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ABSTRACT: - Transfusion-related acute lung injury (TRALI) is a major complication of blood transfusions.- The pathogenesis of TRALI is thought to occur in 2 phases: the 'double-hit theory'.- The first phase is an underlying condition present in the patient, such as a surgical procedure or sepsis, which leads to priming, i.e. the activation of endothelium and subsequent sequestration of neutrophils in the lungs.- The second phase is the transfusion of a blood product resulting in the activation of the neutrophils. Antibodies against human leukocyte antigens (HLA) or against human neutrophil antigens (HNA) present in the donor blood are involved in this step. The long-term storage of cell-containing blood products may also be a causative factor.- The incidence of TRALI in patients with an underlying condition is high; up to 15% of transfused patients are at risk.- Anti-HLA and anti-HNA antibodies are highly prevalent in multiparous female donors. The exclusion of female donors for plasma and thrombocyte products has led to a 33-66% reduction in the incidence of TRALI.
Nederlands tijdschrift voor geneeskunde 01/2013; 157(11):A5524.
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ABSTRACT: Aspirin has been found to improve outcomes in an animal model of transfusion-related acute lung injury. We examined the association of aspirin use before admission to the intensive care unit and the development of transfusion-related acute lung injury in critically ill patients. We performed a post-hoc analysis of a nested case-control study that had been undertaken in a tertiary referral hospital. Transfusion-related acute lung injury cases were matched with controls (transfused patients not developing lung injury). Of these 218 patients, 66 used aspirin (30%). Use of aspirin did not alter the risk of transfusion-related acute lung injury after transfusion of platelets (OR 1.06, CI 0.59-1.91, p = 0.85), plasma (OR 1.06, 95% CI 0.59-1.92, p = 0.84), or red blood cells (OR 1.09, 95% CI 0.61-1.94, p = 0.77). Adjustment for confounding variables using propensity scoring also did not affect the risk of acquiring transfusion-related acute lung injury (p = 0.66). In conclusion, aspirin did not protect against transfusion-related lung injury in this cohort of critically ill patients.
Anaesthesia 02/2012; 67(6):594-9. · 2.96 Impact Factor
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ABSTRACT: Purpose. Onset of transfusion-related acute lung injury (TRALI) is suggested to be a threshold-event. Data is lacking on the relation between titer of antibodies infused and onset of TRALI. We determined whether onset of TRALI is dependent on the titer of MHC-I antibodies infused in a combined model of ventilator-induced lung injury and antibody-induced TRALl. Methods. BALB/c mice were ventilated for five hours with low (7.5 ml/kg) or high (15 ml/kg) tidal volume. After three hours of MV, TRALI was induced by infusion of 0.5 mg/kg, 2.0 mg/kg or 4.5 mg/kg MHC-I antibodies. Control animals received vehicle. After five hours of MV, animals were sacrificed. Results. MV with high tidal volumes resulted in increased levels of all markers of lung injury compared to animals ventilated with low tidal MV. In ventilator-induced lung injury, infusion of 4.5 mg/kg of antibodies further increased pulmonary wet-to-dry ratio, pulmonary neutrophil influx and pulmonary KC levels, whereas infusion of lower dose of antibodies did not augment lung injury. In contrast, mice ventilated with low tidal volumes did not develop lung injury, irrespective of the dose of antibody used. Conclusions. In the presence of injurious MV, onset of TRALI depends on the titer of antibodies infused.
Critical care research and practice 01/2012; 2012:720950.
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ABSTRACT: Activated platelets have been implicated in playing a major role in transfusion-related acute lung injury (TRALI), as platelets can trigger neutrophils, resulting in vascular damage. We hypothesized that binding of platelet CD40 ligand (CD40L) to endothelial CD40 is essential in the onset of TRALI. Mice were challenged with monoclonal major histocompatibility complex (MHC)-1 antibody which induced TRALI, evidenced by pulmonary oedema, accompanied by significantly elevated bronchoalveolar fluid (BALF) levels of total protein and elevated plasma levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) compared to infusion of isotype antibody (all Ps < 0·05). Treatment with ciglitazone, which inhibits platelet CD40L expression, had no effect on pulmonary and systemic inflammation compared to controls. In addition, treatment with anti-CD40L antibody, which antagonizes all CD40-CD40L interactions, also did not abrogate the TRALI reaction. Furthermore, levels of soluble CD40L were measured in a cohort of cardiac surgery patients, who were followed prospectively for the onset of TRALI after transfusion. Plasma levels of sCD40L at baseline and at time of developing TRALI did not differ between TRALI patients and controls (transfused cardiac surgery patients not developing acute lung injury) (275 ± 192 versus 258 ± 346 and 93 ± 82 versus 93 ± 123 pg/ml, respectively, not significant). In conclusion, these results do not support the idea that the CD40-CD40L interaction is involved in mediating TRALI.
