Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk.

Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.

The early career researcher collaboration mindset.

Everyone knows that science is about collaboration, but the degree to which one embraces collaboration can have an outsized impact on the value one derives from collaboration. In this article, different aspects of collaboration are discussed and a list of action-oriented principles is presented to help readers understand what can be done to develop more of a collaboration mindset to get the maximal value out of collaboration.

SHARP: enabling generation of real-world evidence on a pan-European scale to improve the lives of individuals with severe asthma.

Real-world evidence is important to help unravel unanswered problems in severe asthma and is valuable to better understand the patient experience and common clinical practice. The Severe Heterogeneous Asthma Registry, Patient-centred (SHARP) Clinical Research Collaboration is created as a network of national registries and severe asthma centres that work together to perform registry based real-world research and clinical studies on a pan-European scale. Such collaboration requires a new, innovative design to overcome the many issues that arise with large-scale data collection across national borders. SHARP has developed a platform that offers a federated analysis approach where national registry data are transformed and integrated into a common data model (CDM). The CDM then allows a local analysis of de-identified patient data and subsequent aggregate (meta-)analysis. To facilitate an easily accessible way to set up new registries, SHARP enables new registries to take part in a central database, based on already proven technology. Next to being economical, this linkage ensures data from different SHARP central members to be comparable. Technological advancements lead to an ever-expanding rate of patient data that will be collected; with the collective effort of the pan-European severe asthma research community SHARP hopes to ensure that they are well equipped to enter a new era of medical research, with the ultimate goal to positively impact the lives of patients with severe asthma.

Characteristics and treatment regimens across ERS SHARP severe asthma registries.

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Characteristics and determinants of endurance cycle ergometry and six-minute walk distance in patients with COPD.

BACKGROUND: Exercise tolerance can be assessed by the cycle endurance test (CET) and six-minute walk test (6MWT) in patients with Chronic Obstructive Pulmonary Disease (COPD). We sought to investigate the characteristics of functional exercise performance and determinants of the CET and 6MWT in a large clinical cohort of COPD patients. METHODS: A dataset of 2053 COPD patients (43% female, age: 66.9 ± 9.5 years, FEV1% predicted: 48.2 ± 23.2) was analyzed retrospectively. Patients underwent, amongst others, respiratory function evaluation; medical tests and questionnaires, one maximal incremental cycle test where peak work rate was determined and two functional exercise tests: a CET at 75% of peak work rate and 6MWT. A stepwise multiple linear regression was used to assess determinants. RESULTS: On average, patients had impaired exercise tolerance (peak work rate: 56 ± 27% predicted, 6MWT: 69 ± 17% predicted). A total of 2002 patients had CET time of duration (CET-Tend) less than 20 min while only 51 (2.5%) of the patients achieved 20 min of CET-Tend . In former patients, the percent of predicted peak work rate achieved differed significantly between men (48 ± 21% predicted) and women (67 ± 31% predicted). In contrast, CET-Tend was longer in men (286 ± 174 s vs 250 ± 153 s, p < 0.001). Also, six minute walking distance (6MWD) was higher in men compared to women, both in absolute terms as in percent of predicted (443 m, 67%predicted vs 431 m, 72%predicted, p < 0.05). Gender was associated with the CET-Tend but BMI, FEV1 and FRC were related to the 6MWD highlighting the different determinants of exercise performance between CET and 6MWT. CONCLUSIONS: CET-Tend is a valuable outcome of CET as it is related to multiple clinical aspects of disease severity in COPD. Gender difference should temper the interpretation of CET.

Age-graded reductions in quadriceps muscle strength and peak aerobic capacity in COPD / Reduções graduadas por idade na força muscular do quadríceps e no pico de consumo de oxigênio na DPOC

