RESUMEN
OBJECTIVE: To describe the long-term consequences of necrotising pancreatitis, including complications, the need for interventions and the quality of life. DESIGN: Long-term follow-up of a prospective multicentre cohort of 373 necrotising pancreatitis patients (2005-2008) was performed. Patients were prospectively evaluated and received questionnaires. Readmissions (ie, for recurrent or chronic pancreatitis), interventions, pancreatic insufficiency and quality of life were compared between initial treatment groups: conservative, endoscopic/percutaneous drainage alone and necrosectomy. Associations of patient and disease characteristics during index admission with outcomes during follow-up were assessed. RESULTS: During a median follow-up of 13.5 years (range 12-15.5 years), 97/373 patients (26%) were readmitted for recurrent pancreatitis. Endoscopic or percutaneous drainage was performed in 47/373 patients (13%), of whom 21/47 patients (45%) were initially treated conservatively. Pancreatic necrosectomy or pancreatic surgery was performed in 31/373 patients (8%), without differences between treatment groups. Endocrine insufficiency (126/373 patients; 34%) and exocrine insufficiency (90/373 patients; 38%), developed less often following conservative treatment (p<0.001 and p=0.016, respectively). Quality of life scores did not differ between groups. Pancreatic gland necrosis >50% during initial admission was associated with percutaneous/endoscopic drainage (OR 4.3 (95% CI 1.5 to 12.2)), pancreatic surgery (OR 3.2 (95% CI 1.1 to 9.5) and development of endocrine insufficiency (OR13.1 (95% CI 5.3 to 32.0) and exocrine insufficiency (OR6.1 (95% CI 2.4 to 15.5) during follow-up. CONCLUSION: Acute necrotising pancreatitis carries a substantial disease burden during long-term follow-up in terms of recurrent disease, the necessity for interventions and development of pancreatic insufficiency, even when treated conservatively during the index admission. Extensive (>50%) pancreatic parenchymal necrosis seems to be an important predictor of interventions and complications during follow-up.
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Insuficiencia Pancreática Exocrina , Pancreatitis Aguda Necrotizante , Pancreatitis Crónica , Humanos , Pancreatitis Aguda Necrotizante/complicaciones , Pancreatitis Aguda Necrotizante/cirugía , Estudios de Seguimiento , Calidad de Vida , Estudios Prospectivos , Insuficiencia Pancreática Exocrina/etiología , Pancreatitis Crónica/complicaciones , Drenaje/efectos adversos , Necrosis , Resultado del TratamientoRESUMEN
This paper describes the implementation of inflammatory bowel disease (IBD)-specific cognitive behavioural therapy (CBT) for IBD patients with poor quality of life (QoL), anxiety and depression, in four hospitals in the Netherlands. Treatment outcomes were compared with those of a previously published randomized control trial (RCT) of 'IBD-specific CBT', following a benchmark strategy. Primary outcome was IBD-specific QoL (IBDQ) completed before and after CBT, secondary outcomes were anxiety and depressive symptoms (HADS, CES-D). Semi-structured interviews were conducted among a pilot of gastroenterologists, nurse specialists and psychologists to evaluate 'IBD-specific CBT'. 94 patients started treatment (280 screened). At follow-up, 63 participants (67% compared to 81% in the RCT benchmark) completed the IBDQ. Treatment effect sizes of the implementation study were comparable and slightly larger than those of RCT benchmark. Gastroenterologists, IBD nurses and psychologists found CBT necessary for IBD patients with poor QoL, depression and/or anxiety disorders. 'IBD-specific CBT' can be successfully implemented. Regular supervision of psychologists performing 'IBD-specific CBT' treatment is needed.
