RESUMO
Bacteriophages have been shown to be effective for treating acute infections of the respiratory tract caused by antibiotic-resistant bacteria in animal models, but no evidence has yet been presented of their activity against pathogens in complex biological samples from chronically infected patients. We assessed the efficacy of a cocktail of ten bacteriophages infecting Pseudomonas aeruginosa following its addition to 58 sputum samples from cystic fibrosis (CF) patients collected at three different hospitals. Ten samples that did not contain P. aeruginosa were not analysed further. In the remaining 48 samples, the addition of bacteriophages led to a significant decrease in the levels of P. aeruginosa strains, as shown by comparison with controls, taking two variables (time and bacteriophages) into account (p = 0.024). In 45.8% of these samples, this decrease was accompanied by an increase in the number of bacteriophages. We also tested each of the ten bacteriophages individually against 20 colonies from each of these 48 samples and detected bacteriophage-susceptible bacteria in 64.6% of the samples. An analysis of the clinical data revealed no correlation between patient age, sex, duration of P. aeruginosa colonization, antibiotic treatment, FEV1 (forced expiratory volume in the first second) and the efficacy of bacteriophages. The demonstration that bacteriophages infect their bacterial hosts in the sputum environment, regardless of the clinical characteristics of the patients, represents a major step towards the development of bacteriophage therapy to treat chronic lung infections.
Assuntos
Fibrose Cística/complicações , Viabilidade Microbiana , Infecções por Pseudomonas/microbiologia , Fagos de Pseudomonas/crescimento & desenvolvimento , Pseudomonas aeruginosa/virologia , Escarro/microbiologia , Escarro/virologia , Adolescente , Adulto , Carga Bacteriana , Terapia Biológica/métodos , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto JovemRESUMO
The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.
Assuntos
Testes Respiratórios/métodos , Fibrose Cística , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Testes de Função Respiratória , Biomarcadores , Fibrose Cística/diagnóstico , Fibrose Cística/fisiopatologia , Fibrose Cística/terapia , Estudos de Viabilidade , Humanos , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/normas , Reprodutibilidade dos Testes , Testes de Função Respiratória/métodos , Testes de Função Respiratória/normas , Índice de Gravidade de DoençaRESUMO
The aim of this study was to address whether NP might be a predictive factor for severity of CF. The authors collected data from the literature on NP as a unique or associated sign in CF and reviewed the clinical and molecular aspects of CF associated with NP. CF genotypes and clinical severity in NP(+) vs. NP(-) patients were reviewed, taking into account pulmonary function, frequency of P. aeruginosa lung infection, frequency of allergy, nutritional status, and exocrine pancreatic function. The CFTR gene was also analyzed in a patient with isolated severe NP as the unique feature of CF. This review of the literature showed a `milder` phenotype in `NP+` vs. `NP-` CF patients, contrasting with a marked association between NP and `severe` CF mutations. In addition, a complex genotype was identified, associating four heterozygous variants, namely p.Q493X (a severe mutation) on the paternal allele, and p.V562I, p.A1006E, and (TG)11(T)5 (IVS8-5T) on the maternal allele, in a case of CF presenting as isolated NP. The authors speculate that genetic/environmental factors associated with NP might attenuate the functional impact of `severe` CF mutations. The overrepresentation of CF carriers among patients with isolated NP also advocates the need for CFTR molecular screening in such populations for genetic counselling purposes.
Assuntos
Fibrose Cística/epidemiologia , Pólipos Nasais/epidemiologia , Adulto , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Análise Mutacional de DNA , Humanos , Masculino , Pólipos Nasais/genética , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials.
Assuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Fibrose Cística/terapia , Sociedades Médicas/organização & administração , Sociedades Médicas/normas , Comportamento Cooperativo , Europa (Continente) , HumanosRESUMO
In the majority of cases, there is no difficulty in diagnosing Cystic Fibrosis (CF). However, there may be wide variation in signs and symptoms between individuals which encourage the scientific community to constantly improve the diagnostic tests available and develop better methods to come to a final diagnosis in patients with milder phenotypes. This paper is the result of discussions held at meetings of the European Cystic Fibrosis Society Diagnostic Network supported by EuroCareCF. CFTR bioassays in the nasal epithelium (nasal potential difference measurements) and the rectal mucosa (intestinal current measurements) are discussed in detail including efforts to standardize the techniques across Europe. New approaches to evaluate the sweat gland, future of genetic testing and methods on the horizon like CFTR expression in human leucocytes and erythrocytes are discussed briefly.