Clinical & Experimental Immunology 05/2011; 165(2):278-84. · 3.36 Impact Factor
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ABSTRACT: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion related morbidity and mortality. TRALI is suggested to be a "two hit" event. The "first hit" is the underlying condition of the patient which results in sequestration and priming of neutrophils in the pulmonary compartment. The "second hit" is the transfusion of either human leukocyte antibodies or aged blood products which results in activation of the primed neutrophils and finally in pulmonary edema. The present review focuses on pre-clinical studies investigating the role of blood products containing aged cells (red blood cells, RBCs, and platelet concentrates, PLTs) and the onset of TRALI. Several mechanisms are under scrutiny. The first suggested mechanism is that soluble mediators accumulating during storage of RBCs and PLTs may play a role, including bio-active lipids or soluble CD40L. These soluble factors were found to cause lung injury in the presence of a "first hit". Another proposed mechanism involves the aged erythrocyte itself. During storage, the erythrocyte undergoes numerous changes in its biochemical and structural condition and acquires pro-inflammatory properties, sometimes collectively referred to as the "red cell storage lesion". Although it could be speculated that all of these factors may be involved in the onset of TRALI, only one pre-clinical study shows an association between the aged erythrocyte and the onset of TRALI. The suggested mechanism is a decrease in the chemokine scavenging function of the erythrocyte by reduction of the Duffy antigen expression resulting in an increase in lung injury. Further research is needed to elucidate possible mechanisms of onset of TRALI by aged blood products.
Clinical laboratory 01/2011; 57(3-4):267-72. · 0.90 Impact Factor
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ABSTRACT: Induced hypothermia after cardiopulmonary resuscitation provides organ protection and is currently considered standard of care in clinical practice. An increasing number of reports indicate that induced hypothermia is also beneficial in other conditions of hypoxia-induced organ injury, including brain injury, intestinal ischaemia-reperfusion injury and acute lung injury. The mechanism of the protective effect is thought to be caused by a reduction in metabolism. A hibernation-like state, characterised by hypothermia, bradypnoea and a reduction in metabolic rate, was induced in animals that normally do not hibernate, after inhalation of hydrogen sulphide. This state was termed a 'suspended animation-like state'. In critically ill patients, an exaggerated systemic inflammatory response is common, which often results in multiple organ injury. Inducing a hypometabolic state during critical illness may limit organ injury by reducing oxygen consumption, constituting a fascinating new therapeutic perspective for the treatment of critically ill patients. In this manuscript, we describe mitochondrial dysfunction during critical illness and preclinical data that suggest a potential therapeutic possibility of lowering metabolism. In addition, we discuss issues that warrant further research before clinical applicability.
The Netherlands Journal of Medicine 05/2010; 68(5):190-8. · 2.07 Impact Factor
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The Netherlands Journal of Medicine 05/2010; 68(5):228-31. · 2.07 Impact Factor
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ABSTRACT: Transfusion-related acute lung injury (TRALI) occurs more often in critically ill patients than in a general hospital population, possibly due to the presence of underlying inflammatory conditions that may prime pulmonary neutrophils. Mechanical ventilation may be a risk factor for developing TRALI. We examined the influence of mechanical ventilation (MV) on the development of TRALI, combining a murine MV model causing ventilator-induced lung injury with a model of antibody-induced TRALl.
BALB/c mice (n = 84) were ventilated for 5 h with low (7.5 ml/kg) or high (15 ml/kg) tidal volume, a positive end-expiratory pressure of 2 cm H(2)O and a fraction of inspired oxygen of 50%. After 3 h of MV, TRALI was induced by infusion of MHC-I antibodies (4.5 mg/kg); controls received vehicle. Non-ventilated animals receiving vehicle, isotype or MHC-I antibodies served as additional controls.