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Terapia Cognitivo-Conductual , Enfermedades Inflamatorias del Intestino , Calidad de Vida , Humanos , Terapia Cognitivo-Conductual/métodos , Calidad de Vida/psicología , Masculino , Femenino , Enfermedades Inflamatorias del Intestino/psicología , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/complicaciones , Adulto , Persona de Mediana Edad , Países Bajos , Trastornos de Ansiedad/terapia , Trastornos de Ansiedad/psicología , Resultado del Tratamiento , Trastorno Depresivo/terapia , Trastorno Depresivo/psicología , AncianoRESUMEN
BACKGROUND: Cholecystectomy in patients with idiopathic acute pancreatitis (IAP) is controversial. A randomized trial found cholecystectomy to reduce the recurrence rate of IAP but did not include preoperative endoscopic ultrasonography (EUS). As EUS is effective in detecting gallstone disease, cholecystectomy may be indicated only in patients with gallstone disease. This study aimed to determine the diagnostic value of EUS in patients with IAP, and the rate of recurrent pancreatitis in patients in whom EUS could not determine the aetiology (EUS-negative IAP). METHODS: This prospective multicentre cohort study included patients with a first episode of IAP who underwent outpatient EUS. The primary outcome was detection of aetiology by EUS. Secondary outcomes included adverse events after EUS, recurrence of pancreatitis, and quality of life during 1-year follow-up. RESULTS: After screening 957 consecutive patients with acute pancreatitis from 24 centres, 105 patients with IAP were included and underwent EUS. In 34 patients (32 per cent), EUS detected an aetiology: (micro)lithiasis and biliary sludge (23.8 per cent), chronic pancreatitis (6.7 per cent), and neoplasms (2.9 per cent); 2 of the latter patients underwent pancreatoduodenectomy. During 1-year follow-up, the pancreatitis recurrence rate was 17 per cent (12 of 71) among patients with EUS-negative IAP versus 6 per cent (2 of 34) among those with positive EUS. Recurrent pancreatitis was associated with poorer quality of life. CONCLUSION: EUS detected an aetiology in a one-third of patients with a first episode of IAP, requiring mostly cholecystectomy or pancreatoduodenectomy. The role of cholecystectomy in patients with EUS-negative IAP remains uncertain and warrants further study.
Some patients develop acute inflammation of the pancreas without a clear cause. These patients have a high risk of developing more episodes of acute inflammation of the pancreas. Potentially, such inflammation could be caused by tiny gallstones that physicians are not able to detect. If this is true, these patients may also benefit from surgical removal of the gallbladder. However, this is still controversial. Endoscopic ultrasonography is a diagnostic procedure during which a physician looks at the gallbladder and bile ducts in detail via a small ultrasound probe inserted through the mouth. This endoscopic ultrasonography may be able to detect gallstones better than physicians were able to previously. This study tested the value of endoscopic ultrasonography, and the number of patients who developed more episodes of acute inflammation after endoscopic ultrasonography was recorded. Some 106 patients with acute inflammation of the pancreas for the first time without a clear cause participated and were offered endoscopic ultrasonography. The number of times endoscopic ultrasonography found a cause for the acute inflammation was recorded, as well as safety parameters, number of patients who developed more episodes of acute inflammation, and quality of life. After screening 957 patients, 105 ultimately underwent endoscopic ultrasonography. A cause was found in one-third of patients. This was mostly (tiny) gallstones, but chronic inflammation and even tumours were found. These patients were mostly treated surgically for their gallstones and tumours. In the first year after the first acute episode of inflammation, the inflammation came back at least once in almost one in six patients in whom endoscopic ultrasonography did not find a cause. This occurred less in patients in whom a cause was found; the inflammation came back in 1 in 16 of these patients. It was also found that having inflammation coming back negatively affected quality of life. In this study, endoscopic ultrasonography was able to detect a cause in one-third of patients with first-time acute inflammation of the pancreas. In one in four patients, this cause could be treated by a surgical procedure. Whether surgical removal of the gallbladder can be helpful in patients in whom endoscopic ultrasonography is not able to detect an aetiology should be investigated in further studies.
