RESUMO
BACKGROUND: Sinonasal symptoms are common and can have several underlying causes. When symptoms occur in specified patterns lasting 3 months or more they meet criteria for chronic rhinosinusitis (CRS). Approaches to CRS symptom measurement do not specify how to measure symptoms and treat specified sinonasal symptoms as generally interchangeable, suggesting that such symptoms should cluster on 1 or 2 latent factors. METHODS: We used questionnaire responses to 37 questions on the presence, severity, bother, and frequency of cardinal sinonasal and related symptoms lasting 3 months, from 3535 subjects at 3 time points over 16 months. We completed 5 exploratory factor analyses (EFA) to identify symptom clustering, 1 for each time point and 2 for the differences between adjacent questionnaires. The baseline EFA was used to provide factor scores that were described longitudinally and examined by CRS status. RESULTS: Five EFAs identified the same 5 factors (blockage and discharge, pain and pressure, asthma and cold/flu symptoms, smell loss, and ear and eye [mainly allergy] symptoms), with clustering determined by symptom frequency, severity, and degree of bother. Responses to individual questions showed changes over time but when combined into factor scores showed less longitudinal change. All symptom factor scores were progressively higher from never to past to current CRS status. CONCLUSIONS: Although the current approaches to symptom characterization in CRS imply a single underlying latent construct, our results suggest that there are at least 3 latent constructs relevant to CRS. Further studies are needed to evaluate whether these clusters have identifiable underlying pathobiologies.
Assuntos
Rinite/diagnóstico , Sinusite/diagnóstico , Adulto , Idoso , Doença Crônica , Análise Fatorial , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Nasal and sinus symptoms (NSS) are common to many health conditions, including chronic rhinosinusitis (CRS). Few studies have investigated the occurrence and severity of, and risk factors for, acute exacerbations of NSS (AENSS) by CRS status (current, past, or never met European Position Paper on Rhinosinusitis [EPOS] criteria for CRS). METHODS: Four seasonal questionnaires were mailed to a stratified random sample of Geisinger primary care patients. Logistic regression was used to identify individual characteristics associated with AENSS occurrence and severity by CRS status (current long-term, current recent, past, never) using EPOS subjective symptoms-only (EPOSS ) CRS criteria. We operationalized 3 AENSS definitions based on prescribed antibiotics or oral corticosteroids, symptoms, and symptoms with purulence. RESULTS: Baseline and at least 1 follow-up questionnaires were available from 4736 subjects. Self-reported NSS severity with exacerbation was worst in the current long-term CRS group. AENSS was common in all subgroups examined and generally more common among those with current EPOSS CRS. Seasonal prevalence of AENSS differed by AENSS definition and CRS status. Associations of risk factors with AENSS differed by definition, but CRS status, body mass index, asthma, hay fever, sinus surgery history, and winter season consistently predicted AENSS. CONCLUSIONS: In this first longitudinal, population-based study of 3 AENSS definitions, NSS and AENSS were both common, sometimes severe, and differed by EPOSS CRS status. Contrasting associations of risk factors for AENSS by the different definitions suggest a need for a standardized approach to definition of AENSS.
Assuntos
Rinite/epidemiologia , Sinusite/epidemiologia , Doença Crônica , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Vigilância da População , Prevalência , Rinite/diagnóstico , Fatores de Risco , Índice de Gravidade de Doença , Sinusite/diagnóstico , Inquéritos e Questionários , Avaliação de SintomasRESUMO
BACKGROUND: Antibiotic use in early life has been linked to disruptions in the microbiome. Such changes can disturb immune system development. Differences have been observed in the microbiota of children with and without allergies, but there have been few studies on antibiotic use and allergic disease. OBJECTIVE: We evaluated associations of early-life antibiotic use with subsequent occurrence of food allergy and other allergies in childhood using electronic health record data. METHODS: We used longitudinal data on 30 060 children up to age 7 years from Geisinger Clinic's electronic health record to conduct a sex- and age-matched case-control study to evaluate the association between antibiotic use and milk allergy, non-milk food allergies, and other allergies. For each outcome, we estimated conditional logistic regression models adjusting for race/ethnicity, history of Medical Assistance, and mode of birth delivery. Models were repeated separately for penicillins, cephalosporins and macrolides. RESULTS: There were 484 milk allergy cases, 598 non-milk food allergy cases and 3652 other allergy cases. Children with three or more antibiotic orders had a greater odds of milk allergy (Odds Ratio; 95% Confidence interval) (1.78; 1.28-2.48), non-milk food allergy (1.65; 1.27-2.14), and other allergies (3.07; 2.72-3.46) compared with children with no antibiotic orders. Associations were strongest at younger ages and differed by antibiotic class. CONCLUSIONS AND CLINICAL RELEVANCE: We observed associations between antibiotic orders and allergic diseases, providing evidence of a potentially modifiable clinical practice associated with paediatric allergic disease. Differences by antibiotic class should be further explored, as this knowledge could inform paediatric treatment decisions.
