RESUMEN
BACKGROUND AND AIMS: Lack of timely referral and significant waits for specialist review amongst individuals with unresolved gastrointestinal (GI) symptoms can result in delayed diagnosis of Inflammatory Bowel Disease (IBD). AIMS: To determine the frequency and duration of GI symptoms and predictors of timely specialist review before the diagnosis of both Crohn's Disease (CD) and ulcerative colitis (UC). METHODS: Case-control study of IBD matched 1:4 for age and sex to controls without IBD using the Clinical Practice Research Datalink from 1998-2016. RESULTS: We identified 19,555 cases of IBD, and 78,114 controls. 1 in 4 cases of IBD reported gastrointestinal symptoms to their primary care physician more than 6 months before receiving a diagnosis. There is a significant excess prevalence of GI symptoms in each of the 10 years before IBD diagnosis. GI symptoms were reported by 9.6% and 10.4% at 5 years before CD and UC diagnosis respectively compared to 5.8% of controls. Amongst patients later diagnosed with IBD, <50% received specialist review within 18 months from presenting with chronic GI symptoms. Patients with a previous diagnosis of irritable bowel syndrome or depression were less likely to receive timely specialist review (IBS: HR=0.77, 95%CI 0.60-0.99, depression: HR=0.77, 95%CI 0.60-0.98). CONCLUSIONS: There is an excess of GI symptoms 5 years before diagnosis of IBD compared to the background population which are likely attributable to undiagnosed disease. Previous diagnoses of IBS and depression are associated with delays in specialist review. Enhanced pathways are needed to accelerate specialist referral and timely IBD diagnosis.
RESUMEN
BACKGROUND: It is unclear whether adherence to prescribing standards has been achieved in inflammatory bowel disease (IBD). AIM: To determine how prescribing of 5-aminosalicylates (5-ASAs), steroids and thiopurines has changed in response to emerging evidence. METHODS: We examined trends in oral and topical therapies in 23 509 incident IBD cases (6997 with Crohn's disease and 16 512 with ulcerative colitis) using a nationally representative sample between 1990 and 2010. We created five eras according to the year of diagnosis: era 1 (1990-1993), era 2 (1994-1997), era 3 (1998-2001), era 4 (2002-2005) and era 5 (2006-2010). We calculated the proportion of patients treated with prolonged 5-ASAs (>12 months) and steroid dependency, defined as prolonged steroids (>3 months) or recurrent (restarting within 3 months) steroid exposure. We calculated the cumulative probability of receiving each medication using survival analysis. RESULTS: Half of the Crohn's disease patients were prescribed prolonged oral 5-ASAs during the study, although this decreased between era 3 and 5 from 61.8% to 56.4% (P = 0.002). Thiopurine use increased from 14.0% to 47.1% (P < 0.001) between era 1 and 5. This coincided with a decrease in steroid dependency from 36.5% to 26.8% (P < 0.001) between era 1 and 2 and era 4 and 5 respectively. In ulcerative colitis, 49% of patients were maintained on prolonged oral 5-ASAs. Despite increasing thiopurine use, repeated steroid exposure increased from 15.3% to 17.8% (P = 0.02) between era 1 and 2 and era 4 and 5 respectively. CONCLUSIONS: Prescribing in clinical practice insufficiently mirrors the evidence base. Physicians should direct management towards reducing steroid dependency and optimising 5-ASA use in patients with IBD.