Asunto(s)
Colelitiasis , Pancreatitis Crónica , Humanos , Endosonografía , Enfermedad Aguda , Estudios Prospectivos , Estudios de Cohortes , Calidad de VidaRESUMEN
INTRODUCTION: Necrotizing pancreatitis may result in a disrupted or disconnected pancreatic duct (DPD) with the potential for long-lasting negative impact on a patient's clinical outcome. There is a lack of detailed data on the full clinical spectrum of DPD, which is critical for the development of better diagnostic and treatment strategies. METHODS: We performed a long-term post hoc analysis of a prospectively collected nationwide cohort of 896 patients with necrotizing pancreatitis (2005-2015). The median follow-up after hospital admission was 75 months (P25-P75: 41-151). Clinical outcomes of patients with and without DPD were compared using regression analyses, adjusted for potential confounders. Predictive features for DPD were explored. RESULTS: DPD was confirmed in 243 (27%) of the 896 patients and resulted in worse clinical outcomes during both the patient's initial admission and follow-up. During hospital admission, DPD was associated with an increased rate of new-onset intensive care unit admission (adjusted odds ratio [aOR] 2.52; 95% confidence interval [CI] 1.62-3.93), new-onset organ failure (aOR 2.26; 95% CI 1.45-3.55), infected necrosis (aOR 4.63; 95% CI 2.87-7.64), and pancreatic interventions (aOR 7.55; 95% CI 4.23-13.96). During long-term follow-up, DPD increased the risk of pancreatic intervention (aOR 9.71; 95% CI 5.37-18.30), recurrent pancreatitis (aOR 2.08; 95% CI 1.32-3.29), chronic pancreatitis (aOR 2.73; 95% CI 1.47-5.15), and endocrine pancreatic insufficiency (aOR 1.63; 95% CI 1.05-2.53). Central or subtotal pancreatic necrosis on computed tomography (OR 9.49; 95% CI 6.31-14.29) and a high level of serum C-reactive protein in the first 48 hours after admission (per 10-point increase, OR 1.02; 95% CI 1.00-1.03) were identified as independent predictors for developing DPD. DISCUSSION: At least 1 of every 4 patients with necrotizing pancreatitis experience DPD, which is associated with detrimental, short-term and long-term interventions, and complications. Central and subtotal pancreatic necrosis and high levels of serum C-reactive protein in the first 48 hours are independent predictors for DPD.
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Pancreatitis Aguda Necrotizante , Humanos , Pancreatitis Aguda Necrotizante/complicaciones , Proteína C-Reactiva , Páncreas/cirugía , Conductos Pancreáticos/cirugía , Estudios de CohortesRESUMEN
OBJECTIVE: Pain in chronic pancreatitis is subdivided in a continuous or intermittent pattern, each thought to represent a different entity, requiring specific treatment. Because evidence is missing, we studied pain patterns in a prospective longitudinal nationwide study. DESIGN: 1131 patients with chronic pancreatitis (fulfilling M-ANNHEIM criteria) were included between 2011 and 2018 in 30 Dutch hospitals. Patients with continuous or intermittent pain were compared for demographics, pain characteristics, quality of life (Short-Form 36), imaging findings, disease duration and treatment. Alternation of pain pattern and associated variables were longitudinally assessed using a multivariable multinomial logistic regression model. RESULTS: At inclusion, 589 patients (52%) had continuous pain, 231 patients (20%) had intermittent pain and 311 patients (28%) had no pain. Patients with continuous pain had more severe pain, used more opioids and neuropathic pain medication, and had a lower quality of life. There were no differences between pain patterns for morphological findings on imaging, disease duration and treatment. During a median follow-up of 47 months, 552 of 905 patients (61%) alternated at least once between pain patterns. All alternations were associated with the Visual Analogue Scale pain intensity score and surgery was only associated with the change from pain to no pain. CONCLUSION: Continuous and intermittent pain patterns in chronic pancreatitis do not seem to be the result of distinctly different pathophysiological entities. The subjectively reported character of pain is not related to imaging findings or disease duration. Pain patterns often change over time and are merely a feature of how severity of pain is experienced.