Assuntos
Antibacterianos/efeitos adversos , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/etiologia , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Antibacterianos/classificação , Estudos de Casos e Controles , Pré-Escolar , Feminino , Hipersensibilidade Alimentar/diagnóstico , Humanos , Hipersensibilidade/diagnóstico , Imunoglobulina E/imunologia , Lactente , Recém-Nascido , Masculino , Hipersensibilidade a Leite/diagnóstico , Hipersensibilidade a Leite/epidemiologia , Hipersensibilidade a Leite/etiologia , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: The objective of this study was to describe the first US-based study to use the European Position Paper on Rhinosinusitis (EPOS) criteria to study the prevalence of chronic rhinosinusitis (CRS) in a general-population sample. METHODS: A CRS symptom questionnaire was mailed to 23 700 primary care patients from Geisinger Clinic, a health system serving 45 counties in Pennsylvania. CRS cases were categorized into four unique subgroups based on EPOS symptoms: obstruction and discharge with no smell loss or pain/pressure; smell loss without pain/pressure; facial pain and/or pressure without smell loss; and both smell loss and pain/pressure. All cases were required to have nasal obstruction or discharge. Logistic regression was used to evaluate potential factors associated with CRS subgroups. RESULTS: We found that 11.9% of patients met criteria for CRS. Prevalence peaked at 15.9% between ages 50 and 59 years and then dropped to 6.8% after age 69. The odds of CRS was higher among patients who were white, younger, smokers, had a history of Medical Assistance, and had other diseases. When CRS subgroups were modeled separately, these associations were no longer significant for some CRS subgroups. Comorbid diseases were most strongly associated with CRS cases who reported smell loss and facial pain and/or pressure and had the weakest associations with CRS cases who did not report these symptoms. CONCLUSIONS: CRS is a highly prevalent and heterogeneous condition. Differences in risk factors and health outcomes across symptom subgroups may be indicative of differences in etiology that have implications for disease management.
Assuntos
Vigilância da População , Rinite/diagnóstico , Rinite/epidemiologia , Sinusite/diagnóstico , Sinusite/epidemiologia , Avaliação de Sintomas , Adulto , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pennsylvania/epidemiologia , Fenótipo , Prevalência , Fatores Socioeconômicos , Inquéritos e QuestionáriosRESUMO
BACKGROUND/OBJECTIVES: Antibiotics are commonly prescribed for children. Use of antibiotics early in life has been linked to weight gain but there are no large-scale, population-based, longitudinal studies of the full age range among mainly healthy children. SUBJECTS/METHODS: We used electronic health record data on 163 820 children aged 3-18 years and mixed effects linear regression to model associations of antibiotic orders with growth curve trajectories of annual body mass index (BMI) controlling for confounders. Models evaluated three kinds of antibiotic associations-reversible (time-varying indicator for an order in year before each BMI), persistent (time-varying cumulative orders up to BMIj) and progressive (cumulative orders up to prior BMI (BMIj-1))-and whether these varied by age. RESULTS: Among 142 824 children under care in the prior year, a reversible association was observed and this short-term BMI gain was modified by age (P<0.001); effect size peaked in mid-teen years. A persistent association was observed and this association was stronger with increasing age (P<0.001). The addition of the progressive association among children with at least three BMIs (n=79 752) revealed that higher cumulative orders were associated with progressive weight gain; this did not vary by age. Among children with an antibiotic order in the prior year and at least seven lifetime orders, antibiotics (all classes combined) were associated with an average weight gain of approximately 1.4 kg at age 15 years. When antibiotic classes were evaluated separately, the largest weight gain at 15 years was associated with macrolide use. CONCLUSIONS: We found evidence of reversible, persistent and progressive effects of antibiotic use on BMI trajectories, with different effects by age, among mainly healthy children. The results suggest that antibiotic use may influence weight gain throughout childhood and not just during the earliest years as has been the primary focus of most prior studies.