BACKGROUND: Reductions in quadriceps strength and peak aerobic capacity (VO2) in patients with chronic obstructive pulmonary disease (COPD) have been studied in relatively small samples over a short period. Moreover, results were not corrected for confounding variables, such as lean muscle mass, gender, and gas transfer capacity of the lungs. OBJECTIVES: To compare quadriceps muscle strength and peak V.O2 in women and men while stratifying for age and gas transfer capacity. We then corrected for lower-limb lean muscle mass to see whether and to what extent the age-graded reduction remained evident. METHODS: Retrospectively, data of 374 women and 593 men with COPD were analyzed: lung function, current drug therapy, quadriceps strength, peak V.O2, lower-limb lean muscle mass, and gas transfer capacity. RESULTS: Quadriceps strength and peak V.O2 were lower in older women and men with a gas transfer capacity of <50% predicted, also after adjustment for lower-limb lean muscle mass. Moreover, quadriceps strength and peak V.O2 were lower in older women and men with a gas transfer capacity of <50% predicted, also after adjustment for lower-limb lean muscle mass. Moreover, quadriceps strength and peak V.O2 were related to age in COPD, particularly in women and men with a gas transfer capacity of >50% predicted. Yet, counter to our hypothesis, lower-limb lean muscle mass did not show an age-graded reduction and, in turn, could not account for the relationship of age with quadriceps strength and peak V.O2. CONCLUSIONS: It is apparent that there is an age-graded reduction in skeletal muscle function in patients with COPD. Therefore, prevention of an age-graded decline in quadriceps muscle strength and peak V.O2 may need to become an outcome of pulmonary rehabilitation of patients with COPD.

CONTEXTUALIZAÇÃO: As reduções da força do quadríceps e do pico de consumo de oxigênio (V.O2) em pacientes com doença pulmonar obstrutiva crônica (DPOC) são estudadas em amostras relativamente pequenas e por curto período de tempo. Além disso, os resultados não são corrigidos por variáveis confundidoras, como conteúdo de massa magra, gênero e capacidade de difusão pulmonar. OBJETIVOS: Comparar a força muscular do quadríceps e o pico de V.O2 em mulheres e homens estratificados por idade e capacidade de difusão pulmonar e, então, corrigir pela massa magra dos membros inferiores para verificar se e até que ponto a redução graduada por idade permaneceu evidente. MÉTODOS: Retrospectivamente, foram analisados dados de 374 mulheres e 593 homens com DPOC, referentes a: função pulmonar, tratamento medicamentoso, força do quadríceps, pico de V.O2, massa magra dos membros inferiores e capacidade de difusão pulmonar. RESULTADOS: A força muscular do quadríceps e o pico de V.O2 foram menores em idosos com capacidade de difusão pulmonar <50% do previsto, mesmo após correção pela massa magra dos membros inferiores. Além disso, a força do quadríceps e o pico de V.O2 correlacionaram-se com a idade, especialmente em homens e mulheres com capacidade de difusão >50% do previsto. No entanto, a massa magra dos membros inferiores não demonstrou redução graduada por idade e não justificou a relação da idade com a força do quadríceps e o pico de V.O2, contrariando a nossa hipótese. CONCLUSÕES: Aparentemente, há uma redução graduada por idade na função musculoesquelética em pacientes com DPOC. Portanto, a prevenção do declínio graduado por idade na força do quadríceps e no pico de V.O2 deveria ser um objetivo da reabilitação pulmonar em pacientes com DPOC.

Age-graded reductions in quadriceps muscle strength and peak aerobic capacity in COPD.

BACKGROUND: Reductions in quadriceps strength and peak aerobic capacity (VO2) in patients with chronic obstructive pulmonary disease (COPD) have been studied in relatively small samples over a short period. Moreover, results were not corrected for confounding variables, such as lean muscle mass, gender, and gas transfer capacity of the lungs. OBJECTIVES: To compare quadriceps muscle strength and peak V.O2 in women and men while stratifying for age and gas transfer capacity. We then corrected for lower-limb lean muscle mass to see whether and to what extent the age-graded reduction remained evident. METHODS: Retrospectively, data of 374 women and 593 men with COPD were analyzed: lung function, current drug therapy, quadriceps strength, peak V.O2, lower-limb lean muscle mass, and gas transfer capacity. RESULTS: Quadriceps strength and peak V.O2 were lower in older women and men with a gas transfer capacity of <50% predicted, also after adjustment for lower-limb lean muscle mass. Moreover, quadriceps strength and peak V.O2 were lower in older women and men with a gas transfer capacity of <50% predicted, also after adjustment for lower-limb lean muscle mass. Moreover, quadriceps strength and peak V.O2 were related to age in COPD, particularly in women and men with a gas transfer capacity of >50% predicted. Yet, counter to our hypothesis, lower-limb lean muscle mass did not show an age-graded reduction and, in turn, could not account for the relationship of age with quadriceps strength and peak V.O2. CONCLUSIONS: It is apparent that there is an age-graded reduction in skeletal muscle function in patients with COPD. Therefore, prevention of an age-graded decline in quadriceps muscle strength and peak V.O2 may need to become an outcome of pulmonary rehabilitation of patients with COPD.

