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1.
Am J Respir Crit Care Med ; 210(1): 119-127, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38271696

RESUMO

Rationale: COPD and bronchiectasis are commonly reported together. Studies report varying impacts of co-diagnosis on outcomes, which may be related to different definitions of disease used across studies. Objectives: To investigate the prevalence of chronic obstructive pulmonary disease (COPD) associated with bronchiectasis and its relationship with clinical outcomes. We further investigated the impact of implementing the standardized ROSE criteria (radiological bronchiectasis [R], obstruction [FEV1/FVC ratio <0.7; O], symptoms [S], and exposure [⩾10 pack-years of smoking; E]), an objective definition of the association of bronchiectasis with COPD. Methods: Analysis of the EMBARC (European Bronchiectasis Registry), a prospective observational study of patients with computed tomography-confirmed bronchiectasis from 28 countries. The ROSE criteria were used to objectively define the association of bronchiectasis with COPD. Key outcomes during a maximum of 5 years of follow-up were exacerbations, hospitalization, and mortality. Measurements and Main Results: A total of 16,730 patients with bronchiectasis were included; 4,336 had a clinician-assigned codiagnosis of COPD, and these patients had more exacerbations, worse quality of life, and higher severity scores. We observed marked overdiagnosis of COPD: 22.2% of patients with a diagnosis of COPD did not have airflow obstruction and 31.9% did not have a history of ⩾10 pack-years of smoking. Therefore, 2,157 patients (55.4%) met the ROSE criteria for COPD. Compared with patients without COPD, patients who met the ROSE criteria had increased risks of exacerbations and exacerbations resulting in hospitalization during follow-up (incidence rate ratio, 1.25; 95% confidence interval, 1.15-1.35; vs. incidence rate ratio, 1.69; 95% confidence interval, 1.51-1.90, respectively). Conclusions: The label of COPD is often applied to patients with bronchiectasis who do not have objective evidence of airflow obstruction or a smoking history. Patients with a clinical label of COPD have worse clinical outcomes.


Assuntos
Bronquiectasia , Doença Pulmonar Obstrutiva Crônica , Sistema de Registros , Humanos , Bronquiectasia/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/complicações , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Europa (Continente)/epidemiologia , Estudos Prospectivos , Prevalência , Índice de Gravidade de Doença , Fumar/epidemiologia , Fumar/efeitos adversos , Progressão da Doença , Comorbidade
2.
Infect Immun ; 92(5): e0044723, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38629841

RESUMO

Streptococcus pneumoniae, a common colonizer of the upper respiratory tract, invades nasopharyngeal epithelial cells without causing disease in healthy participants of controlled human infection studies. We hypothesized that surface expression of pneumococcal lipoproteins, recognized by the innate immune receptor TLR2, mediates epithelial microinvasion. Mutation of lgt in serotype 4 (TIGR4) and serotype 6B (BHN418) pneumococcal strains abolishes the ability of the mutants to activate TLR2 signaling. Loss of lgt also led to the concomitant decrease in interferon signaling triggered by the bacterium. However, only BHN418 lgt::cm but not TIGR4 lgt::cm was significantly attenuated in epithelial adherence and microinvasion compared to their respective wild-type strains. To test the hypothesis that differential lipoprotein repertoires in TIGR4 and BHN418 lead to the intraspecies variation in epithelial microinvasion, we employed a motif-based genome analysis and identified an additional 525 a.a. lipoprotein (pneumococcal accessory lipoprotein A; palA) encoded by BHN418 that is absent in TIGR4. The gene encoding palA sits within a putative genetic island present in ~10% of global pneumococcal isolates. While palA was enriched in the carriage and otitis media pneumococcal strains, neither mutation nor overexpression of the gene encoding this lipoprotein significantly changed microinvasion patterns. In conclusion, mutation of lgt attenuates epithelial inflammatory responses during pneumococcal-epithelial interactions, with intraspecies variation in the effect on microinvasion. Differential lipoprotein repertoires encoded by the different strains do not explain these differences in microinvasion. Rather, we postulate that post-translational modifications of lipoproteins may account for the differences in microinvasion.IMPORTANCEStreptococcus pneumoniae (pneumococcus) is an important mucosal pathogen, estimated to cause over 500,000 deaths annually. Nasopharyngeal colonization is considered a necessary prerequisite for disease, yet many people are transiently and asymptomatically colonized by pneumococci without becoming unwell. It is therefore important to better understand how the colonization process is controlled at the epithelial surface. Controlled human infection studies revealed the presence of pneumococci within the epithelium of healthy volunteers (microinvasion). In this study, we focused on the regulation of epithelial microinvasion by pneumococcal lipoproteins. We found that pneumococcal lipoproteins induce epithelial inflammation but that differing lipoprotein repertoires do not significantly impact the magnitude of microinvasion. Targeting mucosal innate immunity and epithelial microinvasion alongside the induction of an adaptive immune response may be effective in preventing pneumococcal colonization and disease.