Assuntos
Antibacterianos/efeitos adversos , Índice de Massa Corporal , Obesidade Infantil/induzido quimicamente , Aumento de Peso/efeitos dos fármacos , Adolescente , Antibacterianos/administração & dosagem , Criança , Pré-Escolar , Registros Eletrônicos de Saúde , Feminino , Humanos , Estudos Longitudinais , Masculino , Obesidade Infantil/epidemiologia , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) has a broad range of comorbidities. Due to a lack of longitudinal studies, it is not known whether these comorbidities cause CRS, are promoted by CRS, or share a systemic disease process with CRS. OBJECTIVE: The objective of this study was to determine the risk of incident disease within 5 years after a new diagnosis of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). METHODS: We conducted a case-control study nested within the longitudinal cohort of primary care patients in the Geisinger Clinic using electronic health record data. We evaluated incident disease over 5 years in newly diagnosed CRSwNP and CRSsNP cases compared to controls using multivariable Cox regression models. RESULTS: CRSsNP (n = 3612) cases were at greater risk (HR, 95% confidence interval) than controls for incidence of: upper airway diseases, including adenotonsillitis (3.29, 2.41-4.50); lower aerodigestive tract diseases, including asthma (2.69, 2.14-3.38); epithelial conditions, including atopic dermatitis (2.75, 1.23-6.16); and hypertension (1.38, 1.19-1.61). CRSwNP (n = 241) cases were at greater risk for obesity than controls (1.74, 1.08-2.80), but CRSwNP was not associated with other diseases. CONCLUSION: The risk of other diseases associated with CRS adds to the burden of an already highly burdensome condition, and suggests either that CRS promotes onset of other diseases or is an indicator of systemic disease processes. Different patterns of association with diseases by CRS phenotype may be due to CRSwNP sample size limitations or reflect a different pattern of disease onset by phenotype. These findings have implications for screening guidelines and care of CRS patients.
Assuntos
Comorbidade , Rinite/complicações , Rinite/epidemiologia , Sinusite/complicações , Sinusite/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/complicações , Pólipos Nasais/epidemiologia , Modelos de Riscos Proporcionais , Risco , Adulto JovemRESUMO
In February 2013, the Organ Procurement and Transplantation Network mandated that transplant centers perform screening of living kidney donors prior to transplantation for Strongyloides, Trypanosoma cruzi and West Nile virus (WNV) infection if the donor is from an endemic area. However, specific guidelines for screening were not provided, such as the optimal testing modalities, timing of screening prior to donation and the appropriate selection of donors. In this regard, the American Society of Transplantation Infectious Diseases Community of Practice, together with disease-specific experts, has developed this viewpoint document to provide guidance for the testing of live donors for Strongyloides, T. cruzi and WNV infection, specifically identifying at-risk populations and testing algorithms, including advantages, limitations and interpretation of results.
