Airway and Systemic Immunoglobulin Profiling and Immune Response in Adult Asthma.

INTRODUCTION: Immunoglobulins play a vital role in host immune response and in the pathogenesis of conditions like asthma. Therapeutic agents such as monoclonal antibodies target specific elements of the asthmatic inflammatory cascade. Decisions to utilize these medications are often based on systemic inflammatory profiling without direct insight into the airway inflammatory profile. We sought to investigate the relationship between immunoglobulin and cytokine profiles in the airway and systemic immune compartments of adult asthmatics. METHODS: Blood sampling and bronchoscopy with bronchoalveolar lavage (BAL) were performed in 76 well-defined adult asthmatics. Antibody and cytokine profiles were measured in both BAL and serum using ELISA and quantibody arrays. RESULTS: There was no relationship between BAL and serum levels of IgE. This is of significance in an asthma population. For some analytes, correlation analysis was significant (P < 0.05) indicating representativeness of our cohort and experimental setup in those cases. Nevertheless, the predictive power (r2) of the BAL-to-serum comparisons was mostly low except for TNF-α (r2 = 0.73) when assuming a simple (linear) relationship. CONCLUSION: This study highlights the importance of sample site when investigating the roles of immunoglobulins and cytokines in disease pathogenesis and suggests that both localized and systemic immune responses are at play. The prescription of asthma monoclonal therapy is generally based on systemic evaluation of cytokine and immunoglobulin levels. Our research suggests that this approach may not fully reflect the pathophysiology of the disease and may provide insight into why some patients respond to these targeted therapies while others do not.

Genomic Evolution of SARS-CoV-2 Virus in Immunocompromised Patient, Ireland.

We examined virus genomic evolution in an immunocompromised patient with prolonged severe acute respiratory syndrome coronavirus 2 infection. Genomic sequencing revealed genetic variation during infection: 3 intrahost mutations and possible superinfection with a second strain of the virus. Prolonged infection in immunocompromised patients may lead to emergence of new virus variants.

The presence of Aspergillus fumigatus in asthmatic airways is not clearly related to clinical disease severity.

BACKGROUND: It is suggested that airway fungi, in particular Aspergillus may impinge on clinical phenotype in asthma. Indeed, the term severe asthma with fungal sensitization (SAFS) has been coined. We aimed to ascertain whether the presence of fungi, in particular Aspergillus fumigatus, in the airway correlated with asthma severity and control. Furthermore, we aimed to determine whether traditional markers of Aspergillus sensitization related to the presence of Aspergillus within the airway. METHODS: Sixty-nine patients characterized by asthma severity (GINA) and level of control (ACQ-7) underwent bronchoscopy and bronchoalveolar lavage (BAL). Serum was assessed for A fumigatus-specific IgE and total IgE. Galactomannan and relevant cytokine levels were assessed in serum, plasma and BAL. BAL was analyzed for the presence of A fumigatus. RESULTS: In BAL, fungi were visible by microscopy in 70% and present by qPCR in 86% of patients, while A fumigatus was detectable by qPCR in 46%. Plasma and BAL IL-4, IL-6, IL-10, IL-13 and TNF-α correlated with BAL fungal presence, while plasma IL-17 correlated with BAL fungal presence. Aspergillus positive BAL correlated with increased plasma and BAL IL-6 and BAL IL-13. There was no relationship between fungal airway presence and steroid dose, asthma severity or control. The presence of Aspergillus within the airway did not relate to serum IgE positivity for Aspergillus. CONCLUSIONS: Fungi were present in a large proportion of our asthmatic patients' airways, but their presence was not predicted by traditional markers of sensitization, nor did it appear to be related to measures of disease severity or control.

A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled 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% versus 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.

Reduction in exhaled nitric oxide tracks improved patient inhaler compliance in difficult asthma-a case study.

