Florent Baty

Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study

Objective To study the association between wheezy symptoms in young children and the presence of bacteria in the airways. Design Birth cohort study. Setting Clinical research unit in Copenhagen. Participants Children of asthmatic mothers, from age 4 weeks to 3 years, with planned visits and acute admissions to the research clinic. Main outcome measure Frequency of bacteria and virus carriage in airway aspirates during wheezy episodes and at planned visits without respiratory symptoms. Results 984 samples (361 children) were analysed for bacteria, 844 (299 children) for viruses, and 696 (277 children) for both viruses and bacteria. Wheezy episodes were associated with both bacterial infection (odds ratio 2.9, 95% confidence interval 1.9 to 4.3; P<0.001) and virus infection (2.8, 1.7 to 4.4; P<0.001). The associations of bacteria and viruses were independent of each other. Conclusion Acute wheezy episodes in young children were significantly associated with bacterial infections similar to but independent of the association with virus infections.

Chromosome 17q21 Gene Variants Are Associated with Asthma and Exacerbations but Not Atopy in Early Childhood

RATIONALEnAn asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups.nnnOBJECTIVESnTo characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus.nnnMETHODSnThe single nucleotide polymorphism (SNP), rs7216389, was genotyped in 376 of 411 children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort born to mothers with asthma together with 305 mothers and 224 fathers. Nineteen additional SNPs in the region were genotyped in the children. Investigator-diagnosed clinical endpoints were based on diary cards and clinic visits every 6 months and at acute symptoms from birth. Lung function, bronchial responsiveness, and sensitization were tested longitudinally from early infancy.nnnMEASUREMENTS AND MAIN RESULTSnrs7216389 was significantly associated with the development of wheeze (hazard ratio 1.64 [1.05-2.59], P value = 0.03), asthma (hazard ratio, 1.88 [1.15-3.07], P = 0.01), and acute severe exacerbations (hazard ratio 2.66 [1.58-4.48], P value = 0.0002). The effect on wheeze and asthma was observed for early onset but not late onset of disease. The increased risk of exacerbations persisted from 1 to 6 years of age (incidence ratio 2.48 [1.42-4.32], P value = 0.001), and increased bronchial responsiveness was present in infancy and at 4 years of age, but not at 6 years. In contrast, rs7216389 conferred no risk of eczema, rhinitis, or allergic sensitization.nnnCONCLUSIONSnVariation at the chromosome 17q12-q21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.

Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia

We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1(+)) as well as markers of the B-cell lineage (B220(+)). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets.

Effect of a 14-day course of systemic corticosteroids on the hypothalamic-pituitary-adrenal-axis in patients with acute exacerbation of chronic obstructive pulmonary disease

BackgroundAs supra-physiological intake of corticosteroids is a well known risk factor for the development of adrenal insufficiency, we investigated the function of the hypothalamic-pituitary-adrenal (HPA) axis during a 14-day course of systemic corticosteroids in patients with acute exacerbation of chronic obstructive pulmonary disease using clinical and laboratory measures.MethodsA systematic clinical and laboratory assessment including measurement of basal cortisol levels and the response to low dose (1 μg) ACTH stimulation was performed in nine patients before, on the first and the last day of treatment, as well as 2, 7 and 21 days after corticosteroid withdrawal.ResultsAt baseline, all nine patients had normal responses to 1 μg ACTH. On the first day of steroid treatment, 78% had a blunted peak cortisol response. This percentage increased to 89% after 14 days of steroid treatment. 78%, 33% and 33% of the patients had a blunted cortisol response to ACTH 2, 7, and 21 days after corticosteroid withdrawal, respectively. ROC curve analysis revealed that only basal cortisol concentrations (AUC 0.89), but not ACTH concentrations (AUC 0.49) or clinical signs (AUC 0.47) were predictive of an impaired function of the HPA axis. Basal cortisol levels of > 400 and < 150 nmol/l were 96% and 100% sensitive for a normal or pathological response to the ACTH stimulation test, respectively.ConclusionImmediate and prolonged suppression of the HPA axis is a common finding in otherwise asymptomatic patients undergoing systemic steroid treatment for acute exacerbation of chronic obstructive pulmonary disease and can reliably be assessed with the low-dose ACTH test.