Asunto(s)
Prescripciones de Medicamentos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/mortalidad , Mesalamina/uso terapéutico , Vigilancia de la Población , Esteroides/uso terapéutico , Adolescente , Adulto , Antiinflamatorios no Esteroideos/uso terapéutico , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/mortalidad , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: The role of early thiopurine treatment in inflammatory bowel disease (IBD) is unproven. AIM: To quantify the impact of timing and duration of thiopurines on the risk of first surgery in children and young people with IBD using a population-based cohort. METHODS: We constructed an incident cohort of children and young people aged <25 years, diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) from 1990 to 2009. We used Cox proportional hazards modelling to determine the impact of early thiopurine use, commenced within a year of diagnosis on risk of first surgery. RESULTS: We identified 1595 and 1175 incident cases of CD and UC respectively with a mean length of follow-up of 4.3 years/person. There were 216 (13.5%) and 73 (6.2%) surgeries for CD and UC patients between 1990 and 2009 respectively. In CD among thiopurine users, the absolute risk of surgery at 5 years for early thiopurine use vs. late was 15.3% (95% CI: 10.5-22.1) vs. 22.1% (95% CI: 18.1-26.9) respectively. After adjustment, the early use of thiopurines was associated with a reduction in risk of first surgery of 39% (HR 0.61, 95% CI: 0.41-0.91) over the 20-year study period. In UC, early thiopurine use offered no additional benefit. CONCLUSIONS: In Crohn's disease, early treatment with thiopurines in children and young people is associated with an appreciable reduction in the risk of surgery, but early treatment does not reduce surgical risk in UC.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Intervención Médica Temprana , Factores Inmunológicos/administración & dosificación , Purinas/administración & dosificación , Adolescente , Niño , Preescolar , Estudios de Cohortes , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/cirugía , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/cirugía , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Factores de Riesgo , Reino Unido/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The role of thiopurines in altering the risk of colectomy in ulcerative colitis (UC) remains unclear. AIMS: To examine predictors of colectomy in UC and determine the impact of thiopurines on the risk of colectomy. METHODS: We constructed a population-based cohort of incident cases of UC in the United Kingdom between 1989 and 2009. We determined trends in thiopurine usage and colectomy for three defined cohorts: era 1 (1989-1995), era 2 (1996-2002), era 3 (2003-2009). We used Cox regression to determine predictors of colectomy and quantified the impact of duration and timing of thiopurine use on the risk of colectomy. RESULTS: We identified 8673 incident cases of UC. 5-year colectomy rates increased from 4.2%, 5.1% to 6.9% (P = 0.001) for era 1, era 2 and era 3, respectively, despite increasing thiopurine use. This was not significant after adjustment for predictors of colectomy (P = 0.06). There was a higher risk of colectomy in men (HR 1.44, 95% CI: 1.19-1.73), those diagnosed at an early age (HR 1.35, 95% CI: 1.04-1.75; 16-24 vs. 25-64) and early steroid users (HR 1.94, 95% CI: 1.59-2.37). 5-ASA users were less likely to require a colectomy (HR 0.35, 95% CI: 0.28-0.44). Amongst thiopurine users, those treated for greater than 12 months had a 71% reduction in risk of colectomy (HR 0.29, 95% CI: 0.21-0.40). Early thiopurines offered no additional benefit. CONCLUSIONS: Thiopurine exposure for greater than 12 months reduces the likelihood of colectomy by 71%. Young men and those requiring steroids within 3 months of diagnosis are at greatest risk of colectomy, and most likely to benefit from sustained thiopurine use.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/cirugía , Purinas/administración & dosificación , Compuestos de Sulfhidrilo/administración & dosificación , Adolescente , Adulto , Anciano , Colectomía , Esquema de Medicación , Femenino , Glucocorticoides/uso terapéutico , Humanos , Masculino , Mesalamina/uso terapéutico , Persona de Mediana Edad , Purinas/uso terapéutico , Riesgo , Compuestos de Sulfhidrilo/uso terapéutico , Factores de Tiempo , Reino Unido , Adulto JovenRESUMEN
OBJECTIVES: Increasing use of diagnostic imaging in inflammatory bowel disease (IBD) has led to concerns about the malignant potential of ionising radiation in a cohort that have an increased lifetime risk of gastrointestinal malignancy. The aim was to quantify radiation exposure in IBD patients referred from primary care, determine predictors of high exposure and evaluate temporal trends in diagnostic imaging over a 20-year period. METHODS: This was a retrospective cohort study whereby IBD patients were recruited from the outpatient clinic and evaluated retrospectively. The total cumulative effective dose (CED) received from tests was calculated for each subject. Cox regression was performed to assess factors associated with potentially harmful levels of ionising radiation defined as total CED > 50 milli-sieverts (mSv; equivalent to five CT abdomen scans). RESULTS: The cohort included 415 patients. Median total CED was 7.2 mSv (IQR: 3.0-22.7) in Crohn's disease and 2.8 mSv (IQR: 0.8-8.9) in ulcerative colitis patients, respectively. A total of 32 patients (8%) received a CED > 50 mSv. A history of IBD-related surgery was associated with high exposure (HR 7.7). During the study period, usage of abdominal CT increased by 310%. CONCLUSION: Approximately 1 in 13 patients in the study cohort were exposed to potentially harmful levels of ionising radiation. Strategies to minimise exposure to diagnostic medical radiation in IBD patients are required.
