglobulin+ EVs correlated with better outcome. |
| 25. Hellum (2014) 132 | Meningitis with or without shock | 61% | <4 h from admission and symptoms <72 h | Once | Citrate | Meningitis and septic shock (n=13) and meningitis (n=10), healthy (n=6) | PhtdSer+ EVs | Faster and more efficient thrombin generation by EVs in shock vs. no shock and strong correlation with LPS level in shock. |
| 26. Exline (2014) 110 | Sepsis | 38% in-hospital | <24 h admission | At admission and after 48h | Unknown | Sepsis (n=34), non-infected critically-ill controls (n=16) | Total EV | Higher EV-derived caspase-1 activity on day 1 and day 3 in septic vs. non-septic patients. EVs from septic patients on day 1 induced lymphocyte apoptosis. |
| 27. Woei-A-Jin (2014) 56 | Community-acquired febrile E.coli urinary tract infection | 0% | <24 h of symptoms | At admission and on the 3 days thereafter | ethylene diamine tetraacetic acid | Febrile urinary tract infection (n=215), healthy volunteers (n=19) | Monocytes | Higher TF+ EV activity on admission in patients with higher APACHE II score categories, but weak correlation with soluble E-selectin, soluble vascular cell adhesion molecule, thrombin-antithrombin-complexes and procalcitonin. TF+ EV activity was higher in patients vs. healthy. |
| 28. Matsumoto (2015) 125 | Mixed severe Sepsis + DIC | 12.5% overall ICU mortality | <24 h of diagnosis | Once | Citrate | Severe sepsis (n=24), trauma SIRS (n=12), cerebral hemorrhage SIRS (n=6), healthy (n=23) | ECs | TF+ EEV, TM+ EEV and EPCR+ EEV were increased in both septic shock and trauma vs. healthy; lack of correlation with APACHE II and sequential organ function score; moderate-to-strong correlation with the International Society of Thrombosis and Haemostasis DIC score. |
| 29. Herrmann (2015) 27 | Sepsis (Gram- and Gram+, possibly polymicrobial infections, 62.5% pulmonary, 37.5% abdominal) | Sepsis 40%, ICU control 15% | Within 72 h of ICU admission | Once | Heparin | Sepsis (n=14), SIRS (n=8) | Granulocytes | CD11β+/CD18+ and CD11β+/CD177+ EVs were higher in sepsis vs. control. Similar IL-6 plasma release by septic vs. control. Procoagulant activity increased, clotting time decreased, and bacteria aggregation activity higher in sepsis vs. control. |
| 30. Zhang (2016) 23 | Mixed sepsis | Unknown | <24 h of disease | Once | Citrate | Septic (n=15), healthy (n=10) | Platelets, ECs, erythrocytes, leukocytes, granulocytes, T-lymphocytes, monocytes | All PhtdSer+ EVs were increased in sepsis vs. healthy. EVs induced coagulation at PhtdSer-exposing sites in vitro; partly reversed by PhtdSer antagonism. |
| 31. Trepesch (2016) 163 | Mixed sepsis, severe sepsis, septic shock, survivor vs. non-survivors | 36.7% ICU mortality | At sepsis diagnosis | Daily up to 7 days, then every second day up to day 13 | Unknown | Sepsis (n=6), severe sepsis (n=4), septic shock (n=20) | PhtdSer+ EVs | The amount of PhtdSer+ EVs was not associated with mortality and organ dysfunction. |
| 32. Delabranche (2016) 133 | Mixed septic shock | total 34.4%, without DIC 28.3%, with DIC 45.2% | <6 h of septic shock diagnosis | At admission (day 1), day 3, and day 7 | Unknown | Septic shock (n=259) incl. with DIC at admission (n=61), with DIC within first 24h (n=32) | procoagulant (PhtdSer+) EV, leukocytes, apoptotic ECs, platelets, monocytes/macrophages | Increased CD105+ EVs and decreased CD31+ EVs were associated with DIC. Increased CD11a+ EVs/leukocytes supported leukocyte activation. |
| 33. Lehner (2016) 29 | Septic shock | ICU-mortality 66.7%, hospital-mortality 70% | Median (25-75% interquartile range) 12.6 h (3.1-21) from diagnosis | Once | Citrate | Septic shock (n=30), healthy (n=18) | ECs, leukocytes, platelets | Low but increased counts of EEVs (CD144+, CD62E+, CD106+) and increased CD31+/CD41- EVs vs. healthy. Correlation between CD31+/CD41- EVs and leukocytes. Increased levels of CD41+ EVs and CD31+/CD41-/AnnV- EVs in 48h non-survivors. CD144+, CD62E+ and CD106+ EVs not different between DIC and non-DIC. |
| 34. Stiel (2016) 164 | Septic shock with and without DIC | 7-day mortality: septic shock with DIC 20%; septic shock without DIC 5,5% | At admission | Once | Citrate | Septic shock: with DIC (n=35), without DIC (n=65) | Granulocytes | CD66+ GEV/neutrophilic granulocyte count higher in septic shock with DIC vs. without DIC. |