Assuntos
Fibrose Cística/diagnóstico , Técnicas de Diagnóstico do Sistema Respiratório/tendências , Medicina/tendências , Europa (Continente) , HumanosRESUMO
Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as "a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF". The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/classificação , Fibrose Cística/genética , Medicina/normas , Guias de Prática Clínica como Assunto , Fibrose Cística/fisiopatologia , Europa (Continente) , HumanosRESUMO
Oseltamivir is a prodrug of oseltamivir carboxylate (OC), a neuraminidase inhibitor used for treatment and prevention of influenza. The pharmacokinetics of these 2 compounds were investigated after a single 75-mg oseltamivir dose in 6 patients with cystic fibrosis (CF). Means ± standard deviations of the area under the curve from time zero to infinity (AUC) were 173 ± 58 µg · h/liter for oseltamivir and 2,256 ± 394 µg · h/liter for OC. The concentrations of OC in sputum 4 to 6 h and 22 to 26 h after the intake ranged from 4.1 to 62.2 µg/liter. The AUC of OC was approximately 30% lower than and significantly different from published values for volunteers. On the basis of the present results and because the anti-A/H1N1 influenza virus efficacy of OC is related to its AUC/50% effective concentration (EC(50)) ratio, an increase in the oseltamivir unitary dose could be considered for the treatment of influenza in CF patients. This should nevertheless be confirmed by a controlled pharmacokinetic study performed on a larger number of patients.
Assuntos
Antivirais/farmacocinética , Fibrose Cística/metabolismo , Oseltamivir/análogos & derivados , Oseltamivir/farmacocinética , Escarro/química , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Fungal colonization in cystic fibrosis patient is frequent and dominated by Aspergillus fumigatus (A. fumigatus). Mycological analysis on specific media showed other filamentous species Scedosporium, Geosmithia argillacea. Prospective studies are necessary to appreciate prevalence and pathogenicity in this pathology. A. fumigatus causes the most frequently allergic bronchopulmonary aspergillosis (ABPA). Invasive infection is exceptional in this context. An early diagnosis is important to avoid bronchial deterioration but is very difficult despite international consensus. New more specific biological markers are evaluated. Oral corticotherapy is the cornerstone of therapy but adverse effects are more frequent in cystic fibrosis. Antifungal therapy has a corticosteroid-sparing effect. New therapeutic strategies have to be evaluated.
Assuntos
Fibrose Cística/complicações , Micoses/etiologia , Administração Oral , Antifúngicos/uso terapêutico , Aspergillus fumigatus/isolamento & purificação , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Diagnóstico Precoce , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Micoses/diagnóstico , Micoses/tratamento farmacológico , Micoses/microbiologia , Aspergilose Pulmonar/microbiologia , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: In patients with symptoms suggestive of cystic fibrosis (CF) and intermediate sweat chloride values (30-60 mmol/l), extensive CFTR gene mutation analysis and nasal potential difference (NPD) measurement are used as additional diagnostic tests and a positive result in either test provides evidence of CFTR dysfunction. To define the phenotype of such patients and confirm the validity of grouping them, patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal were compared with subjects in whom this was not the case and patients with classic CF. METHODS: The phenotypic features of four groups were compared: 59 patients with CFTR dysfunction, 46 with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 patients with CF and pancreatic sufficiency (CF-PS) and 62 with CF and pancreatic insufficiency (CF-PI). RESULTS: The CFTR dysfunction group had more lower respiratory tract infections (p = 0.01), more isolation of CF pathogens (p<0.001) and clubbing (p = 0.001) than the CF unlikely group, but less frequent respiratory tract infections with CF pathogens than the CF-PS group (p = 0.05). Patients in the CF-PS group had a milder phenotype than those with PI. Many features showed stepwise changes through the patient groups. CONCLUSION: Patients with intermediate sweat chloride values and two CFTR mutations or an abnormal NPD measurement have a CF-like phenotype compatible with CFTR dysfunction and, as a group, differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients.
Assuntos
Algoritmos , Cloretos/análise , Fibrose Cística/genética , Suor/química , Adolescente , Adulto , Criança , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/análise , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Masculino , Mutação , Fenótipo , Sódio , Adulto JovemRESUMO
A reduction of exhaled nitric oxide (NO) fraction and endothelial-mediated dysfunction have been reported in cystic fibrosis (CF). The aims of the present study were to search for relationships between flow-independent NO exchange parameters (bronchial NO flux (J'(aw,NO)) and alveolar NO concentration (C(A,NO))) and lung function tests characterising airflow limitation and pulmonary vascular bed (capillary blood volume and physiological dead space/tidal volume (V(D)/V(T)) ratio on exercise). In total, 34 patients (16 children, 18 adults) with CF, without resting pulmonary hypertension, underwent spirometry, exhaled NO measurement (multiple constant flow analytical method), gas transfer assessment (carbon monoxide and NO, allowing the calculation of capillary volume and membrane conductance) and a graded exercise test with oxygen uptake (V'(O(2))), carbon dioxide production (V'(CO(2))) and arterial blood gas evaluations. Both J'(aw,NO) and C(A,NO )correlated positively with airflow limitation. C(A,NO) correlated positively with capillary/alveolar volume. During exercise, criteria of mild pulmonary vascular disease were evidenced in some patients that participated in exercise limitation (negative correlation between physiological V(D)/V(T) and peak V'(O(2))). C(A,NO )at rest correlated positively with these parameters of wasted ventilation during exercise (physiological V(D)/V(T), minute ventilation (V'(E))/V'(CO(2)) at ventilatory threshold and V'(E)/V'(CO(2)) slope). Flow-independent exhaled NO parameters are linked to airway and early vascular diseases in patients with CF.