All animals receiving MHC-I antibodies developed TRALI within 2 h. In mice in which TRALI was induced, MV with low tidal volumes aggravated pulmonary injury, as evidenced by an increase in neutrophil influx, pulmonary and systemic levels of cytokines and lung histopathological changes compared to unventilated controls. The use of high tidal volume ventilation resulted in a further increase in protein leakage and pulmonary edema.
Mechanical ventilation (MV) synergistically augmented lung injury during TRALI, which was even further enhanced by the use of injurious ventilator settings. Results suggest that MV may be a risk factor for the onset of TRALI and may aggravate the course of disease.
European Journal of Intensive Care Medicine 03/2010; 36(5):879-87. · 5.17 Impact Factor
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ABSTRACT: Two decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, TRALI has emerged as the leading cause of transfusion-related mortality, presumably as a consequence of reaching international agreement on defining TRALI with subsequent increased recognition and reporting of TRALI cases. Specific patient populations such as critically ill patients have an increased risk of developing TRALI, which may be explained by the two-event hypothesis. The first event is the underlying condition of the patient resulting in priming of neutrophils. The second event is the transfusion of a blood product, after which either antibodies or bioactive lipids activate the primed neutrophils, resulting in pulmonary oedema. As opposed to the traditional view that TRALI has a good prognosis, TRALI may have a significant impact on morbidity and outcome, at least in specific patient groups. The association of transfusion with adverse outcome calls for blood product and donor management strategies aimed at decreasing the risk of acquiring TRALI. Excluding female donors from plasma donation seems to have reduced, but not prevented the occurrence of TRALI . Additional research is needed to determine whether the use of fresh blood products may be an additional measure to reduce TRALI. Studies are also needed to identify at-risk patients. In these studies, we advocate the use of the consensus definition to improve comparability of risk factors and outcome of TRALI across patient populations.
The Netherlands Journal of Medicine 11/2009; 67(10):320-6. · 2.07 Impact Factor
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ABSTRACT: Data on the rationality of transfusion practice of fresh frozen plasma (FFP) and platelets in the critically ill are sparse and may contribute to efforts to reduce transfusion rates. To provide insight into determinants of the decision of intensive care unit (ICU)-physicians to transfuse, a survey study was performed. The reasons of ICU-physicians to transfuse FFP and platelets were determined during a 10-week period. Transfusion triggers were assessed, as well as correction of prolonged coagulation test results. Of 310 admissions, 44 patients (14%) received a transfusion of FFP and 35 patients (11%) received a platelet transfusion. In 67% patients, FFPs were transfused in bleeding patients and in 33% in non-bleeding patients. FFP was transfused at a prothrombin time (PT) of 19 s (17-22). After FFP transfusion, PT levels of 15-18, 18-20 and 20-26 s decreased with a median of 0.7, 1.9 and 3.5 s, respectively. On average, 3.2 FFP units were ordered, of which 28% was not transfused. The major reason to transfuse platelets was bleeding. Platelets were transfused at a platelet count of 95 (36-116) x 10(9) L(-1) in bleeding and 13 (10-18) x 10(9) L(-1) in non-bleeding patients. On average, 1.4 platelet units were ordered, of which 20% was not transfused. The agreement between physicians reporting a major bleeding and a definition of bleeding was poor (kappa < 0.10 for FFP and 0.20 for platelets). In conclusion, one-third of FFP transfusions was given to non-bleeding patients. FFP transfusion failed to normalize prolonged coagulation test results in the majority of the patients. Transfusion of platelets was restrictive in non-bleeding patients and liberal in bleeding patients. Education on indications of FFP transfusion and improved identification of bleeding may reduce transfusion rates.
Transfusion Medicine 09/2009; 19(4):207-12. · 1.14 Impact Factor
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ABSTRACT: Incidence reports on acute lung injury (ALI) vary widely. An insight into the diagnostic preferences of critical care physicians when diagnosing ALI may improve identification of the ALI patient population.
Critical care physicians in the Netherlands were surveyed using vignettes involving hypothetical patients and a questionnaire. The vignettes varied in seven diagnostic determinants based on the North American European Consensus Conference and the lung injury score. Preferences were analyzed using a mixed-effects logistic regression model and presented as an odds ratio (OR) with a 95% confidence interval.