INTRODUCTION: Exhaled nitric oxide is believed be a useful surrogate for airways inflammation while non-adherence with therapy is known to be associated with worsening of asthma control. CASE: We present the case of a 49-year-old female with steroid-dependent asthma and an exacerbation rate of >20/year. She was enrolled in a 3-month-long prospective study using a validated diagnostic inhaler device that provided objective evidence of inhaler compliance. Fractional exhaled nitric oxide (FeNO), peak expiratory flow rates, asthma control questionnaires were measured throughout the study period. Peripheral eosinophil count was obtained prior to the study, during the study, and immediately afterwards. RESULTS: Improvement in compliance at the end of the study led to significant improvements in lung function peak expiratory flow rate (PEFR), and objective scores of asthma. There was an observed improvement in PEFR after 4 weeks, with an associated decrease in FeNO from 92 to 9 ppb that plateaued over the remainder of the study. Her eosinophil count was 0.79 × 109/litre prior to starting in the study, 0.37 × 109/litre after 2 months, and 0.1 × 109/litre at the end of the study. CONCLUSION: We believe that this is the first case study to objectively prove that improvements in compliance can lead to dramatic reductions in the overall inflammatory airway response and in particular that improvements in patient compliance are mirrored by marked reduction in FeNO levels. These changes occurred in tandem with an observed clinical improvement in our patient.

'The Microbiome and the Pathophysiology of Asthma'.

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.

Breathlessness and Respiratory Disability After Kidney Transplantation.

BACKGROUND: Dyspnea is a common symptom in patients with end-stage kidney disease being treated with dialysis. This study aimed to ascertain the level of respiratory disability in patients after kidney transplantation through assessing a cohort of kidney allograft recipients for respiratory compromise and thereby identifying a potential target for therapeutic intervention. METHODS: Kidney transplant recipients who were under active observation in a single tertiary referral center were invited to take part in this prevalence study at the time of clinic follow-up. All patients agreed to take part in the study, which involved completing a Medical Research Council (MRC) dyspnea scale, completing the St George's Respiratory Questionnaire, and performing basic spirometry. An MRC score of ≥2 and/or a forced expiratory volume in 1 second <90% predicted prompted formal clinical assessment by a respiratory physician. RESULTS: This study enrolled 103 patients; 35% of all patients reported breathlessness, and 56% of all patients warranted formal respiratory medicine review. After completion of their investigations, 33 patients were found to have an underlying condition accounting for their symptoms. CONCLUSION: Our study highlights the issues of respiratory disability and breathlessness in patients who have undergone kidney transplantation. Although extensive cardiologic evaluation is performed routinely and can rule out many causes of dyspnea, respiratory assessment is not a preoperative prerequisite. This study could suggest that a formal pulmonological evaluation and basic spirometry should be part of the pretransplant evaluation of the kidney transplant recipient.

Effects of non-invasive respiratory support on gas exchange and outcomes in COVID-19 outside the ICU.

Non-invasive respiratory support (NRS) outside of the ICU has played an important role in the management of COVID-19 pneumonia. There is little data to guide selection of NRS modality. We present outcomes of NRS outside the ICU and discuss the effects of NRS on gas exchange with implications for management.

Current therapies for gastro-oesophageal reflux in the setting of chronic lung disease: state of the art review.

The inter-relationship between chronic respiratory disease and reflux disease in the airway reflux paradigm is extremely complex and remains poorly characterised. Reflux disease is reported to cause or contribute to the severity of a number of respiratory tract diseases including laryngeal disorders, sinusitis, chronic cough, asthma, COPD, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis and bronchiolitis obliterans post lung transplant. It is now appreciated that reflux disease is not simply caused by liquid acid reflux but rather by a variety of chemical refluxates originating from the stomach and duodenum due to a number of different mechanisms. Reflux disease can be challenging to diagnose, particularly proving its role in the causation of direct respiratory epithelial damage. Significant advances in oesophageal assessment and gastric biomarkers have emerged in recent years as our understanding increases. There are a number of treatments available for reflux disease, both medical and surgical, but there is a paucity of large randomised trials to evaluate their efficacy in the setting of chronic respiratory disease. Everyday clinical practice, however, informs us that treatment failure in reflux disease is common. This clinical review summarises associations between reflux disease in the setting of chronic respiratory diseases and examines available evidence regarding potential therapeutic strategies.

Post-tuberculosis mycetoma: bronchoscopic removal.