Task-related oxygen uptake and symptoms during activities of daily life in CHF patients and healthy subjects.

Patients with chronic heart failure (CHF) have a significantly lower peak aerobic capacity compared to healthy subjects, and, may therefore experience more inconvenience during the performance of domestic activities of daily life (ADLs). To date, the extent to which task-related oxygen uptake, heart rate, ventilation and symptoms during the performance of ADLs in CHF patients is different than in healthy subjects remains uncertain. General demographics, pulmonary function, body composition and peak aerobic capacity were assessed in 23 CHF outpatients and 20 healthy peers. In addition, the metabolic requirement of five simple self-paced domestic ADLs was assessed using a mobile oxycon. Task-related oxygen uptake (ml/min) was similar or lower in CHF patients compared to healthy subjects. In contrast, patients with CHF performing ADLs consumed oxygen at a higher proportion of their peak aerobic capacity than healthy subjects (p < 0.05). For example, getting dressed resulted in a mean task-related oxygen uptake of 49% of peak aerobic capacity, while sweeping the floor resulted in a mean task-related oxygen uptake of 52% of peak aerobic capacity, accompanied by significantly higher Borg symptom scores for dyspnea and fatigue (p < 0.05). Patients with CHF experience use a higher proportion of their peak aerobic capacity, peak ventilation and peak heart rate during the performance of simple self-paced domestic ADL than their healthy peers. These findings represent a necessary step in improving our understanding of improving what troubles patients the most-not being able to do the things that they could when they were healthy.

Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI).

Patients with severe refractory asthma pose a major healthcare problem. Over the last decade it has become increasingly clear that, for the development of new targeted therapies, there is an urgent need for further characterisation and classification of these patients. The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium is a pan-European public-private collaboration funded by the European Commission Innovative Medicines Initiative of the European Union. U-BIOPRED aims to subphenotype patients with severe refractory asthma by using an innovative systems biology approach. This paper presents the U-BIOPRED international consensus on the definition and diagnosis of severe asthma, aligning the latest concepts in adults as well as in children. The consensus is based on existing recommendations up to 2010 and will be used for the selection of patients for the upcoming U-BIOPRED study. It includes the differentiation between 'problematic', 'difficult' and 'severe refractory' asthma, and provides a systematic algorithmic approach to the evaluation of patients presenting with chronic severe asthma symptoms for use in clinical research and specialised care.

Effects of neuromuscular electrical stimulation of muscles of ambulation in patients with chronic heart failure or COPD: a systematic review of the English-language literature.

INTRODUCTION: Despite optimal drug treatment, many patients with congestive heart failure (CHF) or COPD still experience disabling dyspnea, fatigue, and exercise intolerance. They also exhibit significant changes in body composition. Attempts to rehabilitate these patients are often futile because conventional exercise-training modalities are limited by the severity of exertional dyspnea. Therefore, there is substantial interest in new training modalities that do not evoke dyspnea, such as transcutaneous neuromuscular electrical stimulation (NMES). MATERIALS AND METHODS: In this article, we systematically review the literature that addresses the effects of NMES applied to the muscles of ambulation. We focused on the effects of NMES on strength, exercise capacity, and disease-specific health status in patients with CHF or COPD. We also address the methodological quality of the reported studies as well as the safety of NMES. Manuscripts published prior to December 2007 were identified by searching the Medline/PubMed, Embase, Cochrane Controlled Trials Register, CINAHL, and Physiotherapy Evidence Database (PEDro) databases. RESULTS: Fourteen trials were identified (nine trials that examined NMES in CHF patients, and five in COPD patients). PEDro scores for methodological quality of the trials were generally moderate to good. Many of the studies reported significant improvements in muscle strength, exercise capacity, and/or health status. DISCUSSION: Nonetheless, the limited number of studies, the disparity in patient populations, and the variability in NMES methodology prohibit the use of metaanalysis. Yet, from the viewpoint of a systematic review, NMES looks promising as a means of rehabilitating patients with CHF and COPD. There is at least sufficient evidence to warrant more large prospective, randomized, controlled trials.

Intrinsic and antigen-induced airway hyperresponsiveness are the result of diverse physiological mechanisms.