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Dolor/etiología , Pancreatitis Crónica/complicaciones , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Dolor/epidemiología , Dimensión del Dolor , Estudios Prospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Idiopathic acute pancreatitis (IAP) remains a dilemma for physicians as it is uncertain whether patients with IAP may actually have an occult aetiology. It is unclear to what extent additional diagnostic modalities such as endoscopic ultrasonography (EUS) are warranted after a first episode of IAP in order to uncover this aetiology. Failure to timely determine treatable aetiologies delays appropriate treatment and might subsequently cause recurrence of acute pancreatitis. Therefore, the aim of the Pancreatitis of Idiopathic origin: Clinical added value of endoscopic UltraSonography (PICUS) Study is to determine the value of routine EUS in determining the aetiology of pancreatitis in patients with a first episode of IAP. METHODS AND ANALYSIS: PICUS is designed as a multicentre prospective cohort study of 106 patients with a first episode of IAP after complete standard diagnostic work-up, in whom a diagnostic EUS will be performed. Standard diagnostic work-up will include a complete personal and family history, laboratory tests including serum alanine aminotransferase, calcium and triglyceride levels and imaging by transabdominal ultrasound, magnetic resonance imaging or magnetic resonance cholangiopancreaticography after clinical recovery from the acute pancreatitis episode. The primary outcome measure is detection of aetiology by EUS. Secondary outcome measures include pancreatitis recurrence rate, severity of recurrent pancreatitis, readmission, additional interventions, complications, length of hospital stay, quality of life, mortality and costs, during a follow-up period of 12 months. ETHICS AND DISSEMINATION: PICUS is conducted according to the Declaration of Helsinki and Guideline for Good Clinical Practice. Five medical ethics review committees assessed PICUS (Medical Ethics Review Committee of Academic Medical Center, University Medical Center Utrecht, Radboud University Medical Center, Erasmus Medical Center and Maastricht University Medical Center). The results will be submitted for publication in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: Netherlands Trial Registry (NL7066). Prospectively registered.
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Endosonografía , Pancreatitis , Enfermedad Aguda , Humanos , Estudios Multicéntricos como Asunto , Países Bajos , Pancreatitis/diagnóstico por imagen , Estudios Prospectivos , Calidad de VidaRESUMEN
OBJECTIVES: Typhoid fever caused by Salmonella Typhi remains a major burden worldwide. Gastrointestinal bleeding can be seen in up to 10 percent of patients and may be fatal. The coagulopathy, which may be the driver of this severe complication in patients with typhoid fever, however is ill defined. The aim of this study was to evaluate the activation of coagulation, anticoagulation, and fibrinolysis in patients with acute typhoid fever. METHODS: Parameters of coagulation and fibrinolysis were measured in 28 hospitalized patients with culture-confirmed or PCR-confirmed typhoid fever and compared to 38 age- and sex-matched healthy volunteers. RESULTS: Patients demonstrated activation of the coagulation system, as reflected by elevated in vitro thrombin generation and high plasma levels of fibrinogen, D-dimer and prothrombin fragment F1â¯+â¯2 in concert with consumption of coagulation factors resulting in a prolonged prothrombin-time and activated-partial-thromboplastin-time. Concurrently, the anticoagulant proteins, protein C and antithrombin, were significantly lower in comparison to healthy controls. Patients also demonstrated evidence of activation and inhibition of fibrinolysis and a marked activation of endothelial cells. The extent of coagulation activation was associated with the course of the disease, repeated testing during convalescence showed a return toward normal values. CONCLUSIONS: Activation of coagulation is an important clinical feature of typhoid fever and is associated with severity of disease.
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Coagulación Sanguínea , Endotelio/patología , Fibrinólisis , Fiebre Tifoidea/sangre , Fiebre Tifoidea/complicaciones , Adulto , Anticoagulantes , Bangladesh , Células Endoteliales/microbiología , Células Endoteliales/patología , Endotelio/citología , Endotelio/microbiología , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Protrombina , Salmonella typhi/genética , Salmonella typhi/aislamiento & purificación , Índice de Severidad de la Enfermedad , Trombocitopenia , Fiebre Tifoidea/patología , Adulto JovenRESUMEN
Tuberculosis is a devastating infectious disease causing many deaths worldwide. Recent investigations have implicated neutrophil extracellular traps (NETs) in the host response to tuberculosis. The aim of the current study was to obtain evidence for NETs release in the circulation during human tuberculosis. For this we measured the plasma concentrations of nucleosomes in conjunction with neutrophil elastase, in 64 patients with active pulmonary tuberculosis and 32 healthy controls. Patients with active tuberculosis had elevated plasma levels of nucleosomes and elastase when compared with local healthy blood donors. Furthermore nucleosome and elastase levels showed a positive correlation. These findings provide the first evidence for the release of NETs in the circulation of patients with active pulmonary tuberculosis.