A 76-year-old male non-smoker presented to our institution with cough and haemoptysis. He had been treated for cavitatory pulmonary Mycobacterium tuberculosis of the right upper lobe 10 years previously. Chest radiograph and subsequent computed tomography (CT) of the chest demonstrated a right upper cavity containing a mass suspicious for mycetoma. Flexible bronchoscopy under conscious sedation demonstrated a mass obstructing the anterior segment of the right upper lobe. The abnormality was subsequently removed using a flexible endobronchial cryoprobe. Histopathological analysis demonstrated abundant fungal organisms morphologically consistent with Aspergillus species. Microbiological culture of the bronchoalveolar lavage (BAL) from the cavity isolated both Aspergillus fumigatus and Staphylococcus aureus. The patient was commenced on the anti-fungal drug posaconazole and received a course of flucloxacillin. Three months later, there was no endobronchial obstruction and lavage of the affected cavity again isolated Staphylococcus aureus without Aspergillus species. Repeat thoracic CT and flexible bronchoscopy demonstrated no further re-occurrence of the mycetoma at 3 months.

The Potential Role of Aspiration in the Asthmatic Airway.

BACKGROUND: Many people with asthma remain suboptimally controlled despite current treatments. Reasons include comorbidities that could aggravate asthma, including gastroesophageal reflux. We aimed to investigate whether aspiration occurs in patients with asthma and, if so, does it correlate with asthma control? METHODS: Patients had Asthma Control Questionnaire 7 (ACQ-7), fractional exhaled nitric oxide, and spirometry performed to characterize their level of asthma control. Barium swallow with provocation was performed to assess for predisposition to aspiration. Patients underwent bronchoscopic investigation, with BAL pepsin measured as a marker of aspiration. RESULTS: Seventy-eight patients stratified by disease severity (Global Initiative for Asthma) into mild (35.8%), moderate (21.7%) and severe (42.3%) were studied. Pepsin was detectable in BAL in 46/78 (58.9%). There were no differences between pepsin levels in patients with different disease severity. Furthermore, no significant associations were seen between pepsin level and measures of asthma control, FEV1, ACQ-7 or exacerbation frequency. Similarly no associations were found with adjustments for smoking history, BMI, proton pump inhibitor use, eosinophil count or IgE. When stratified into eosinophilic or neutrophilic asthmatic populations on the basis of BAL, there was no relationship to detected pepsin concentrations. A positive barium swallow (seen in 33/60 patients) did not correlate with BAL pepsin level and we found no significant association between barium swallow result and ACQ-7, Global Initiative for Asthma, exacerbation frequency or FEV1 using either univariate or multivariate analyses. CONCLUSIONS: This study suggests that the importance of aspiration on current asthma symptom control and exacerbation rate may be overstated. However, this study did not address the role of aspiration and future risk of exacerbation.

In patients with severe uncontrolled asthma, does knowledge of adherence and inhaler technique using electronic monitoring improve clinical decision making? A protocol for a randomised controlled trial.

INTRODUCTION: Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes. METHODS AND ANALYSIS: This prospective, randomised, multicentre study will compare the impact of using information on adherence to influence asthma treatment. Patients with severe uncontrolled asthma will be included. Data on adherence, inhaler technique and electronically recorded peak expiratory flow rate will be used to promote adherence and guide a clinical decision protocol to guide management in the active group. The control group will receive standard inhaler and adherence education. Medications will be adjusted using a protocol based on Global Initiativefor Asthma (GINA) recommendations. The primary outcome is the between-group difference in the proportion of patients who have refractory disease and are prescribed appropriate medications at the end of 32 weeks. A co-primary outcome is the difference between groups in the rate of adherence to salmeterol/fluticasone inhaler over the last 12 weeks. Secondary outcomes include changes in symptoms, lung function, type-2 cytokine biomarkers and clinical outcomes between both groups. Cost-effectiveness and cost-utility analyses of the INCA device intervention will be performed. The economic impact of a national implementation of the INCA-SUN programme will be evaluated. ETHICS AND DISSEMINATION: The results of the study will be published as a manuscript in peer-reviewed journals. The study has been approved by the ethics committees in the five participating hospitals. TRIAL REGISTRATION: NCT02307669; Pre-results.

A protocol for a randomised clinical trial of the effect of providing feedback on inhaler technique and adherence from an electronic device in patients with poorly controlled severe asthma.

INTRODUCTION: In clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma. METHODS: This is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05. TRIAL REGISTRATION NUMBER: NCT01529697; Pre-results.