There has been an increased understanding, over the past 2 decades, that asthma is a chronic, immunologically mediated condition with a disturbance of the normal airway repair mechanism, which ...results in inflammatory changes and airway remodeling. The airway inflammation and remodeling together likely explain the clinical manifestations of asthma. The mechanisms by which the external environmental cues, together with the complex genetic actions, propagate the inflammatory process that characterize asthma are beginning to be understood. There is also an evolving awareness of the active participation of structural elements, such as the airway epithelium, airway smooth muscle, and endothelium, in this process. In tandem with this has come the realization that inflammatory cells respond in a coordinated, albeit dysfunctional manner, via an array of complex signaling pathways that facilitate communication between these cells; these structural elements within the lung and the bone marrow serve as reservoirs for and the source of inflammatory cells and their precursors. Although often viewed as separate mechanistic entities, so-called innate and acquired immunity often overlap in the propagation of the asthmatic response. This review examines the newer information on the pathophysiologic characteristics of asthma and focuses on papers published over the past 3 years that have helped to improve current levels of understanding.
Asthma is a chronic respiratory disease whose prevalence is increasing in the western world. Recently research has begun to focus on the role the microbiome plays in asthma pathogenesis in the hope ...of further understanding this respiratory disorder. Considered sterile until recently, the lungs have revealed themselves to contain a unique microbiota. A shift towards molecular methods for the quantification and sequencing of microbial DNA has revealed that the airways harbour a unique microbiota with apparent, reproducible differences present between healthy and diseased lungs. There is a hope that in classifying the microbial load of the asthmatic airway an insight may be afforded as to the possible role pulmonary microbes may have in propagating an asthmatic airway response. This could potentially pave the way for new therapeutic strategies for the treatment of chronic lung conditions such as asthma.
In severe asthma, poor control could reflect issues of medication adherence or inhaler technique, or that the condition is refractory. This study aimed to determine if an intervention with ...(bio)feedback on the features of inhaler use would identify refractory asthma and enhance inhaler technique and adherence.Patients with severe uncontrolled asthma were subjected to a stratified-by-site random block design. The intensive education group received repeated training in inhaler use, adherence and disease management. The intervention group received the same intervention, enhanced by (bio)feedback-guided training. The primary outcome was rate of actual inhaler adherence. Secondary outcomes included a pre-defined assessment of clinical outcome. Outcome assessors were blinded to group allocation. Data were analysed on an intention-to-treat and per-protocol basis.The mean rate of adherence during the third month in the (bio)feedback group (n=111) was higher than that in the enhanced education group (intention-to-treat, n=107; 73%
63%; 95% CI 2.8%-17.6%; p=0.02). By the end of the study, asthma was either stable or improved in 54 patients (38%); uncontrolled, but poorly adherent in 52 (35%); and uncontrolled, but adherent in 40 (27%).Repeated feedback significantly improved inhaler adherence. After a programme of adherence and inhaler technique assessment, only 40 patients (27%) were refractory and adherent, and might therefore need add-on therapy.
Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact ...of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment.
Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed.
Significant improvements in FEV
, BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-1β, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03).
Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.
The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health ...utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1 s (ppFEV
), and a mean difference in sweat chloride of -39.3 mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6 weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients' preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12 weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV
was 80.7% on standard dose, and 83.4% at 12 weeks on reduced dose; sweat chloride was 33.4 and 34 mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24 weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.
Early life dietary patterns and timely maturation of mucosa‐associated microbial communities are important factors influencing immune development and for establishing robust immune tolerance ...networks. Microbial fermentation of dietary components in vivo generates a vast array of molecules, some of which are integral components of the molecular circuitry that regulates immune and metabolic functions. These in turn protect against aberrant inflammatory processes and promote effector immune responses that quickly eliminate pathogens. Multiple studies suggest that changes in dietary habits, altered microbiome composition, and microbial metabolism are associated with asthma risk and disease severity. While it remains unclear whether these microbiome alterations are a cause or consequence of dysregulated immune responses, there is significant potential for using diet in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health. In this article, we will summarize our knowledge to date on the role of dietary patterns and microbiome activities on immune responses within the airways. Given the malleability of the human microbiome, its integration into the immune system, and its responsiveness to diet, this makes it a highly attractive target for therapeutic and nutritional intervention in children with asthma.
A well‐functioning 68 year old gentleman presented to our hospital with a macular rash 2 weeks after starting a course of Ciprofloxacin. There was rapid progression of skin involvement including the ...mucosa, complicated by pancytopaenia. Toxic Epidermal Necrolysis (TEN) was suspected and the patient was administered intravenous immunoglobulins and granulocyte colony stimulating factor. TEN was confirmed on skin biopsy and a lymphocyte transformation test demonstrated sensitisation to Ciprofloxacin. The patient developed multifocal pulmonary infiltrates with evidence of pulmonary involvement and probable pneumonia after 1 week and was treated with broad spectrum antibiotics. He also became dysphagic and suffered recurrent aspiration pneumonias. Follow up studies revealed fixed airways obstruction and features of bronchiolitis on computed tomography. This case highlights pulmonary involvement which can become a chronic complication of TEN, itself precipitated by the rare drug cause of Ciprofloxacin.
We describe infective pneumonia secondary to disruption of the bronchial epithelium from a severe case of Toxic Epidermal Necrolysis Syndrome (TENS). This syndrome was due to Ciprofloxacin which is a very rare cause. Our patient recovered well with conventional treatment of TENS and pneumonia.
Ivacaftor in a G551D homozygote with cystic fibrosis Harrison, Michael J; Murphy, Desmond M; Plant, Barry J
New England journal of medicine/The New England journal of medicine,
09/2013, Letnik:
369, Številka:
13
Journal Article
Objective: Information on the preferences of people with asthma for support in managing a flare-up can inform service design which may facilitate appropriate help-seeking. To date, little is known ...about support preferences for managing a flare-up. The aim of this study was to develop and pilot a discrete choice experiment (DCE) to elicit the preferences of people with asthma with regards to support in managing a flare-up.
Methods: Steps in developing the DCE included identification and selection of attributes and levels of the support services, construction of choice tasks, experimental design, construction of DCE instrument, and pretest (n=16) and pilot (n=38) studies of the DCE instrument. A multinomial logit model was used to examine the strength and direction of the six attributes in the pilot study.
Results: Our results indicate that from a patient perspective, having a healthcare professional that listens to their concerns was the most valued attribute of support in asthma flare-up management. The other features of support valued by participants were timely access to consultation, a healthcare professional with knowledge of their patient history, a specialist doctor and face-to-face communication. Having a written action plan was the least valued attribute.
Conclusions: Our findings suggest patient preference for a model of support in managing their symptoms which includes timely, face-to-face access to a healthcare professional that knows them and listens to their concerns. The findings of the pilot study need to be verified with a larger sample and using models to account for preference heterogeneity.
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