Assuntos
Células Epiteliais , Lipoproteínas , Infecções Pneumocócicas , Streptococcus pneumoniae , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/patogenicidade , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Lipoproteínas/imunologia , Células Epiteliais/microbiologia , Células Epiteliais/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Nasofaringe/microbiologia , Mutação , Aderência Bacteriana
3.
Am J Respir Crit Care Med ; 208(8): 868-878, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37556679

RESUMO

Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).


Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Adulto , Humanos , Virulência , Nariz , Infecções Pneumocócicas/prevenção & controle , Imunização , Anticorpos Antibacterianos , Imunoglobulina G , Vacinas Pneumocócicas/uso terapêutico
4.
Infect Immun ; 90(1): e0084618a, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35076289

RESUMO

Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes and has led to nonvaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp; thought to be immune adjuvants). Proteomics and immunoblot analyses demonstrated that, compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognized protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including nonpneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonized after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, while passive transfer of rabbit serum from MAV-vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.

5.
Infect Immun ; 89(11): e0037421, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34338550

RESUMO

The Streptococcus pneumoniae capsule is essential for disease pathogenesis, suggesting that even minor genetic changes within the cps locus could potentially have important consequences. Arends et al. (D. W. Arends, W. R. Miellet, J. D. Langereis, T. H. A. Ederveen, et al., Infect Immun 89:e00246-21, 2021, https://doi.org/10.1128/IAI.00246-21) have identified 79 different nonsynonymous single-nucleotide polymorphisms (SNPs) in the cps locus of 338 19A serotype strains and shown significant variations between strains in nucleotide sugar content and capsule shedding. Further work is required to characterize whether any of these changes have important functional consequences on capsule-host interactions.


Assuntos
Loci Gênicos , Polimorfismo de Nucleotídeo Único , Polissacarídeos Bacterianos/genética , Streptococcus pneumoniae/genética , Cápsulas Bacterianas/classificação , Humanos
6.
Thorax ; 76(4): 396-398, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33172844

RESUMO

Large numbers of people are being discharged from hospital following COVID-19 without assessment of recovery. In 384 patients (mean age 59.9 years; 62% male) followed a median 54 days post discharge, 53% reported persistent breathlessness, 34% cough and 69% fatigue. 14.6% had depression. In those discharged with elevated biomarkers, 30.1% and 9.5% had persistently elevated d-dimer and C reactive protein, respectively. 38% of chest radiographs remained abnormal with 9% deteriorating. Systematic follow-up after hospitalisation with COVID-19 identifies the trajectory of physical and psychological symptom burden, recovery of blood biomarkers and imaging which could be used to inform the need for rehabilitation and/or further investigation.


Assuntos
COVID-19/diagnóstico , Diagnóstico por Imagem , Pulmão/diagnóstico por imagem , Pandemias , SARS-CoV-2 , Biomarcadores/sangue , COVID-19/sangue , Estudos Transversais , Feminino , Hospitalização/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
7.
Microb Pathog ; 141: 103999, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31996316

RESUMO

Streptococcus pneumoniae capsular serotype 1 continues to pose a huge infectious disease burden in low- and middle-income countries, particularly in West Africa. However, studies on this important serotype have been hampered by the inability to genetically modify these strains. In this study we have genetically modified a serotype 1 strain (519/43), the first time that this has been achieved for this serotype, providing the methodology for a deeper understanding of its biology and pathogenicity. As proof of principle we constructed a defined pneumolysin mutant and showed that it lost its ability to lyse red blood cells. We also showed that when mice were infected intranasally with the mutant 519/43Δply there was no significant difference between the load of bacteria in lungs and blood when compared to the wild type 519/43. When mice were infected intraperitoneally there were significantly fewer bacteria recovered from blood for the mutant 519/43Δply strain, although all mice still displayed signs of disease. Our study demonstrates S. pneumoniae serotype 1 strains can be genetically manipulated using our methodology and demonstrate that the ability to cause pneumonia in mice is independent of active pneumolysin for the 519/43 serotype 1 strain.