Assuntos
Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/transmissão , Seleção do Doador , Doenças Endêmicas , Transplante de Rim , Programas de Rastreamento , Doadores de Tecidos , Coleta de Tecidos e Órgãos/normas , Algoritmos , Doenças Transmissíveis/diagnóstico , Humanos , Estados Unidos/epidemiologiaRESUMO
No U.S. general population-based study has characterized the epidemiology and risk factors, including skin and soft tissue infection (SSTI), for healthcare-associated (HA) and community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA). We estimated the incidence of HA- and CA-MRSA and SSTI over a 9-year period using electronic health record data from the Geisinger Clinic in Pennsylvania. MRSA cases were frequency-matched to SSTI cases and controls in a nested case-control analysis. Logistic regression was used to assess risk factors, while accounting for antibiotic administration. We identified 1713 incident CA- and 1506 HA-MRSA cases and 78 216 SSTI cases. On average, from 2005 to 2009, the annual incidence of CA-MRSA increased by 34%, HA-MRSA by 7%, and SSTI by 4%. Age, season, community socioeconomic deprivation, obesity, smoking, previous SSTI, and antibiotic administration were identified as independent risk factors for CA-MRSA.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Criança , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pennsylvania/epidemiologia , Fatores de Risco , Estações do Ano , Fatores Socioeconômicos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/epidemiologia , Infecções Cutâneas Estafilocócicas/microbiologia , Adulto JovemRESUMO
Despite the adoption of antifungal prophylaxis, fungal infections remain a significant concern in lung transplant recipients. Indeed, some concern exists that such prophylaxis may increase the risk of infection with drug-resistant fungal organisms. Here, we describe a case of disseminated Scedosporium prolificans infection, presenting as pericarditis, which developed in a lung transplant patient receiving prophylactic voriconazole for 8 months. The epidemiology and clinical presentation of S. prolificans infections are reviewed, and controversies surrounding antifungal prophylaxis and the development of resistant infections are discussed.
Assuntos
Aneurisma Infectado/microbiologia , Aneurisma Aórtico/microbiologia , Transplante de Pulmão , Micoses/microbiologia , Pericardite/microbiologia , Pirimidinas/uso terapêutico , Scedosporium/isolamento & purificação , Triazóis/uso terapêutico , Idoso , Aneurisma Infectado/diagnóstico , Aneurisma Infectado/prevenção & controle , Antifúngicos/uso terapêutico , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/prevenção & controle , Farmacorresistência Fúngica/efeitos dos fármacos , Feminino , Humanos , Micoses/diagnóstico , Micoses/prevenção & controle , Pericardite/diagnóstico , Pericardite/prevenção & controle , VoriconazolRESUMO
Mycobacterium tuberculosis is a ubiquitous organism that infects one-third of the world's population. In previous decades, access to organ transplantation was restricted to academic medical centers in more developed, low tuberculosis (TB) incidence countries. Globalization, changing immigration patterns, and the expansion of sophisticated medical procedures to medium and high TB incidence countries have made tuberculosis an increasingly important posttransplant infectious disease. Tuberculosis is now one of the most common bacterial causes of solid-organ transplant donor-derived infection reported in transplant recipients in the United States. Recognition of latent or undiagnosed active TB in the potential organ donor is critical to prevent emergence of disease in the recipient posttransplant. Donor-derived tuberculosis after transplantation is associated with significant morbidity and mortality, which can best be prevented through careful screening and targeted treatment. To address this growing challenge and provide recommendations, an expert international working group was assembled including specialists in transplant infectious diseases, transplant surgery, organ procurement and TB epidemiology, diagnostics and management. This working group reviewed the currently available data to formulate consensus recommendations for screening and management of TB in organ donors.
Assuntos
Doadores de Tecidos , Tuberculose/diagnóstico , Tuberculose/terapia , Antituberculosos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Humanos , Incidência , Doadores Vivos , Tuberculose/epidemiologiaRESUMO
Donor-derived Trypanosoma cruzi infection in solid organ transplant recipients is associated with significant morbidity and mortality. Little is known about T. cruzi screening practices among U.S. organ procurement organizations (OPOs). We distributed a questionnaire to all U.S. OPO directors, requesting data on T. cruzi screening strategies, laboratory methods, number of donors screened, disposition of organs from positive donors and attitudes toward screening. Fifty-eight (100%) U.S. OPOs responded to the survey. Donor screening began in 2002 and is presently performed by 11 (19%) OPOs. Among screening OPOs, four screen all donors and seven use a risk-based strategy. Three different T. cruzi serology tests are used for donor screening. During 2008, 9/993 (0.9%) donors screened positive by a T. cruzi screening test, 6/9 (66%) had confirmatory tests performed and 4/6 (66%) had positive confirmatory tests. These results led to the nonuse of five donors and 17 organs. Five organs from three seropositive donors were transplanted in 2008 without recognized disease transmission. Variability of T. cruzi donor screening strategies, laboratory methods and disposition of organs from positive donors currently exists. Further research is needed to identify the risk of donor-derived T. cruzi infections to help inform the best screening strategy.