Assuntos
Fibrose Cística/diagnóstico , Pulmão/patologia , Óxido Nítrico/metabolismo , Espirometria/métodos , Adolescente , Adulto , Índice de Massa Corporal , Monóxido de Carbono/metabolismo , Criança , Fibrose Cística/metabolismo , Teste de Esforço , Expiração , Feminino , Humanos , Pulmão/metabolismo , Masculino , MutaçãoRESUMO
Screening newborns for cystic fibrosis (CF) is considered to be an ethical undertaking in regions with a significant incidence of the condition. Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants. We have undertaken a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database. This consensus document will provide guidance to CF specialists with established screening programmes and those who are in the process of implementing newborn screening in their region.
Assuntos
Fibrose Cística/diagnóstico , Triagem Neonatal/métodos , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Testes Genéticos/métodos , Humanos , Recém-Nascido , Mutação , Cloreto de Sódio/metabolismo , Suor/metabolismoRESUMO
Lobular emphysema and soft-tissue emphysema can exceptionally complicate malnutrition. We report the case of a teenager presenting malnutrition with cystic fibrosis and anorexia nervosa with soft-tissue emphysema.
Assuntos
Fibrose Cística/complicações , Enfisema Subcutâneo/complicações , Adulto , Anorexia Nervosa/complicações , Feminino , Humanos , Desnutrição/complicações , Pneumotórax/complicaçõesRESUMO
The p.Val754Met variant, described in 1996 in a CF patient, has been considered a CF mutation. However, biochemical aspects, results of functional studies and, finally, the identification of a complex deletion removing exons 3 to 10 and 14b to 16 in cis of p.Val754Met in a CF patient, argue against a strong deleterious effect. An inventory through the French CF network of patients carrying p.Val754Met led to the registration of seven patients (CF: n=4; idiopathic chronic pancreatitis: n=3) and six healthy individuals, all heterozygous for the variation. Extensive CFTR gene analysis was carried out, including the search for large rearrangements and other possible mutations. The complex deletion, whose breakpoints are described here, was found only in the four CF patients, in association with the same haplotype. This data, added to the fact that the p.[Phe508del]+[Val754Met] genotype was found in a healthy individual, bring further arguments against the association of p.Val754Met with CF. We thus suggest looking for a possible complex allele whenever p.Val754Met is detected and considering it neutral regarding genetic counseling when found in isolation.
Assuntos
Alelos , Aberrações Cromossômicas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Adolescente , Adulto , Sequência de Bases , Criança , Fibrose Cística/diagnóstico , Análise Mutacional de DNA , Feminino , Testes Genéticos , Haplótipos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo Genético , Deleção de SequênciaRESUMO
The use and complications of totally implantable vascular access devices (TIVADs) were examined during multiple courses of antibiotics in cystic fibrosis (CF) patients. This retrospective study involved 36 CF centres. Risk factors for removal and septicaemia were sought by survival analysis of censored data. Multivariate Cox models were constructed with removal or septicaemia as the event and the characteristics of TIVADs as explanatory variables. TIVADs (n = 452) were implanted in 315 patients. The mean functional time per device was 32 +/- 25 months. Long-term complications occurred with 188 devices (42%); they consisted mainly of occlusion (21%, requiring removal in 77%), infection (9.3%, requiring removal in 851%; septicaemia in 7.3%; rate 0.3 per 1,000 days, Candida in 66%), and vascular thrombosis (4.7%, removal in 58%). Multivariate survival analysis showed that removal, whatever the reason, was associated with polyurethane (versus silicone) and routine use of the device for blood sampling (versus never). No risk factors, including heparin lock, were identified for septicaemia or for removal for obstruction. Totally implantable venous access devices appear to be safe and reliable for long-term intermittent venous access. Although retrospective, this study suggests that the characteristics of the material and blood sampling are risk factors for removal.
Assuntos
Cateteres de Demora , Fibrose Cística/terapia , Antibacterianos/administração & dosagem , Coleta de Amostras Sanguíneas , Cateteres de Demora/efeitos adversos , Criança , Infecção Focal/epidemiologia , Seguimentos , Humanos , Infusões Intravenosas , Nutrição Parenteral , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Sepse/epidemiologia , Trombose/epidemiologia , Fatores de TempoRESUMO
Cystic fibrosis (CF) is considered as a rare disease in black Africans. In fact, this disease is likely to be underestimated since clinical features consistent with CF diagnosis are often ascribed to environmental factors such as malnutrition. Very little is known about CFTR mutations in affected patients from Central Africa. We report here four novel mutations, i.e., IVS2 + 28 (intron 2), 459T > A (exon 4), EX17a_EX18del (exons 17-18), and IVS22 + IG > A (intron 22), in such patients. An update of CFTR mutations reported in black patients from various ethnies is included. These data might be helpful for genetic counselling regarding CF in black patients.