Assuntos
Streptococcus pneumoniae , Estreptolisinas/genética , Animais , Proteínas de Bactérias/genética , Sangue/microbiologia , Técnicas de Inativação de Genes , Hemólise , Pulmão/microbiologia , Camundongos , Mutagênese , Mutação , Infecções Pneumocócicas/microbiologia , Sorogrupo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pneumoniae/patogenicidade , Virulência/genética
8.
Infect Immun ; 87(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30530620

RESUMO

Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes and has led to nonvaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp; thought to be immune adjuvants). Proteomics and immunoblot analyses demonstrated that, compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognized protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including nonpneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonized after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, while passive transfer of rabbit serum from MAV-vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.


Assuntos
Antígenos de Bactérias/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/patogenicidade , Animais , Camundongos
10.
PLoS Pathog ; 13(1): e1006137, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28135322

RESUMO

Naturally acquired immunity against invasive pneumococcal disease (IPD) is thought to be dependent on anti-capsular antibody. However nasopharyngeal colonisation by Streptococcus pneumoniae also induces antibody to protein antigens that could be protective. We have used human intravenous immunoglobulin preparation (IVIG), representing natural IgG responses to S. pneumoniae, to identify the classes of antigens that are functionally relevant for immunity to IPD. IgG in IVIG recognised capsular antigen and multiple S. pneumoniae protein antigens, with highly conserved patterns between different geographical sources of pooled human IgG. Incubation of S. pneumoniae in IVIG resulted in IgG binding to the bacteria, formation of bacterial aggregates, and enhanced phagocytosis even for unencapsulated S. pneumoniae strains, demonstrating the capsule was unlikely to be the dominant protective antigen. IgG binding to S. pneumoniae incubated in IVIG was reduced after partial chemical or genetic removal of bacterial surface proteins, and increased against a Streptococcus mitis strain expressing the S. pneumoniae protein PspC. In contrast, depletion of type-specific capsular antibody from IVIG did not affect IgG binding, opsonophagocytosis, or protection by passive vaccination against IPD in murine models. These results demonstrate that naturally acquired protection against IPD largely depends on antibody to protein antigens rather than the capsule.


Assuntos
Imunidade Adaptativa , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Adulto , Idoso , Animais , Proteínas de Bactérias/imunologia , Feminino , Humanos , Imunização Passiva , Imunoglobulina G/imunologia , Masculino , Proteínas de Membrana/imunologia , Camundongos , Pessoa de Meia-Idade , Nasofaringe/imunologia , Nasofaringe/microbiologia , Fagocitose/imunologia , Infecções Pneumocócicas/microbiologia , Adulto Jovem
12.
Respir Res ; 20(1): 166, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340825

RESUMO

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have elevated cardiovascular risk, and cardiovascular disease is a major cause of death in COPD. The current literature indicates that changes in cardiovascular risk during pulmonary rehabilitation (assessed using aortic stiffness) are heterogeneous suggesting that there may be sub-groups of patients who do and do not benefit. OBJECTIVES: To investigate the characteristics of COPD patients who do and do not experience aortic stiffness reduction during pulmonary rehabilitation, examine how changes relate to physical activity and exercise capacity, and assess whether changes in aortic stiffness are maintained at 6 weeks following rehabilitation. METHODS: We prospectively measured arterial stiffness (aortic pulse-wave velocity), exercise capacity (Incremental Shuttle Walk Test) and physical activity (daily step count) in 92 COPD patients who started a six week pulmonary rehabilitation programme, 54 of whom completed rehabilitation, and 29 of whom were re-assessed six weeks later. RESULTS: Whilst on average there was no influence of pulmonary rehabilitation on aortic stiffness (pre- vs. post pulse-wave velocity 11.3 vs. 11.1 m/s p = 0.34), 56% patients responded with a significant reduction in aortic stiffness. Change in aortic stiffness (absolute and/or percentage) during rehabilitation was associated with both increased physical activity (rho = - 0.30, p = 0.042) and change in exercise capacity (rho = - 0.32, p = 0.02), but in multivariable analysis most closely with physical activity. 92% of the responders who attended maintained this response six weeks later. CONCLUSION: Elevated aortic stiffness in COPD is potentially modifiable in a subgroup of patients during pulmonary rehabilitation and is associated with increased physical activity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03003208. Registered 26/12/ 2016.