Assuntos
Anticorpos Antiprotozoários/imunologia , Doença de Chagas/transmissão , Seleção do Doador , Transplante de Órgãos , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/normas , Trypanosoma cruzi/imunologia , Anticorpos Antiprotozoários/sangue , Doença de Chagas/diagnóstico , Doença de Chagas/prevenção & controle , Inquéritos Epidemiológicos , Humanos , Estudos Prospectivos , Inquéritos e Questionários , Estados UnidosRESUMO
Donor-derived transmission of Trypanosoma cruzi, the etiologic agent of Chagas disease, has emerged as an issue in the United States over the past 10 years. Acute T. cruzi infection causes substantial morbidity and mortality in the posttransplant setting if not recognized and treated early. We assembled a working group of transplant infectious disease specialists, laboratory medicine specialists, organ procurement organization representatives and epidemiologists with expertise in Chagas disease. Based on review of published and unpublished data, the working group prepared evidence-based recommendations for donor screening, and follow-up testing and treatment of recipients of organs from infected donors. We advise targeted T. cruzi screening of potential donors born in Mexico, Central America and South America. Programs can consider transplantation of kidneys and livers from T. cruzi-infected donors with informed consent from recipients. However, we recommend against heart transplantation from infected donors. For other organs, we recommend caution based on the anticipated degree of immunosuppression. Our recommendations stress the need for systematic monitoring of recipients by polymerase chain reaction, and microscopy of buffy coat and advance planning for immediate antitrypanosomal treatment if recipient infection is detected. Data on management and outcomes of all cases should be collected to inform future guidelines and to assist in coordination with public health authorities.
Assuntos
Doença de Chagas/diagnóstico , Doença de Chagas/terapia , Transplante de Órgãos/efeitos adversos , Guias de Prática Clínica como Assunto , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/isolamento & purificação , Doença de Chagas/transmissão , Humanos , Doadores de TecidosRESUMO
OBJECTIVES: To evaluate associations of community types and features with new onset type 2 diabetes in diverse communities. Understanding the location and scale of geographic disparities can lead to community-level interventions. DESIGN: Nested case-control study within the open dynamic cohort of health system patients. SETTING: Large, integrated health system in 37 counties in central and northeastern Pennsylvania, USA. PARTICIPANTS AND ANALYSIS: We used electronic health records to identify persons with new-onset type 2 diabetes from 2008 to 2016 (n=15 888). Persons with diabetes were age, sex and year matched (1:5) to persons without diabetes (n=79 435). We used generalised estimating equations to control for individual-level confounding variables, accounting for clustering of persons within communities. Communities were defined as (1) townships, boroughs and city census tracts; (2) urbanised area (large metro), urban cluster (small cities and towns) and rural; (3) combination of the first two; and (4) county. Community socioeconomic deprivation and greenness were evaluated alone and in models stratified by community types. RESULTS: Borough and city census tract residence (vs townships) were associated (OR (95% CI)) with higher odds of type 2 diabetes (1.10 (1.04 to 1.16) and 1.34 (1.25 to 1.44), respectively). Urbanised areas (vs rural) also had increased odds of type 2 diabetes (1.14 (1.08 to 1.21)). In the combined definition, the strongest associations (vs townships in rural areas) were city census tracts in urban clusters (1.41 (1.22 to 1.62)) and city census tracts in urbanised areas (1.33 (1.22 to 1.45)). Higher community socioeconomic deprivation and lower greenness were each associated with increased odds. CONCLUSIONS: Urban residence was associated with higher odds of type 2 diabetes than for other areas. Higher community socioeconomic deprivation in city census tracts and lower greenness in all community types were also associated with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Cidades , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Geografia , Humanos , Masculino , Pessoa de Meia-Idade , Pennsylvania/epidemiologia , Características de Residência , Fatores Socioeconômicos , Adulto JovemRESUMO