Analysis with respect to instrumental variables for the exploration of microarray data structures

BackgroundEvaluating the importance of the different sources of variations is essential in microarray data experiments. Complex experimental designs generally include various factors structuring the data which should be taken into account. The objective of these experiments is the exploration of some given factors while controlling other factors.ResultsWe present here a family of methods, the analyses with respect to instrumental variables, which can be easily applied to the particular case of microarray data. An illustrative example of analysis with instrumental variables is given in the case of microarray data investigating the effect of beverage intake on peripheral blood gene expression. This approach is compared to an ANOVA-based gene-by-gene statistical method.ConclusionInstrumental variables analyses provide a simple way to control several sources of variation in a multivariate analysis of microarray data. Due to their flexibility, these methods can be associated with a large range of ordination techniques combined with one or several qualitative and/or quantitative descriptive variables.

Gene Profiling of Clinical Routine Biopsies and Prediction of Survival in Non–Small Cell Lung Cancer

RATIONALEnGlobal gene expression analysis provides a comprehensive molecular characterization of non-small cell lung cancer (NSCLC).nnnOBJECTIVESnTo evaluate the feasibility of integrating expression profiling into routine clinical work-up by including both surgical and minute bronchoscopic biopsies and to develop a robust prognostic gene expression signature.nnnMETHODSnTissue samples from 41 chemotherapy-naive patients with NSCLC and 15 control patients with inflammatory lung diseases were obtained during routine clinical work-up and gene expression profiles were gained using an oligonucleotide array platform (NovaChip; 34207 transcripts). Gene expression signatures were analyzed for correlation with histological and clinical parameters and validated on independent published data sets and immunohistochemistry.nnnMEASUREMENTS AND MAIN RESULTSnDiagnostic signatures for adenocarcinoma and squamous cell carcinoma reached a sensitivity of 80%/80% and a specificity of 83%/94%, respectively, dependent on the proportion of tumor cells. Sixty-seven of the 100 most discriminating genes were validated with independent observations from the literature. A 13-gene metagene refined on four external data sets was built and validated on an independent data set. The metagene was a strong predictor of survival in our data set (hazard ratio = 7.7, 95% CI [2.8-21.2]) and in the independent data set (hazard ratio = 1.6, 95% CI [1.2-2.2]) and in both cases independent of the International Union against Cancer staging. Vascular endothelial growth factor-beta, one of the key prognostic genes, was further validated by immunohistochemistry on 508 independent tumor samples.nnnCONCLUSIONSnIntegration of functional genomics from small bronchoscopic biopsies allows molecular tumor classification and prediction of survival in NSCLC and might become a powerful adjunct for the daily clinical practice.

Sedative Drug Requirements during Flexible Bronchoscopy

Background: There is a paucity of data comparing doses of sedative medication during bronchoscopy in immunosuppressed and non-immunosuppressed patients. Objectives: The aim of this study was to define the sedative medication doses used in specific patient groups during bronchoscopy. Methods: Bronchoscopy was performed under local anesthesia, sedation with intermittent boluses of intravenous midazolam and intravenous hydrocodone 5 mg. Two hundred and thirty-nine consecutive bronchoalveolar lavage procedures were included. Procedures in non-immunosuppressed patients were classified as controls (n = 91). Procedures in immunosuppressed patients who received midazolam consisted of stem cell transplant (34), solid organ transplant (25), chemotherapy (33), HIV with drug abuse (10), HIV (5), prednisone (17) and immunosuppression for other diseases (12). Intravenous propofol was administered during 12 procedures due to inability to achieve optimal sedation with midazolam in a previous bronchoscopy (stem cell transplant recipient 1, lung transplant for cystic fibrosis 5) and during the same bronchoscopy due to inadequate sedation with a high dose of midazolam – renal transplant recipient 1, drug abuse (HIV 1, renal transplant recipient 1), bronchoscopy combined with gastroscopy (2) and a hypoxemic patient (1). The mean dose of propofol administered was 2.8 ± 1.3 mg/kg. Results: Midazolam requirement was significantly higher in patients with stem cell transplantation (0.09 ± 0.05 mg/kg) compared with controls (0.06 ± 0.03 mg/kg; p = 0.0002). In the HIV patients with drug abuse (0.12 ± 0.10 mg/kg), there was a tendency for the need of a higher dose of midazolam compared with the control group (p = 0.0754). Conclusion: Stem cell transplant recipients and selected HIV patients with drug abuse need higher doses of midazolam for bronchoscopy.