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Trampas Extracelulares/metabolismo , Mycobacterium tuberculosis/metabolismo , Neutrófilos/metabolismo , Tuberculosis Pulmonar/sangre , Adulto , Femenino , Humanos , Masculino , Activación Neutrófila/fisiología , Tuberculosis Pulmonar/diagnóstico , Adulto JovenRESUMEN
BACKGROUND: Groove pancreatitis (GP) is a focal form of chronic pancreatitis affecting the paraduodenal groove area, for which consensus on diagnosis and management is lacking. GOALS: We performed a systematic review of the literature to determine patient characteristics and imaging features of GP and to evaluate clinical outcomes after treatment. RESULTS: Eight studies were included reporting on 335 GP patients with a median age of 47 years (range, 34 to 64 y), with 90% male, 87% smokers, and 87% alcohol consumption, and 47 months (range, 15 to 122 mo) of follow-up. Most patients presented with abdominal pain (91%) and/or weight loss (78%). Imaging frequently showed cystic lesions (91%) and duodenal stenosis (60%).Final treatment was conservative (eg, pain medication) in 29% of patients. Endoscopic treatment (eg, pseudocyst drainage) was applied in 19% of patients-34% of these patients were subsequently referred for surgery. Overall, 59% of patients were treated surgically (eg, pancreatoduodenectomy). Complete symptom relief was observed in 50% of patients who were treated conservatively, 57% who underwent endoscopic treatment, and 79% who underwent surgery. CONCLUSIONS: GP is associated with male gender, smoking, and alcohol consumption. The vast majority of patients presents with abdominal pain and with cystic lesions on imaging. Although surgical treatment seems to be the most effective, both conservative and endoscopic treatment are successful in about half of patients. A stepwise treatment algorithm starting with the least invasive treatment options seems advisable.
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Pancreatitis Crónica/terapia , Drenaje , Endoscopía , Humanos , Stents , Resultado del TratamientoRESUMEN
The Gram-negative bacterium Burkholderia pseudomallei causes melioidosis and is a CDC category B bioterrorism agent. Toll-like receptor (TLR)-2 impairs host defense during pulmonary B.pseudomallei infection while TLR4 only has limited impact. We investigated the role of TLRs in B.pseudomallei-lipopolysaccharide (LPS) induced inflammation. Purified B.pseudomallei-LPS activated only TLR2-transfected-HEK-cells during short stimulation but both HEK-TLR2 and HEK-TLR4-cells after 24 h. In human blood, an additive effect of TLR2 on TLR4-mediated signalling induced by B.pseudomallei-LPS was observed. In contrast, murine peritoneal macrophages recognized B.pseudomallei-LPS solely through TLR4. Intranasal inoculation of B.pseudomallei-LPS showed that both TLR4-knockout(-/-) and TLR2x4-/-, but not TLR2-/- mice, displayed diminished cytokine responses and neutrophil influx compared to wild-type controls. These data suggest that B.pseudomallei-LPS signalling occurs solely through murine TLR4, while in human models TLR2 plays an additional role, highlighting important differences between specificity of human and murine models that may have important consequences for B.pseudomallei-LPS sensing by TLRs and subsequent susceptibility to melioidosis.