It has previously been described that soluble antigen:antibody complexes in antigen excess can induce an increase in the procoagulant activity of human peripheral blood mononuclear cells. It has been proposed that this response may explain the presence of fibrin in immune complex-mediated tissue lesions. In the present study we define cellular participants and their roles in the procoagulant response to soluble immune complexes. Monocytes were shown by cell fractionation and by a direct cytologic assay to be the cell of origin of the procoagulant activity; and virtually all monocytes were able to participate in the response. Monocytes, however, required the presence of lymphocytes to respond. The procoagulant response required cell cooperation, and this collaborative interaction between lymphocytes and monocytes appeared to be unidirectional. Lymphocytes once triggered by immune complexes induced monocytes to synthesize the procoagulant product. Intact viable lymphocytes were required to present instructions to monocytes; no soluble mediator could be found to subserve this function. Indeed, all that appeared necessary to induce monocytes to produce procoagulant activity was an encounter with lymphocytes that had previously been in contact with soluble immune complexes. The optimum cellular ratio for this interaction was four lymphocytes per monocyte, about half the ratio in peripheral blood. The procoagulant response was rapid, reaching a maximum within 6 h after exposure to antigen:antibody complexes. The procoagulant activity was consistent with tissue factor because Factors VII and X and prothrombin were required for clotting of fibrinogen. WE propose that this pathway differs from a number of others involving cells of the immune system. Elucidation of the pathway may clarify the role of this lymphocyte-instructed monocyte response in the Shwartzman phenomenon and other thrombohemorrhagic events associated with immune cell function and the formation of immune complexes.
Assuntos
Complexo Antígeno-Anticorpo , Coagulação Sanguínea , Linfócitos/imunologia , Monócitos/imunologia , Animais , Temperatura Alta , Humanos , Imunoglobulina G , Cooperação LinfocíticaRESUMO
Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolated Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolated
Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Fatores de Coagulação Sanguínea , Lipopolissacarídeos/farmacologia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Cálcio/farmacologia , Precursores Enzimáticos/biossíntese , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Monócitos/enzimologia , Ativadores de Plasminogênio/metabolismo , Protrombina/metabolismo , Tromboplastina/metabolismoRESUMO
The present study explores the interactions between lymphocytes and monocytes that are required for expression of procoagulant activity (PCA) by monocytes in response to purified protein derivative of the tubercle bacillus (PPD) or tularemia antigen. The PCA response was antigen specific: peripheral blood mononuclear cells (PBM) from donors sensitive to PPD or tularemia showed an increase in PCA only in response to the sensitizing antigen. The PCA was tissue factorlike in that Factors VII and X were required for expression of the activity, whereas Factor VIII was not. Maximum PCA developed only after 36 to 72 h. Fractionation of PBM into lymphocytes and monocytes after antigenic stimulation demonstrated that greater than 90% of the PCA was associated with monocytes. Isolated monocytes or lymphocytes incubated with sensitizing antigen had the same PCA as control cells. Purified lymphocytes that had been pulsed with antigen were unable to elicit a PCA response from monocytes to which they were added. However, adherent monocytes incubated with antigen, then washed free of unbound protein, were able to trigger lymphocytes to become stimulatory for PCA toward responding monocytes. The development of antigen-specific PCA in PBM could be blocked by including a monoclonal antibody to HLA-DR antigen in the incubation. The antibody had no effect on the clotting assay, on preformed PCA, cell viability, or on stimulatory antigen itself. These results indicate that elaboration of PCA by mononuclear cells may be an intrinsic part of the classical immune response to antigen, and may explain the presence of fibrin in immune lesions, as well as the occurrence of thrombotic complications in many immune disorders.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Coagulação Sanguínea , Antígenos de Histocompatibilidade Classe II/imunologia , Monócitos/fisiologia , Fatores de Coagulação Sanguínea/fisiologia , Comunicação Celular , Relação Dose-Resposta Imunológica , Epitopos , Francisella tularensis/imunologia , Antígenos HLA-DR , Humanos , Imunidade Celular , Cinética , Monócitos/imunologia , Tuberculina/imunologiaRESUMO
Platelet consumption is a prominent feature of disseminated intravascular coagulation. We investigated whether monocyte procoagulant activity (PCA) might play a role in platelet consumption associated with gram-negative septicemia. Human mononuclear cells exposed in vitro to lipopolysaccharide demonstrated parallel dose-dependent increases in PCA and ability to induce platelet aggregation. Induction of platelet aggregation required the generation of thrombin dependent on coagulation Factors VII, X, and II, and calcium. This is consistent with monocyte tissue factor initiating thrombin generation. A specific monoclonal antimonocyte antibody was used to identify monocytes via indirect immunofluorescence, and demonstrated that all monocytes were included in platelet aggregates. Mononuclear cells that did not express PCA did not induce platelet aggregation and monocytes were not surrounded by platelet clumps. These data suggest that monocytes induced to express tissue factor on their surface may be important mediators of endotoxin-induced platelet, as well as fibrinogen, consumption.