From 243 surveys sent to 30 hospitals, 101 were returned (42%). ORs were as follows: chest X-ray consistent with ALI: OR 1.7 (1.3-2.3), high positive end-expiratory pressure (PEEP) (15 cmH(2)O): OR 5.0 (3.9-6.6), low pulmonary artery occlusion pressures (PAOP) (<18 mmHg): OR 4.7 (3.6-6.1), low compliance (30 ml/cmH(2)O): OR 0.7 (0.5-0.9), low PaO(2)/FiO(2) (<250 mmHg): OR 9.2 (6.9-12.3), absence of heart failure: OR 1.2 (0.9-1.5), presence of a risk factor for ALI (sepsis): OR 1.0 (0.8-1.3). The questionnaire revealed that critical care physicians with an anesthesiology background differed from physicians with an internal medicine background with regard to hemodynamic variables when considering an ALI diagnosis (P<0.05).
Dutch critical care physicians consider the PEEP level, but not the presence of a risk factor for ALI, as an important factor to diagnose ALI. Background specialty of critical care physicians influences diagnostic preferences and may account for variance in the reported incidence of ALI.
Acta Anaesthesiologica Scandinavica 08/2009; 53(10):1293-9. · 2.19 Impact Factor
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Nederlands tijdschrift voor geneeskunde 09/2008; 152(35):1945-6.
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ABSTRACT: A 32-year-old man who had undergone kidney transplantation presented with malaise, severe diarrhoea, nausea and vomiting, productive cough and shortness of breath. A 42-year-old woman with no relevant medical history presented with fever, weight loss and abdominal pain. Both patients had lactic acidosis and hypoglycaemia. Initially, the hyperlactataemia was thought to result from tissue hypoxia (sepsis) but it persisted after correction of the hypovolaemia; therefore, alternative causes were considered. Both patients were found to have T-cell lymphoma with liver infiltration. The male patient died before treatment could be initiated. The lactic acidosis resolved in the female patient following lymphoma treatment, but she died subsequently from the lymphoma. Lymphoreticular malignancies should be considered for cases of lactic acidosis with sufficient oxygen supply, particularly when hypoglycaemia is also present. The lactic acidosis and hypoglycaemia result from increased anaerobic glycolysis in tumour cells. Tumour reduction with chemotherapy can reduce the lactic acidosis.
Nederlands tijdschrift voor geneeskunde 01/2007; 150(50):2770-3.
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ABSTRACT: During treatment for inflammatory bowel disease (IBD) 2 men with ulcerative colitis, aged 52 and 38 years, and a 37-year-old man with Crohn's disease developed Epstein-Barr virus (EBV)-related non-Hodgkin's B-cell lymphoma. The first 2 patients underwent proctocolectomy and the use of immunosuppressive agents was discontinued, after which the lymphoma disappeared. The third patient had icterus, hepatosplenomegaly and pancytopenia; he died from multiple organ failure. Azathioprine and 6-mercaptopurine are first choice therapy in the treatment of steroid-refractory IBD. These immunomodulating agents are associated with the development of EBV-positive lymphomas in the setting of solid organ transplantation. This type of lymphoma is a rare complication in IBD, although the incidence in referral centres appears to be increasing. Since azathioprine is an important drug in IBD, there is a need for identification of IBD patients at risk of developing a lymphoma. EBV-DNA in plasma or in faeces may be a candidate tumour marker.
Nederlands tijdschrift voor geneeskunde 09/2005; 149(33):1859-63.
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ABSTRACT: Patients with tuberculosis had higher expression of monocyte urokinase receptor (uPAR) and CD11b than controls. In vitro, lipoarabinomannan and lipopolysaccharide (LPS) from Escherichia coli shared the ability to enhance uPAR and CD11b expression on monocytes and granulocytes. In healthy volunteers, LPS induced increases in monocyte and granulocyte uPAR and CD11b.
Infection and Immunity 09/2001; 69(8):5182-5. · 4.16 Impact Factor
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ABSTRACT: Ingestion of thalidomide was associated with a reduction in the upregulation of the granulocyte activation marker CD11b and a reduced capacity to release elastase and lactoferrin after stimulation with lipopolysaccharide or lipoteichoic acid. A single oral dose of thalidomide attenuates neutrophil activation upon ex vivo stimulation with bacterial antigens.