Asunto(s)
Colitis Ulcerosa/diagnóstico por imagen , Enfermedad de Crohn/diagnóstico por imagen , Adulto , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Dosis de Radiación , Estudios Retrospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos X/efectos adversosRESUMEN
BACKGROUND: Diagnostic imaging plays a pivotal role in the diagnosis and management of inflammatory bowel disease (IBD); however, increasing use has led to concerns about the malignant potential of ionising radiation. Several studies have demonstrated that diagnostic imaging can result in exposure to potentially harmful levels of ionising radiation in IBD patients. AIM: To determine the pooled prevalence of increased exposure and pooled odds ratio of risk factors associated with exposure to potentially harmful levels of diagnostic medical radiation. METHODS: We searched Medline, EMBASE, CINHAL and reference lists of identified articles, without language restrictions in October 2011. RESULTS: Six studies with 1704 participants provided data on the proportion of patients receiving potentially harmful levels of radiation defined as ≥50 milli-sieverts (mSv)-equivalent to 5 CT abdomen scans. The pooled prevalence was 8.8% (95% CI 4.4-16.8) for IBD patients and 11.1% (95% CI 5.7-20.5%) and 2% (95% CI 0.8-4.9%) for Crohn's disease and ulcerative colitis patients respectively. Five studies involving 2627 participants provided data for risk factors. IBD-related surgery and corticosteroid use were significant with pooled adjusted odds ratio of 5.4 (95% CI 2.6-11.2) and 2.4 (95% CI 1.7-3.4) respectively. CONCLUSIONS: About 1 in 10 patients may be exposed to potentially harmful levels of diagnostic medical radiation. Corticosteroid use and IBD related surgery increased this risk. Strategies to reduce radiation exposure while assessing disease activity need to be considered.
Asunto(s)
Enfermedades Inflamatorias del Intestino/diagnóstico por imagen , Traumatismos por Radiación/etiología , Cintigrafía/efectos adversos , Humanos , Radiografía , Dosificación Radioterapéutica , Factores de RiesgoRESUMEN
AIM: To evaluate the usefulness of small intestine contrast-enhanced ultrasonography (SICUS) using an oral contrast agent in routine clinical practice by assessing the level of agreement with the established techniques, small bowel follow-through (SBFT) and computed tomography (CT), and diagnostic accuracy compared with the final diagnosis in the detection of small bowel Crohn's disease (CD) and luminal complications in a regional centre. MATERIALS AND METHODS: All symptomatic known or suspected cases of CD who underwent SICUS were retrospectively reviewed. The level of agreement between SICUS and SBFT, CT, histological findings, and C-reactive protein (CRP) level was assessed using kappa (κ) coefficient. Sensitivity was demonstrated using the final diagnosis as the reference standard defined by the outcome of clinical assessment, follow-up, and results of investigations other than SICUS. RESULTS: One hundred and forty-three patients underwent SICUS of these 79 (55%) were female. Eighty-six (60%) were known to have CD and 57 (40%) had symptoms suggestive of intestinal disease with no previous diagnosis. Forty-six (55%) of the known CD patients had had at least one previous surgical resection. The sensitivity of SICUS in detecting active small bowel CD in known CD and undiagnosed cases was 93%. The kappa coefficient was 0.88 and 0.91 with SBFT and CT, respectively. SICUS detected nine patients who had one or more small bowel strictures and six patients with a fistula all detected by SBFT or CT. CONCLUSION: SICUS is not only comparable to SBFT and CT but avoids radiation exposure and should be more widely adopted in the UK as a primary diagnostic procedure and to monitor disease complications in patients with CD.