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Burkholderia pseudomallei/patogenicidad , Interacciones Huésped-Patógeno , Lipopolisacáridos/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Burkholderia pseudomallei/metabolismo , Células HEK293/metabolismo , Células HEK293/microbiología , Humanos , Lipopolisacáridos/aislamiento & purificación , Lipopolisacáridos/toxicidad , Melioidosis/metabolismo , Melioidosis/microbiología , Ratones Endogámicos C57BL , Ratones Mutantes , Neumonía Bacteriana/inducido químicamente , Neumonía Bacteriana/metabolismo , Neumonía Bacteriana/microbiología , Transducción de Señal , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genética , Factores de Virulencia/metabolismoRESUMEN
For two years, every 6 weeks a 23-year-old man presented with episodes of severe abdominal pain and fever. After an extensive diagnostic workup, showing only slightly increased infectious parameters during the pain attacks and infiltration around the terminal ileum, a diagnostic laparoscopy diagnosed 'chronic recurrent appendicitis'. A 40-year-old female had severe attacks of abdominal pain and fever every 4-6 weeks for 1.5 years. Some inflammation around the appendix was seen on colonoscopy, and a diagnostic laparoscopy finally confirmed the same diagnosis 'chronic recurrent appendicitis'. Patients with recurrent abdominal pain often are a diagnostic challenge for the clinician. The appendix is rarely recognized as the causative factor and the diagnosis 'chronic recurrent appendicitis' is not widely accepted. This disease entity often has an atypical presentation and well-defined criteria are lacking. In this article we plea for a broader acceptance of this diagnosis, which, in our opinion, deserves to be included in the differential diagnosis of longstanding or recurrent abdominal pain attacks.
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Apendicitis/diagnóstico , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Adulto , Apendicectomía , Apendicitis/complicaciones , Apendicitis/cirugía , Enfermedad Crónica , Colonoscopía , Diagnóstico Diferencial , Femenino , Humanos , Laparoscopía , Masculino , Recurrencia , Adulto JovenRESUMEN
Asthma patients show evidence of a procoagulant state in their airways, accompanied by an impaired function of the anticoagulant protein C system. We aimed to study the effect of recombinant human activated protein C (rhAPC) in allergic asthma patients.We conducted a randomised, double-blind, placebo-controlled, proof-of-concept study in house dust mite (HDM) allergic asthma patients. Patients were randomised to receive intravenous rhAPC (24â µg·kg(-1)·h(-1); n=12) or placebo (n=12) for 11â h. 4â h after the start of infusion, a first bronchoscopy was performed to challenge one lung segment with saline (control) and a contralateral segment with a combination of HDM extract and lipopolysaccharide (HDM+LPS), thereby mimicking environmental house dust exposure. A second bronchoscopy was conducted 8â h after intrabronchial challenge to obtain bronchoalveolar lavage fluid (BALF).rhAPC did not influence HDM+LPS induced procoagulant changes in the lung. In contrast, rhAPC reduced BALF leukocyte counts by 43% relative to placebo, caused by an inhibitory effect on neutrophil influx (64% reduction), while leaving eosinophil influx unaltered. rhAPC also reduced neutrophil degranulation products in the airways.Intravenous rhAPC attenuates HDM+LPS-induced neutrophil migration and protein release in allergic asthma patients by an effect that does not rely on coagulation inhibition.