Antimicrobial Agents and Chemotherapy 06/2001; 45(5):1547-9. · 4.84 Impact Factor
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ABSTRACT: Mycobacterium tuberculosis bacilli are intracellular organisms that reside in phagosomes of alveolar macrophages (AMs). To determine the in vivo role of AM depletion in host defense against M. tuberculosis infection, mice with pulmonary tuberculosis induced by intranasal administration of virulent M. tuberculosis were treated intranasally with either liposome-encapsulated dichloromethylene diphosphonate (AM(-) mice), liposomes, or saline (AM(+) mice). AM(-) mice were completely protected against lethality, which was associated with a reduced outgrowth of mycobacteria in lungs and liver, and a polarized production of type 1 cytokines in lung tissue, and by splenocytes stimulated ex vivo. AM(-) mice displayed deficient granuloma formation, but were more capable of attraction and activation of T cells into the lung and had increased numbers of pulmonary polymorphonuclear cells. These data demonstrate that depletion of AMs is protective during pulmonary tuberculosis.
The Journal of Immunology 05/2001; 166(7):4604-11. · 5.79 Impact Factor
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ABSTRACT: Expression of human immunodeficiency virus (HIV) coreceptors CXCR4 and CCR5 was found to be elevated on CD4(+) T cells (1) in blood samples obtained from patients with tuberculosis and (2) in blood samples obtained from healthy subjects and stimulated with mycobacterial lipoarabinomannan in vitro. These data suggest that the increase in HIV viremia that occurs in association with tuberculosis may result from up-regulation of CXCR4 and CCR5 on CD4(+) T cells, thereby causing acceleration of HIV infection.
Clinical Infectious Diseases 03/2001; 32(4):650-2. · 9.15 Impact Factor
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ABSTRACT: p38 mitogen-activated protein kinase (MAPK) has been suggested as a mediator of cytokine release and is currently being targeted for anti-inflammatory therapy. However, experimental data are contradictory and lack sufficient affirmation in vivo. We tested the effect of p38 MAPK inhibition in several cell types and in different murine models of infectious disease. We observed that most cell types react to p38 MAPK inhibition with diminished cytokine release, but that this treatment induced increased cytokine release in macrophages. Furthermore, we observed increased cytokine production in mouse models of pneumococcal pneumonia and tuberculosis accompanied by severely reduced bacterial clearance. This apparent inefficacy of p38 MAPK inhibition in reducing cytokine release in infectious disease, as well as its immune-compromising action, suggest that targeting p38 MAPK may not be a suitable anti-cytokine strategy in patients with such disease or at risk for infection.
The Journal of Immunology 02/2001; 166(1):582-7. · 5.79 Impact Factor
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ABSTRACT: Concurrent infections in patients with human immunodeficiency virus (HIV) infection stimulate HIV replication. Chemokine receptors CXCR4 and CCR5 can act as HIV coreceptors. The authors hypothesized that concurrent infection increases the HIV load through up-regulation of CXCR4 and CCR5. Using experimental endotoxemia as a model of infection, changes in HIV coreceptor expression were assessed in 8 subjects injected with lipopolysaccharide (LPS, 4 ng/kg). The expression of CXCR4 and CCR5 on CD4(+) T cells was increased 2- to 4-fold, 4 to 6 hours after LPS injection. In whole blood in vitro, LPS induced a time- and dose-dependent increase in the expression of CXCR4 and CCR5 on CD4(+) T cells. Similar changes were observed after stimulation with cell wall components of Mycobacterium tuberculosis (lipoarabinnomannan) or Staphylococcus aureus (lipoteichoic acid), or with staphylococcal enterotoxin B. LPS increased viral infectivity of CD4-enriched peripheral blood mononuclear cells (PBMCs) with a T-tropic HIV strain. In contrast, M-tropic virus infectivity was reduced, possibly because of elevated levels of the CCR5 ligand cytokines RANTES and MIP-1beta. LPS-stimulated up-regulation of CXCR4 and CCR5 in vitro was inhibited by anti-TNF and anti-IFN gamma. Incubation with recombinant TNF or IFN gamma mimicked the LPS effect. Anti-interleukin 10 (anti-IL-10) reduced CCR5 expression, without influencing CXCR4. In accordance, rIL-10 induced up-regulation of CCR5, but not of CXCR4. Intercurrent infections during HIV infection may up-regulate CXCR4 and CCR5 on CD4(+) T cells, at least in part via the action of cytokines. Such infections may favor selectivity of HIV for CD4(+) T cells expressing CXCR4. (Blood. 2000;96:2649-2654)
Blood 11/2000; 96(8):2649-54. · 9.90 Impact Factor