Asunto(s)
Medios de Contraste , Enfermedad de Crohn/diagnóstico por imagen , Intestino Delgado/diagnóstico por imagen , Administración Oral , Adulto , Proteína C-Reactiva , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Aumento de la Imagen/métodos , Enfermedades Intestinales/diagnóstico por imagen , Yohexol , Masculino , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X/métodos , Ultrasonografía Doppler/métodos , Reino UnidoRESUMEN
BACKGROUND: Clostridium difficile (C. difficile) infection in hospitals in developed countries continues to be a major public health hazard despite increased control measures including review of antibiotic policies and hygiene measures. Patients with colitis are thought to be particularly vulnerable to C. difficile associated diarrhoea (CDAD). Identifying the clinical burden among hospitalised patients admitted with inflammatory bowel disease is an essential first step towards identifying and treating severe C. difficile infection in such individuals. AIM: To determine excess morbidity and in-hospital mortality associated with hospital acquired CDAD in patients with inflammatory bowel disease (IBD-CDAD-HAI) admitted to NHS hospitals in England compared with those admitted for inflammatory bowel disease alone. METHODS: Time trends study of all admissions to NHS hospitals between 2002/03 and 2007/08. We developed case definitions for IBD-CDAD-HAI patients. The primary outcomes were in-hospital mortality and length of stay. The secondary outcome was gastrointestinal surgery. RESULTS: Patients in the IBD-CDAD-HAI group were more likely to die in hospital (adjusted OR 6.32), had 27.9 days longer in-patient stays and higher gastrointestinal surgery rates (adjusted OR 1.87) than patients admitted for inflammatory bowel disease alone. CONCLUSION: Patients with inflammatory bowel disease admitted to NHS hospitals in England with co-existent C. difficile infection are at risk of greater in-hospital mortality and morbidity than patients admitted for inflammatory bowel disease alone.
Asunto(s)
Clostridioides difficile/aislamiento & purificación , Diarrea/microbiología , Enterocolitis Seudomembranosa/microbiología , Enfermedades Inflamatorias del Intestino/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Diarrea/tratamiento farmacológico , Diarrea/mortalidad , Inglaterra/epidemiología , Enterocolitis Seudomembranosa/mortalidad , Heces/microbiología , Femenino , Mortalidad Hospitalaria , Hospitalización , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/mortalidad , Tiempo de Internación , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Calcitonina/sangre , Carcinoma Medular/complicaciones , Diarrea/etiología , Glándula Tiroides/patología , Neoplasias de la Tiroides/complicaciones , Adulto , Biopsia con Aguja Fina , Carcinoma Medular/diagnóstico , Carcinoma Medular/cirugía , Enfermedad Crónica , Femenino , Humanos , Imagen por Resonancia Magnética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/cirugía , Tiroidectomía/métodos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Assessing the extent of ulcerative colitis determines therapeutic strategies and provides prognostic information. Colonoscopy with mucosal biopsy is considered unsafe in patients with severe disease. AIM: To assess the correlation between proximal extent of ulcerative colitis as determined by Technitium-99-m hexamethylpropylene amine oxime labelled leucocyte scan (white cell scan) with that determined by histological assessment. METHODS: One hundred and thirty-five patients, with histologically-confirmed ulcerative colitis, who had a white cell scan and histological assessment of colonic inflammation within 6 months of each other, during the years 1991-2004, were included. Overall agreement, quadratic-weighted kappa (kappa) and polychoric correlations (rho) were calculated to estimate the inter-rater reliability. RESULTS: The correlation between white cell scan and histological extent was excellent (kappa = 0.7 rho = 0.8). Macroscopic appearance on colonoscopy did not correlate as well with histological extent (kappa = 0.62 and rho = 0.67). White cell scans correlated significantly better in patients with extensive disease (P = 0.02). Colonoscopy predicted disease extent more accurately in patients with limited colitis (P = 0.002). CONCLUSIONS: Proximal extent of ulcerative colitis determined by white cell scans correlates well with histological assessment especially in patients with more extensive disease. White cell scans offer a reasonable alternative to colonoscopy with mucosal biopsies in determining the proximal extent of colitis.