Assuntos
Aorta/fisiopatologia , Exercício Físico/fisiologia , Volume Expiratório Forçado/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/reabilitação , Rigidez Vascular/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Análise de Onda de Pulso/métodos , Teste de Caminhada/métodos
14.
PLoS Pathog ; 12(3): e1005500, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26975045

RESUMO

Bacterial uptake by phagocytic cells is a vital event in the clearance of invading pathogens such as Streptococcus pneumoniae. A major role of the P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes against invasive pneumococcal disease is described in this study. Phagocytosis experiments using different serotypes demonstrated that PSGL-1 is involved in the recognition, uptake and killing of S. pneumoniae. Co-localization of several clinical isolates of S. pneumoniae with PSGL-1 was demonstrated, observing a rapid and active phagocytosis in the presence of PSGL-1. Furthermore, the pneumococcal capsular polysaccharide and the main autolysin of the bacterium--the amidase LytA--were identified as bacterial ligands for PSGL-1. Experimental models of pneumococcal disease including invasive pneumonia and systemic infection showed that bacterial levels were markedly increased in the blood of PSGL-1-/- mice. During pneumonia, PSGL-1 controls the severity of pneumococcal dissemination from the lung to the bloodstream. In systemic infection, a major role of PSGL-1 in host defense is to clear the bacteria in the systemic circulation controlling bacterial replication. These results confirmed the importance of this receptor in the recognition and clearance of S. pneumoniae during invasive pneumococcal disease. Histological and cellular analysis demonstrated that PSGL-1-/- mice have increased levels of T cells migrating to the lung than the corresponding wild-type mice. In contrast, during systemic infection, PSGL-1-/- mice had increased numbers of neutrophils and macrophages in blood, but were less effective controlling the infection process due to the lack of this functional receptor. Overall, this study demonstrates that PSGL-1 is a novel receptor for S. pneumoniae that contributes to protection against invasive pneumococcal disease.


Assuntos
Leucócitos/imunologia , Glicoproteínas de Membrana/imunologia , Infecções Pneumocócicas/imunologia , Pneumonia Pneumocócica/imunologia , Streptococcus pneumoniae/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/imunologia , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , N-Acetil-Muramil-L-Alanina Amidase/metabolismo , Neutrófilos/imunologia , Fagocitose/imunologia , Sepse/microbiologia
16.
Eur Respir J ; 50(5)2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29167299

RESUMO

Patients with bronchiectasis are at increased risk of cardiovascular disease. We aimed to identify factors associated with elevated cardiovascular risk in bronchiectasis, measured using aortic stiffness and cardiac biomarkers. In addition, we sought to compare these direct measures against calculated QRISK2 scores.Aortic stiffness, cardiac biomarkers and systemic inflammation were measured in 101 adults with stable bronchiectasis. In addition, clinical and demographic data were collected to allow calculation of QRISK2 score and the bronchiectasis severity index (BSI) for each patient.The BSI score correlated with measured cardiovascular risk assessments, partly due to greater exacerbation frequency and lower forced expiratory volume in 1 s. Pulse-wave velocity was significantly higher in frequent exacerbators (≥3 events·year-1) than infrequent exacerbators (<3 events·year-1; 10.5 versus 9.2 m·s-1, p=0.01). In addition, frequent exacerbators had elevated serum C-reactive protein concentration, suggesting increased systemic inflammation (4.8 versus 2.2 mg·L-1, p=0.005). QRISK2 systematically underestimated cardiovascular risk in this population (median change in relative risk 1.29). Underestimation was associated with frequent exacerbations and male sex.Patients with bronchiectasis have greater cardiovascular risk than published reference populations. Excess cardiovascular risk is associated with exacerbation frequency and impaired lung function. Cardiovascular risk assessment in bronchiectasis should be individualised, as calculation tools are likely to underestimate the risk in this population.


Assuntos
Bronquiectasia/complicações , Bronquiectasia/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Progressão da Doença , Medição de Risco/métodos , Idoso , Feminino , Volume Expiratório Forçado , Humanos , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Onda de Pulso , Análise de Regressão , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Escarro/microbiologia , Rigidez Vascular
17.
Curr Opin Pulm Med ; 23(3): 225-230, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28198725