Airway hyperresponsiveness (AHR) is a defining feature of asthma. We have previously shown, in mice sensitized and challenged with antigen, that AHR is attributable to normal airway smooth muscle contraction with exaggerated airway closure. In the present study we sought to determine if the same was true for mice known to have intrinsic AHR, the genetic strain of mice, A/J. We found that A/J mice have AHR characterized by minimal increase in elastance following aerosolized methacholine challenge compared with mice (BALB/c) that have been antigen sensitized and challenged [concentration that evokes 50% change in elastance (PC(50)): 22.9 +/- 5.7 mg/ml for A/J vs. 3.3 +/- 0.4 mg/ml for antigen-challenged and -sensitized mice; P < 0.004]. Similar results were found when intravenous methacholine was used (PC(30) 0.22 +/- 0.08 mg/ml for A/J vs. 0.03 +/- 0.004 mg/ml for antigen-challenged and -sensitized mice). Computational model analysis revealed that the AHR in A/J mice is dominated by exaggerated airway smooth muscle contraction and that when the route of methacholine administration was changed to intravenous, central airway constriction dominates. Absorption atelectasis was used to provide evidence of the lack of airway closure in A/J mice. Bronchoconstriction during ventilation with 100% oxygen resulted in a mean 9.8% loss of visible lung area in A/J mice compared with 28% in antigen-sensitized and -challenged mice (P < 0.02). We conclude that the physiology of AHR depends on the mouse model used and the route of bronchial agonist administration.

Exaggerated airway narrowing in mice treated with intratracheal cationic protein.

Airway hyperresponsiveness in mice with allergic airway inflammation can be attributed entirely to exaggerated closure of peripheral airways (Wagers S, Lundblad LK, Ekman M, Irvin CG, and Bates JHT. J Appl Physiol 96: 2019-2027, 2004). However, clinical asthma can be characterized by hyperresponsiveness of the central airways as well as the lung periphery. We, therefore, sought to establish a complementary model of hyperresponsiveness in the mouse due to excessive narrowing of the airways. We treated mice with a tracheal instillation of the cationic protein poly-l-lysine (PLL), hypothesizing that this would reduce the barrier function of the epithelium and thereby render the underlying airway smooth muscle more accessible to aerosolized methacholine. The PLL-treated animals were hypersensitive to methacholine: they exhibited an exaggerated response to submaximal doses but had a maximal response that was similar to controls. With the aid of a computational model of the mouse lung, we conclude that the methacholine responsiveness of PLL-treated mice is fundamentally different in nature to the hyperresponsiveness that we found previously in mice with allergically inflamed lungs.

Peak pressures during manual ventilation.

INTRODUCTION: Manual (bag) ventilation sometimes achieves better oxygenation than does a mechanical ventilator. We speculated that clinicians might generate very high airway pressure during manual ventilation (much higher than the pressure delivered by a mechanical ventilator), and that the high airway pressure causes alveolar recruitment and thus improves oxygenation. Such high pressure might injure alveoli in some patients. METHODS: We tested the hypothesis that manual ventilation may involve substantially higher pressure than is delivered by a mechanical ventilator. We asked experienced respiratory therapists to manually ventilate a lung model that was set to represent several typical clinical scenarios. RESULTS: We found that the peak airway pressure generated by the therapists was sometimes in excess of 100 cm H(2)O. CONCLUSIONS: The high airway pressure during manual ventilation would be considered extreme in the context of conventional mechanical ventilation, which raises questions about whether manual ventilation causes barotrauma.

Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness.

Mechanisms underlying airway hyperresponsiveness are not yet fully elucidated. One of the manifestations of airway inflammation is leakage of diverse plasma proteins into the airway lumen. They include fibrinogen and thrombin. Thrombin cleaves fibrinogen to form fibrin, a major component of thrombi. Fibrin inactivates surfactant. Surfactant on the airway surface maintains airway patency by lowering surface tension. In this study, immunohistochemically detected fibrin was seen along the luminal surface of distal airways in a patient who died of status asthmaticus and in mice with induced allergic airway inflammation. In addition, we observed altered airway fibrinolytic system protein balance consistent with promotion of fibrin deposition in mice with allergic airway inflammation. The airways of mice were exposed to aerosolized fibrinogen, thrombin, or to fibrinogen followed by thrombin. Only fibrinogen followed by thrombin resulted in airway hyperresponsiveness compared with controls. An aerosolized fibrinolytic agent, tissue-type plasminogen activator, significantly diminished airway hyperresponsiveness in mice with allergic airway inflammation. These results are consistent with the hypothesis that leakage of fibrinogen and thrombin and their accumulation on the airway surface can contribute to the pathogenesis of airway hyperresponsiveness.