Asunto(s)
Colitis Ulcerosa/patología , Colonoscopía , Leucocitos , Adulto , Progresión de la Enfermedad , Femenino , Humanos , Mucosa Intestinal/patología , Masculino , Persona de Mediana EdadRESUMEN
Accumulating evidence suggests that intestinal epithelial cells (IECs) constitutively express the immunoregulatory cytokine interleukin (IL)-18. IECs also serve as the host cell for the intracellular parasitic protozoan Cryptosporidium parvum. In the present study, C. parvum infection of a human enterocyte cell-line HCT-8 resulted in increased expression of IL-18 mRNA as measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). IL-18 protein was detected in control uninfected cells and following infection there was increased expression as measured by enzyme-linked immunosorbent assay (ELISA). Gene expression revealed the presence of the IL-18 receptor subunits not only in cell-lines but also in freshly isolated IECs, suggesting that IL-18-mediated signalling events may contribute to epithelial host defence during infection. Recombinant IL-18 inhibited intracellular development of the parasite in HCT-8 and HT-29 cells. Increased expression of bactericidal antibiotic peptides LL-37 and alpha-defensin 2 by IL-18 in HCT-8 and HT-29 cells may represent one mode of action by which this pluripotent cytokine aids in limiting the development of intracellular pathogens such as C. parvum in the gastrointestinal tract.
Asunto(s)
Criptosporidiosis/inmunología , Cryptosporidium parvum/fisiología , Enterocitos/inmunología , Enterocitos/microbiología , Interleucina-18/fisiología , Animales , Antibacterianos/metabolismo , Péptidos Catiónicos Antimicrobianos/metabolismo , Estudios de Casos y Controles , Línea Celular , Criptosporidiosis/metabolismo , Cryptosporidium parvum/efectos de los fármacos , Células HT29 , Humanos , Interleucina-18/genética , Subunidad alfa del Receptor de Interleucina-18 , ARN Mensajero/análisis , Receptores de Interleucina/metabolismo , Receptores de Interleucina-18 , Proteínas Recombinantes/farmacología , alfa-Defensinas/metabolismo , CatelicidinasRESUMEN
BACKGROUND: This systematic review examined the use of immunomodulators and the risk of postoperative complications after abdominal surgery in patients with inflammatory bowel disease. METHODS: Electronic databases (PubMed, Embase, Ingenta, Zetoc and Ovid) were searched and the reference lists in all articles identified were hand-searched for further relevant papers. Studies were included if they evaluated postoperative complications and defined exposure to individual immunomodulators. RESULTS: All 11 studies that met the inclusion criteria were observational studies; two were reported only in abstract form. Five studies reported risks associated with azathioprine, five reported risks associated with cyclosporin and three reported risks associated with infliximab. None showed an increased risk of either total or infectious complications associated with immunomodulator use. However, subgroup analysis in one study, published as an abstract, suggested increased rates of anastomotic complications and reoperation associated with azathioprine. CONCLUSION: Available evidence does not suggest an increased rate of postoperative complications associated with immunomodulator use.
Asunto(s)
Inmunosupresores/efectos adversos , Enfermedades Inflamatorias del Intestino/cirugía , Complicaciones Posoperatorias/prevención & control , Anciano , Anticuerpos Monoclonales/efectos adversos , Azatioprina/efectos adversos , Ciclosporina/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab , Mercaptopurina/efectos adversos , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Factores de RiesgoRESUMEN
In the Cryptosporidium parvum-infected intestinal epithelial cell, the parasite occupies an unusual extracytoplasmic location at the luminal surface, but how the invading zoites interact with the host cell to achieve this niche is poorly understood. This study examined the role of secretory phospholipase A(2) (sPLA(2)), a known virulence factor for several pathogenic microorganisms, in establishing C. parvum intracellularly. Initially, it was established that there was sPLA(2) activity in homogenates of C. parvum oocysts. C. parvum reproduction in two human enterocyte cell lines was significantly reduced by a specific PLA inhibitor, p-bromophenacylbromide, and by sheep anti-sPLA(2) antibodies developed against PLA(2) of bee ( Apis mellifera) venom. Treatment of either C. parvum sporozoites or enterocytes with sPLA(2) derived from cobra ( Naja naja) venom before initiation of infection increased the numbers of intracellular parasites. Thus, C. parvum PLA(2 )may play an important part in establishing the parasite within the enterocyte.