RESUMO

PURPOSE OF REVIEW: Preventing pneumonia in the elderly and individuals with comorbidities is an unmet clinical need. Streptococcus pneumoniae is the commonest bacterial cause of pneumonia, and we summarize recent findings regarding current S. pneumoniae vaccines, and debate their efficacy and cost-effectiveness in risk groups. We also discuss potential future vaccine strategies such as protein antigen vaccines. RECENT FINDINGS: Current vaccination with pneumococcal polysaccharide vaccine does not prevent S. pneumoniae pneumonia. Vaccination with pneumococcal conjugated vaccine (PCV) prevents nasopharyngeal colonization, but although PCV13 has recently been shown to prevent S. pneumoniae pneumonia in adults, its overall efficacy was relatively low. The results of cost-effectiveness studies of PCV vaccination in adults are variable with some showing this is a cost-effective strategy, whereas others have not. The lack of cost-effectiveness is predominantly because of the current cost of the PCV vaccine and the existing herd immunity effect from childhood PCV vaccination on vaccine serotypes. SUMMARY: S. pneumoniae pneumonia is a vaccine-preventable disease but remains a common cause of morbidity and mortality. Advances in vaccination using approaches that induce serotypes-independent immunity and are immunogenic in high-risk groups are required to reduce the burden of disease because of S. pneumoniae.


Assuntos
Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/uso terapêutico , Adulto , Análise Custo-Benefício , Humanos , Vacinas Pneumocócicas/economia , Streptococcus pneumoniae/imunologia , Vacinação
18.
J Immunol ; 194(12): 6024-34, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25948816

RESUMO

Neutrophils are key effector cells of the innate immune response to pathogenic bacteria, but excessive neutrophilic inflammation can be associated with bystander tissue damage. The mechanisms responsible for neutrophil recruitment to the lungs during bacterial pneumonia are poorly defined. In this study, we focus on the potential role of the major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), during the development of pneumonia to the common lung pathogen Streptococcus pneumoniae. Our studies demonstrate that neutrophils were indispensable for controlling S. pneumoniae outgrowth but contributed to alveolar barrier disruption. We further report that intra-alveolar coagulation (bronchoalveolar lavage fluid thrombin-antithrombin complex levels) and PAR-1 immunostaining were increased in this model of bacterial lung infection. Functional studies using the most clinically advanced PAR-1 antagonist, SCH530348, revealed a key contribution for PAR-1 signaling in influencing neutrophil recruitment to lung airspaces in response to both an invasive and noninvasive strain of S. pneumoniae (D39 and EF3030) but that PAR-1 antagonism did not impair the ability of the host to control bacterial outgrowth. PAR-1 antagonist treatment significantly decreased pulmonary levels of IL-1ß, CXCL1, CCL2, and CCL7 and attenuated alveolar leak. Ab neutralization studies further demonstrated a nonredundant role for IL-1ß, CXCL1, and CCL7 in mediating neutrophil recruitment in response to S. pneumoniae infection. Taken together, these data demonstrate a key role for PAR-1 during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators.


Assuntos
Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/metabolismo , Receptor PAR-1/metabolismo , Animais , Coagulação Sanguínea , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocinas/metabolismo , Quimiotaxia/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Permeabilidade , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/patologia , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/patologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/microbiologia , Alvéolos Pulmonares/patologia , Receptor PAR-1/antagonistas & inibidores , Streptococcus pneumoniae/imunologia
20.
Eur Respir J ; 47(1): 186-93, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26541539

RESUMO

There is a paucity of data on incidence, prevalence and mortality associated with non-cystic fibrosis bronchiectasis.Using the Clinical Practice Research Datalink for participants registered between January 1, 2004 and December 31, 2013, we determined incidence, prevalence and mortality associated with bronchiectasis in the UK and investigated changes over time.The incidence and point prevalence of bronchiectasis increased yearly during the study period. Across all age groups, the incidence in women increased from 21.2 per 100 000 person-years in 2004 to 35.2 per 100 000 person-years in 2013 and in men from 18.2 per 100 000 person-years in 2004 to 26.9 per 100 000 person-years in 2013. The point prevalence in women increased from 350.5 per 100 000 in 2004 to 566.1 per 100 000 in 2013 and in men from 301.2 per 100 000 in 2004 to 485.5 per 100 000 in 2013. Comparing morality rates in women and men with bronchiectasis in England and Wales (n=11 862) with mortality rates in the general population from Office of National Statistics data showed that in women the age-adjusted mortality rate for the bronchiectasis population was 1437.7 per 100 000 and for the general population 635.9 per 100 000 (comparative mortality figure of 2.26). In men, the age-adjusted mortality rate for the bronchiectasis population was 1914.6 per 100 000 and for the general population 895.2 per 100 000 (comparative mortality figure of 2.14).Bronchiectasis is surprisingly common and is increasing in incidence and prevalence in the UK, particularly in older age groups. Bronchiectasis is associated with a markedly increased mortality.


Assuntos
Bronquiectasia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bronquiectasia/mortalidade , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Reino Unido/epidemiologia , Adulto Jovem
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