Physical activity in young children is reduced with increasing bronchial responsiveness

BACKGROUNDnPhysical activity is essential for young children to develop adequately and for quality of life. It can be lower in children with subclinical asthma, and therefore methods to reveal subclinical reduction in physical activity in young children are warranted.nnnOBJECTIVEnWe sought to study an association between physical activity in preschool children and objectively assessed intermediary asthma phenotypes.nnnMETHODSnWe studied 253 five-year-old children (127 girls) participating in the Copenhagen Prospective Studies on Asthma in Childhood. The main outcome measure was level of physical activity assessed objectively with accelerometers worn on an ankle for 4 weeks. Objective assessment of asthma intermediary phenotypes included prebronchodilator and postbronchodilator specific airway resistance, bronchial responsiveness to cold dry-air hyperventilation, and exhaled nitric oxide levels. Analyses were performed with generalized linear model and principal component analysis.nnnRESULTSnPhysical activity was inversely associated with bronchial responsiveness (relative rate, 0.89; 95% CI, 0.83-0.95; P = .007) and significantly increased in the months of spring and summer (P < .001) and in boys (relative rate, 1.16; 95% CI, 1.09-1.25; P < .001). Physical activity was independent of asthma diagnosis, age, body mass index, baseline specific airway resistance, reversibility to beta(2)-agonist, sensitization, and exhaled nitric oxide level.nnnCONCLUSIONnPhysical activity in preschool children was reduced with increasing bronchial responsiveness. The reduced physical activity was subclinical and not realized by parents or doctors despite daily diary cards and close clinical follow-up since birth. This observation warrants awareness of even very mild asthma symptoms in clinical practice.

Therapeutic bronchoscopy for malignant airway stenoses: choice of modality and survival.

BACKGROUNDnThere are no data regarding the factors influencing the choice of therapeutic bronchoscopic modality in the management of malignant airway stenoses.nnnOBJECTIVESnTo assess the choice of therapeutic bronchoscopy modality and analyze factors influencing survival in patients with malignant central airway obstruction.nnnMATERIALS AND METHODSnWe performed 167 procedures in 130 consecutive patients, for malignant central airway obstruction, over six years.nnnRESULTSnLaser was used either alone or in combination with stent insertion in 76% procedures. Laser only was used in 53% procedures for lesions below the main bronchi. Stents alone were used for extrinsic compression or stump insufficiency. Combined laser and stent insertion was most frequently used for lesions involving the trachea plus both main bronchi or only the main bronchi. The Dumon stent was preferred in lesions of the trachea and the right bronchial tree, the Ultraflex stent for lesions on the left side and stenoses below the main bronchi. Survival was better in patients with lung cancer, lesions restricted to one lung and when laser alone was used compared to esophageal cancer, metastases and tracheal involvement.nnnCONCLUSIONnThe choice of different airway stents can be made based on the nature and site of the lesion. Dumon stents are suited for lesions in trachea and right main bronchus and the Ultraflex stents on the left side and stenoses beyond the main bronchi. Survival can be estimated based on the diagnosis, site of the lesion and treatment modality used.

Combined Oximetry-Cutaneous Capnography in Patients Assessed for Long-term Oxygen Therapy

STUDY AIMnTo evaluate the feasibility of combined oximetry (pulse oximetric saturation [Spo(2)]) and cutaneous capnography (transcutaneous carbon dioxide tension [Ptcco(2)]) for oxygen titration in patients requiring long-term oxygen therapy.nnnMETHODSnTwenty patients with obstructive or restrictive lung disease underwent oxygen titration using a combined cutaneous oximetry-capnography sensor. The goal of titration was to achieve an oxygen saturation of > 90% without a significant rise in carbon dioxide. Spo(2) and Ptcco(2) measurements at the end of titration were compared with blood gas levels using Bland-Altman analysis and linear regression analysis.nnnRESULTSnThe mean (+/- SE of the estimate) Pao(2) while breathing room air was 53.2 +/- 8.1 mm Hg and increased to 75.9 +/- 13.3 mm Hg with oxygen supplementation (p < 0.0001). The mean Paco(2) was 45.9 +/- 8.7 mm Hg at baseline and 47.8 +/- 9.0 mm Hg after oxygen titration (p = 0.003). Bland-Altman analysis for comparison of Ptcco(2) and Paco(2) showed a bias of 0.86 mm Hg with a precision of 3.48 mm Hg. Bland-Altman analysis for the comparison of Spo(2) and arterial oxygen saturation showed a bias of 0.14% with a precision of 1.13%.nnnCONCLUSIONnCombined oximetry and cutaneous capnography is feasible during oxygen titration in patients needing long-term oxygen therapy. This noninvasive approach has the potential to reduce the number of arterial blood gas samplings performed.