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Asma/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Dermatophagoides pteronyssinus/inmunología , Neutrófilos/efectos de los fármacos , Proteína C/farmacología , Hipersensibilidad Respiratoria/tratamiento farmacológico , Extractos de Tejidos/farmacología , Administración Intravenosa , Adulto , Alérgenos/farmacología , Animales , Anticoagulantes/farmacología , Asma/inmunología , Líquido del Lavado Bronquioalveolar/citología , Broncoscopía , Movimiento Celular/inmunología , Método Doble Ciego , Femenino , Humanos , Lipopolisacáridos/farmacología , Masculino , Neutrófilos/inmunología , Proteínas Recombinantes/farmacología , Hipersensibilidad Respiratoria/inmunología , Extractos de Tejidos/inmunología , Adulto JovenAsunto(s)
Leucocitos Mononucleares/inmunología , Glicoproteínas de Membrana/sangre , Receptores Inmunológicos/sangre , Tuberculosis Pulmonar/inmunología , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Receptor Activador Expresado en Células Mieloides 1 , Tuberculosis Pulmonar/sangre , Adulto JovenRESUMEN
Tuberculosis (TB) is an important cause of morbidity and mortality worldwide. Granzymes (gzms) are proteases mainly found in cytotoxic lymphocytes, but also extracellularly. While the role of gzms in target cell death has been widely characterized, considerable evidence points towards broader roles related to infectious and inflammatory responses. To investigate the expression of the gzms in TB, intracellular gzms A, B and K were measured by flow cytometry in lymphocyte populations from peripheral blood mononuclear cells from 18 TB patients and 12 healthy donors from Bangladesh, and extracellular levels of gzmA and B were measured in serum from 58 TB patients and 31 healthy controls. TB patients showed increased expression of gzmA in CD8(+) T, CD4(+) T and CD56(+) T, but not NK, cells, and of gzmB in CD8(+) T cells, when compared to controls. GzmK expression was not altered in TB patients in any lymphocyte subset. The extracellular levels of gzmA and, to a lesser extent, of gzmB, were increased in TB patients, but did not correlate with intracellular gzm expression in lymphocyte subsets. Our results reveal enhanced intra- and extracellular expression of gzmA and B in patients with pulmonary TB, suggesting that gzms are part of the host response to tuberculosis.
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Granzimas/sangre , Linfocitos T/enzimología , Tuberculosis/sangre , Tuberculosis/enzimología , Adulto , Bangladesh , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Interacciones Huésped-Patógeno , Humanos , Masculino , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Linfocitos T/inmunología , Linfocitos T/microbiología , Tuberculosis/diagnóstico , Tuberculosis/inmunología , Tuberculosis/microbiología , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Tuberculosis (TB) is an important cause of morbidity and mortality worldwide. Toll-like-receptors (TLRs) are important for the recognition of the causative agent Mycobacterium tuberculosis. Negative regulation of TLRs is necessary to control deleterious inflammatory damage, but could provide a means of immune evasion by M. tuberculosis as well. METHODS: To obtain insight in the extent of expression of inhibitory regulators of immunity in patients with active TB, peripheral-blood-mononuclear-cells (PBMCs) and plasma were obtained from 54 TB patients and 29 healthy blood donors from Chittagong, Bangladesh. Bilateral alveolar macrophages were obtained from an infected versus a contralateral normal lung segment of 9 patients. Statistical analyses were performed using Mann-Whitney U and Wilcoxon matched pairs testing. Correlations were calculated using the Spearman rho test. RESULTS: PBMCs harvested from TB patients demonstrated increased mRNA expression of IL-1-receptor-associated-kinase-M, suppressor-of-cytokine-signalling-3 and Toll-interacting-protein. Flow cytometry revealed enhanced expression of IL-1-receptor-like-1 (ST2) on lymphocytes. Plasma soluble ST2 was elevated in patients with TB and correlated with established TB biomarkers, most strongly with soluble interleukin-2 receptor subunit α and interleukin-8. Alveolar macrophage mRNA expression of negative TLR regulators did not differ between the infected and contralateral lung side. CONCLUSION: These results show enhanced expression of distinct negative regulators of innate immunity in PBMCs of patients with TB and identify plasma soluble ST2 as a potential novel biomarker for TB disease activity.
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Inmunidad Innata/inmunología , Tuberculosis Pulmonar/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bangladesh/epidemiología , Femenino , Citometría de Flujo , Humanos , Interleucina-8/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Receptores Toll-Like/inmunología , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/epidemiología , Adulto JovenRESUMEN
OBJECTIVES: Human tuberculosis (TB) remains an important cause of death globally. Bangladesh is one of the most affected countries. We aimed to investigate the impact of pulmonary TB on pro- and anticoagulant mechanisms. METHODS: This prospective study was conducted in Chittagong, Bangladesh. We performed an in-depth analysis of coagulation activation and inhibition in plasma obtained from 64 patients with primary lung TB and 11 patients with recurrent lung TB and compared these with 37 healthy controls. Additionally, in nine patients coagulation activation was studied in bronchoalveolar lavage fluid (BALF) harvested from the site of infection and compared with BALF from a contralateral unaffected lung subsegment. RESULTS: Relative to uninfected controls, primary and recurrent TB were associated with a systemic net procoagulant state, as indicated by enhanced activation of coagulation (elevated plasma levels of thrombin-antithrombin complexes, D-dimer and fibrinogen) together with impaired anticoagulant mechanisms (reduced plasma levels of antithrombin, protein C activity, free protein S, and protein C inhibitor). Activation of coagulation did not correlate with plasma concentrations of established TB biomarkers. Coagulation activation could not be detected at the primary site of infection in a subset of TB patients. CONCLUSIONS: Pulmonary TB is associated with a systemic hypercoagulable state.