Asunto(s)
Cryptosporidium parvum/enzimología , Cryptosporidium parvum/patogenicidad , Fosfolipasas A/metabolismo , Acetofenonas/farmacología , Animales , Células CACO-2 , Línea Celular Tumoral , Cryptosporidium parvum/crecimiento & desarrollo , Enterocitos/parasitología , Inhibidores Enzimáticos/farmacología , Células Epiteliales/parasitología , Humanos , Intestinos/parasitología , Fosfolipasas A/antagonistas & inhibidores , VirulenciaRESUMEN
Opportunistic viral enteritis is an important gastrointestinal manifestation of HIV related disease. Cytomegalovirus (CMV) is a well established aetiological agent of disease in the gastrointestinal tract in this group. CMV enteritis may affect any region of the bowel, most commonly the colon. Diagnosis and management of these infections may be difficult. The role of other viruses in so-called 'pathogen-negative' diarrhoea remains controversial. The clinical importance of HIV-specific enteropathy is probably limited. Several viruses including astrovirus, picobirnavirus, small round structured virus and rotavirus have been implicated HIV-related diarrhoea. In addition, adenovirus has been linked to persistent diarrhoea in patients with a characteristic adenovirus colitis. The spectrum of disease morbidity and mortality amongst HIV patients has altered dramatically since the wide spread use of highly active antiretroviral therapy (HAART). Opportunistic infections, including CMV infection of the gastrointestinal tract in patients with AIDS, have diminished greatly. AIDS patients with CMV are able successfully to discontinue anti-CMV treatment without disease reactivation and with a parallel reduction in CMV viraemia following the initiation of HAART.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adenovirus Humanos/fisiología , Citomegalovirus/fisiología , Diarrea/complicaciones , Diarrea/virología , VIH/fisiología , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Diarrea/diagnóstico , Diarrea/tratamiento farmacológico , Humanos , Intestinos/patología , Intestinos/virologíaRESUMEN
BACKGROUND & AIMS: Interferon (IFN)-gamma plays an important role in the immunologic control of infection by the protozoan enteropathogen Cryptosporidium parvum. We tested the hypothesis that IFN-gamma may directly inhibit infection of enterocytes by this pathogen. METHODS: HT-29, Caco-2, and H4 human enterocyte cell lines were grown in monolayers and incubated with IFN-gamma before exposure with C. parvum. IFN-gamma receptor expression in the cell lines was determined by Western blot analysis. RESULTS: IFN-gamma inhibited C. parvum infection of both HT-29 and Caco-2 cells but not H4 cells. Response to IFN-gamma was related to the expression of the IFN-gamma receptor in the respective cell lines. The effect of IFN-gamma was partially reversed by inhibition of the JAK/STAT signaling pathway. IFN-gamma mediated its action by at least 2 mechanisms: (1) inhibition of parasite invasion and (2) by modification of intracellular Fe(2+) concentration. No role for tryptophan starvation or nitric oxide synthase activity was found. TNF-alpha and IL-1beta also had anti-C. parvum activity but had no synergistic effect with IFN-gamma. CONCLUSIONS: IFN-gamma directly induces enterocyte resistance against C. parvum infection; this observation may have important consequences for our understanding of the mucosal immune response to invasive pathogens.