| 35. O'Dea (2016) 48 | Major burn injury vs. severe sepsis | Severe sepsis: ICU-mortality (27%), hospital-mortality (33%) | Within 24 h of burn injury, within 48 h of sepsis diagnosis | At admission and on day 2 (burn injury), once (sepsis) | Heparin | Major burn injury (n=15), severe sepsis (n=15), healthy (n=12) | Leukocytes, monocytes, granulocytes, ECs | EVs increase on admission in burns vs. healthy. Only CD45+/Cd14+ MEVs and CD66b+/CD11b+ GEVs increased in sepsis vs. healthy. CD45+/Cd14+ MEVs and CD105+ EEVs lower in sepsis vs. burns. CD45+ LEVs and CD66b+/CD11b+ GEVs increased in dying vs. surviving burn patients. No difference between dying and surviving sepsis patient. |
| 36. Matsumoto (2017) 19 | Mixed SIRS vs. severe sepsis | 16% | Within 24 h of injury/diagnosis | Once | Citrate | Trauma patients (24), severe sepsis (n=25), healthy (n=23) | Monocytes | Increased AnnV+/CD13+/CD142+ EVs in both trauma and severe sepsis vs. healthy. Moderate association between AnnV+/CD13+/CD142+ EVs and APACHE II score, IL-6, Injury Severity Score (in trauma), and International Society of Thrombosis and Haemostasis-DIC score (in sepsis). |
| 37. Panich (2017) 165 | Sepsis, septic shock | Sepsis with AKI 11.4%, Sepsis without AKI 6.7% | At admission | Daily day 1 to day 7 | N/A (Urine) | Sepsis with AKI (n=79), sepsis without AKI (n=60), healthy (n=8) | Exosomes | Activating transcriptional factor-3+ exosomes increased on day 1 of admission in sepsis with AKI vs. sepsis without AKI. Area under receiver operating curve for AKI 0.84. |
| 38. Reithmair (2017) 66 | Sepsis, septic shock | unknown | Day 0 | Day 0 and day 4 | Serum | Sepsis (n=22), healthy (n=23) | miRNA in serum, blood cells and EVs (exosomes, Tumor susceptibility gene 101+) by next generation sequencing | Compartment-specific (serum, cellular, extracellular) differences over time. |
| 39. Lehner (2017) 73 | Severe sepsis or sepsis shock, medical ICU | 33% ICU survival, 25% hospital survival | On average 7 h post start hemofiltration | Once | Citrate | Severe sepsis or septic shock (n=12) | Microparticles expressing platelet endothelial cell adhesion molecule (from platelets, leukocytes and/or ECs) and platelets. | Increase of CD31+/CD41- EVs post-filter vs. pre-filter. Decreased total PhtdSer-exposing EVs and decreased TF+ EVs post-filter vs. pre-filter. No PhtdSer-exposing EVs and no TF activity measurable in ultrafiltrate. |
|
40. Lashin (2017) 16
|
Sepsis due to CAP or fecal peritonitis | 50% in sepsis due to CAP, 50% in sepsis due to fecal peritonitis (selected based on survival) | Day 1 post ICU admission | Day 1, 3, and 5 post ICU admission | ethylene diamine tetraacetic acid | CAP (n=60), fecal peritonitis (n=40), healthy (n=10) | Granulocytes, monocytes, T-lymphocytes, platelets, erythrocytes, and ECs | Circulating GEVs, MEVs, T-lymphocyte-derived EVs, and alpha-2-macroglobulin+ EVs (from all studied cell types) at day 1 were higher in CAP vs. fecal peritonitis and healthy volunteers, EEVs only vs. healthy, PEVs and EryEVs were not different. Alpha-2-macroglobulin+ EVs were higher in survivors of CAP, but not in fecal peritonitis. |
AKI: acute kidney injury; AnnV +/-: Annexin V positive/negative; APC: activated protein C; BAL: broncho-alveolar lavage; CAP: community acquired pneumonia; CD: cluster of differentiation; DIC: disseminated intravascular coagulation; EC: endothelial cell; EEVs: endothelial cell derived EVs; EPCR: endothelial protein C receptor; EryEVs: erythrocyte-derived EVs; EVs: extracellular vesicles; GEVs: granulocyte-derived EVs; ICU: intensive care unit; IL: interleukin; LEVs: leukocyte-derived EVs; LPS: lipopolysaccharide; MEVs: monocyte-derived EVs; PEVs: platelet-derived EVs; PhtdSer: phosphatidylserine; rhAPC: recombinant human APC; ROS: reactive oxygen species; SIRS: non-infectious systemic inflammatory response syndrome; TF: tissue factor; TNF: tumor necrosis factor.
The following search terms were used (PubMed; accessed on 15 Feb 2018): “extracellular vesicles OR microvesicles OR microparticles OR exosomes AND sepsis AND patients”. This search yielded 85 studies with following exclusions: 14 reviews, 1 editorial, 1 acute respiratory distress syndrome oriented study: 7 in vitro studies, 8 animals studies, 6 studies without EVs assessment, 7 studies without/unclear number of septic patients, 1 article in Chinese language. The final selection included 40 studies in English language that analyzed the abundance, composition or effect of EVs in samples from septic patients.