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Coagulación Sanguínea/fisiología , Trombofilia/etiología , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/complicaciones , Antitrombina III , Bangladesh , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar , Broncoscopía , Femenino , Fibrinógeno/análisis , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Péptido Hidrolasas/sangre , Estudios ProspectivosRESUMEN
BACKGROUND: During pneumonia, inflammation and coagulation are activated as part of anti-bacterial host defense. Activated protein C (APC) has anticoagulant and anti-inflammatory properties and until recently was a registered drug for the treatment of severe sepsis. Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. METHODS: We aimed to investigate the effect of high APC levels during experimental pneumococcal pneumonia. Wild type (WT) and APC overexpressing (APC(high))-mice were intranasally infected with S. pneumoniae and sacrificed after 6, 24 or 48 hours, or followed in a survival study. RESULTS: In comparison to WT mice, APC(high)-mice showed decreased bacterial dissemination to liver and spleen, while no differences in bacterial loads were detected at the primary site of infection. Although no differences in the extent of lung histopathology were seen, APC(high)-mice showed a significantly decreased recruitment of neutrophils into lung tissue and bronchoalveolar lavage fluid. Activation of coagulation was not altered in APC(high)-mice. No differences in survival were observed between WT and APC(high)-mice (P =0.06). CONCLUSION: APC overexpression improves host defense during experimental pneumococcal pneumonia. This knowledge may add to a better understanding of the regulation of the inflammatory and procoagulant responses during severe Gram-positive pneumonia.
Asunto(s)
Neumonía Neumocócica/microbiología , Proteína C/metabolismo , Streptococcus pneumoniae/patogenicidad , Animales , Carga Bacteriana , Modelos Animales de Enfermedad , Femenino , Hígado/microbiología , Ratones , Ratones Endogámicos C57BL , Organismos Libres de Patógenos Específicos , Bazo/microbiologíaAsunto(s)
Adenocarcinoma/diagnóstico , Poliposis Intestinal/congénito , Síndromes Neoplásicos Hereditarios/diagnóstico , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/complicaciones , Adenocarcinoma/genética , Adenocarcinoma/terapia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biopsia , Quimioterapia Adyuvante/efectos adversos , Análisis Mutacional de ADN , Endoscopía Gastrointestinal , Resultado Fatal , Femenino , Predisposición Genética a la Enfermedad , Humanos , Poliposis Intestinal/complicaciones , Poliposis Intestinal/diagnóstico , Poliposis Intestinal/genética , Poliposis Intestinal/terapia , Mutación , Terapia Neoadyuvante/efectos adversos , Síndromes Neoplásicos Hereditarios/complicaciones , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Fenotipo , Proteína Smad4/genética , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a dreadful disease common in South-East Asia and Northern Australia and is characterized by chronic suppurative lesions and pneumonia. Melioidosis may evolve into severe sepsis with multi-organ failure with high mortalities, despite proper antibiotic therapy. Besides activation of a strong pro-inflammatory host response, the coagulation system plays an important role during melioidosis, which is thought to be host-protective. In particular, a procoagulant state together with downregulation of anticoagulant pathways and activation of fibrinolysis are present, all closely interrelated with parameters of inflammation. This review presents an overview of recent studies in which the role of coagulation, anti-coagulation and fibrinolysis during melioidosis was investigated both in patients and in experimental settings.