Asunto(s)
Antineoplásicos/farmacología , Criptosporidiosis/tratamiento farmacológico , Cryptosporidium parvum/inmunología , Interferón gamma/farmacología , Mucosa Intestinal/parasitología , Animales , Antineoplásicos/inmunología , Células CACO-2 , Criptosporidiosis/inmunología , Cryptosporidium parvum/crecimiento & desarrollo , Sinergismo Farmacológico , Enterocitos/citología , Enterocitos/enzimología , Enterocitos/parasitología , Inhibidores Enzimáticos/farmacología , Células HT29 , Humanos , Interferón gamma/inmunología , Interleucina-1/inmunología , Interleucina-1/farmacología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Hierro/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitroarginina/farmacología , Receptores de Interferón/biosíntesis , Triptófano/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/farmacología , omega-N-Metilarginina/farmacología , Receptor de Interferón gammaRESUMEN
HIV-related diarrhoea is an important cause of morbidity and mortality in HIV infection. Cytomegalovirus is a well-established cause of diarrhoea, but the role of other enteric viruses is less clear and will be discussed here. The clinical manifestations, disease mechanisms, diagnostic techniques and current treatments for the management of these infections are reviewed.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/virología , Adenovirus Humanos , Citomegalovirus , Diarrea/virología , Virus ARN , Infecciones Oportunistas Relacionadas con el SIDA/fisiopatología , Adenovirus Humanos/aislamiento & purificación , Adenovirus Humanos/patogenicidad , Citomegalovirus/aislamiento & purificación , Diarrea/fisiopatología , Humanos , Virus ARN/aislamiento & purificación , Virus ARN/patogenicidad , Virosis/fisiopatología , Virosis/virologíaRESUMEN
BACKGROUND & AIMS: Nonimmune mechanisms of mucosal defense seem to be biologically important and might explain the observed variability in the course of enteric infection in immunodeficiency. Mannose-binding lectin (MBL) deficiency is associated with persistent diarrhea in children. We found that genetic determinants of MBL deficiency appear to predispose to cryptosporidiosis in patients with the acquired immunodeficiency syndrome (AIDS), and went on to study interactions of MBL and complement on Cryptosporidium parvum sporozoites. METHODS: This study involved cross-sectional study of MBL genotype and enteric infection in 72 Zambian AIDS patients with diarrhea, immunofluorescence analysis of MBL and C4 binding to C. parvum, and immunoblotting for MBL and complement in small intestinal fluid. RESULTS: Individuals homozygous for MBL structural gene mutations were at increased risk of cryptosporidiosis (odds ratio, 8.2; 95% confidence interval, 1. 5-42; P = 0.02). Lectin-mediated and concentration-dependent binding of purified MBL was detected on sporozoites but not oocysts, and MBL activated C4 on sporozoites. MBL, C3, C4, and albumin were detected in small intestinal fluid in half the patients tested, suggesting transudation of serum components into the enteropathic gut. CONCLUSIONS: The increased risk of cryptosporidiosis in MBL deficiency appears to include patients with AIDS. It may operate through MBL-mediated complement activation on sporozoites.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Proteínas Portadoras/inmunología , Cryptosporidium parvum/inmunología , Mucosa Intestinal/inmunología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Animales , Proteínas Sanguíneas/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Colectinas , Activación de Complemento , Complemento C4/fisiología , Estudios Transversales , Criptosporidiosis/complicaciones , Cryptosporidium parvum/crecimiento & desarrollo , Duodeno/metabolismo , Humanos , Immunoblotting , Enfermedades Intestinales/complicaciones , Enfermedades Intestinales/parasitología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Fenotipo , Serina Endopeptidasas/inmunologíaRESUMEN
We report two cases of factitious diarrhoea caused by stool dilution. In the first report stools from a patient with chronic diarrhoea were found to have been diluted with urine, and the diarrhoea further compounded by surreptitious laxative misuse. In the second report, after prolonged investigation of high output ileostomy, the patient's ileal effluent was found to have been diluted with water. We conclude that factitious diarrhoea, in particular dilutional diarrhoea, is over-investigated and underdiagnosed. Stool weights, complete input/output measurement, analysis of stool osmolality and electrolytes, and laxative screening are essential in the investigation of chronic watery diarrhoea.