Assuntos
Lipopolissacarídeos/farmacologia , Monócitos/fisiologia , Agregação Plaquetária , Coagulação Sanguínea , Células Cultivadas , Deficiência do Fator XII/sangue , Imunofluorescência , Humanos , Técnicas In Vitro , Monócitos/efeitos dos fármacosRESUMO
The Shwartzman reaction is a classic biologic response in which the coagulation system is activated in vivo. Cellular initiation of the extrinsic coagulation protease cascade can be mediated by one or more limbs of the lymphoid response to diverse biological stimuli. The T cell-instructed monocyte and macrophage responses that have been implicated are mediated by a number of different cellular pathways and are elicited not only by antigens and allogeneic cells but also by other stimuli such as immune complexes and the lipid A moiety of bacterial lipopolysaccharide (LPS). The latter response has been implicated in the pathogenesis of the disseminated intravascular coagulation associated with bacterial infection. In the rapid collaborative cellular pathway response to LPS, we have described a relatively rigorous requirement for T helper cells in induction of the biosynthesis of tissue factor and Factor VII by monocytes. To elucidate potential regulatory aspects of this cellular procoagulant response, we provide the first evidence for the existence of T suppressor cells for the cellular procoagulant response to LPS by the rapid T cell-instructed pathway. Human peripheral blood lymphocytes were separated by cytoaffinity into Fc gamma-positive and Fc mu-positive cells and were characterized for their functional properties in the procoagulant response. T mu cells mediated the monocyte response, consistent with their identity with instructor cells. T gamma cells suppressed the response of monocytes to LPS in the presence of T mu cells, suggesting that they possess suppressor function for this response. The T gamma suppressor cells required stimulation by LPS to express their suppressor function and they exerted their suppressive effect directly on the monocyte. The existence and participation of LPS-responsive T suppressor cells on the cellular procoagulant response in vitro add a new dimension to the complexity of the rapid pathway of the collaborative cellular procoagulant response and may be important in the pathogenesis of disseminated intravascular coagulation.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Linfócitos T/citologia , Anticorpos Monoclonais/análise , Fator VII/metabolismo , Humanos , Cinética , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Linfócitos T/fisiologia , Linfócitos T Auxiliares-Indutores/fisiologia , Linfócitos T Reguladores/fisiologiaRESUMO
A panel of human purified protein derivative of the tubercle bacillus (PPD)-reactive T cell clones was derived by cloning out of soft agar followed by cultivation on inactivated feeder cells in the presence of interleukin-2. 1 of 4 clones tested was able to mediate an increase in monocyte procoagulant activity (PCA) in response to PPD. All four clones had identical surface marker phenotypes (T4+, T8-) and proliferated in response to antigen. The reactive T cell clone possessed no PCA of its own, but upon being presented with PPD was able to instruct monocytes to increase their expression of PCA. Antigen presentation could be performed only by autologous monocytes; allogeneic monocytes from donors unrelated to the donor of the reactive clone could not present antigen to cells of the clone in a way that would initiate the procoagulant response. Cells of the reactive clone did not mediate increased monocyte PCA in response to Candida, even though peripheral blood mononuclear cells from the donor demonstrated increased PCA to both Candida and PPD. Thus, the PCA response to specific antigen can be mediated by a single clone of cells that shows specificity in the recognition of both antigen and antigen presenting cell.