Treatment-refractory Asthma Research Articles

IMPACT OF ALLERGEN SENSITIZATION ON AIRFLOW LIMITATION IN CHILDREN WITH SEVERE ASTHMA

<h3>Introduction</h3> Airflow limitation (AFL) has been shown to predict poor asthma outcomes across maturation. The objective of our study is to identify significant predictors of AFL in children with severe asthma from school-age to adolescence. <h3>Methods</h3> Children ages 5-18 years with treatment-refractory asthma underwent spirometry and diagnostic bronchoscopy. AFL was defined as pre-bronchodilator FEV₁/FVC <0.85 or <90% predicted. Demographics, treatments, and blood and lung markers of inflammation were analyzed with between group non-parametric tests and logistic regression models. <h3>Results</h3> 226 children were included in this analysis. Nearly one-half (n=105, 46%) had AFL. There was no difference in age, gender, BMI, or age of symptom onset between groups. Compared to children without AFL, those with AFL were more likely to have previous ICU admission for asthma, treatment with higher-dose inhaled corticosteroids (ICS), and reported black race. Children with AFL had significantly higher total blood and bronchoalveolar lavage (BAL) eosinophil count, total IgE, and greater number of positive allergen specific serum IgE. In younger children, those with sensitization to ≥4 allergens had greater airflow limitation but the opposite relationship was seen in adolescent children. Similarly, the effects of higher total IgE (>130 IU/mL) on airflow limitation were most prominent in younger children. <h3>Conclusion</h3> Significant predictors of airflow limitation in children with severe asthma include black race, previous ICU admission for asthma, higher-dose ICS treatment, and increased absolute blood and BAL eosinophil count. AFL is driven in part by allergic sensitization in the younger children whereas in older children this associated more with the absence of allergic sensitization.

P38 Dupilumab Improves Quality of Life in Caregivers of Children with Uncontrolled Moderate-to-Severe Asthma: Liberty Asthma Voyage Study

Children with uncontrolled treatment-refractory asthma have poor quality of life (QoL), which also affects their caregivers. Dupilumab blocks interleukin (IL)-4/IL-13 signaling, key and central drivers of type 2 inflammation. In VOYAGE, a 52-week (wk), randomized, double-blind, placebo-controlled phase–3 study (NCT02948959), add-on dupilumab demonstrated efficacy/safety in children aged 6–11 years with uncontrolled moderate-to-severe type 2 asthma. This analysis assessed QoL in caregivers of pediatric participants in VOYAGE.

Low Bronchoalveolar Lavage Absolute Granulocytes Differentiate A Novel Phenotype of Children with Severe Asthma: Decreased Allergen Sensitization and Normal Lung Function

Lung granulocyte patterns are useful to select therapies for patients with treatment-refractory asthma. Although common, little is known about the clinical features of patients with a pauci-granulocytic phenotype. The purpose of this analysis was to define differentiating clinical features in children with pauci-granulocytic asthma.

Expression of IL-5 receptor alpha by murine and human lung neutrophils.

The role of eosinophilia in atopic diseases, including asthma, is well established, as is the well-known role of IL-5 as a major eosinophilopoeitin and chemoattractant. Following influenza A virus infection of mice, type 2 innate lymphoid cells are recruited to the respiratory tract and produce large quantities of IL-5, which contributes to the recruitment of eosinophils into the infected lungs during the recovery phase of infection. We demonstrate here that while IL-5 is required for optimal recovery from influenza A virus infection in BALB/c and C57BL/6 mice, the protective effect of IL-5 is independent of eosinophils, suggesting an alternative cellular target. We describe the unexpected finding of IL-5 receptor alpha (CD125) expression on neutrophils infiltrating the inflamed mouse lungs, as well as on neutrophils at other anatomic sites. We extend this finding of neutrophil CD125 expression to humans, specifically to neutrophils found in the bronchoalveolar lavage fluid from the inflamed lungs of children with treatment-refractory asthma. We further demonstrate that the IL-5 receptor on neutrophils is capable of signal transduction. Our data provide further evidence that neutrophils can play a role bridging atopic type 2 and innate anti-microbial immunity.

“Two Stones on One Bird”: A Case Report on Severe Biphasic Anaphylaxis Masquerading as Life-Threatening Acute Asthma

BACKGROUND:Anaphylaxis often misdiagnosed and treated as acute asthma, especially when it has a predominant respiratory symptom, and there are no obvious precipitants or previous allergic history. This morbid outcome is preventable if the level of suspicion for anaphylaxis is high among healthcare provider when treating a patient who is not responding to the standard management of acute asthma. A proportion of anaphylactic patient shows a biphasic reaction which potentially fatal when it is under-anticipated and prematurely discharge without adequate observation period after the recovery of the initial episode.CASE REPORT:Here, we present a case of a young man who has childhood asthma with the last attack more than 10 years ago presented with symptoms suggestive of acute exacerbation of bronchial asthma. As the symptoms failed to improve after standard asthma management, anaphylaxis was suspected, and he was given intramuscular adrenaline 0.5 mg which leads to symptom improvement. However, he developed another attack shortly after improvement while under observation.CONCLUSION:The objective of this case report is to emphasise the importance of keeping anaphylaxis in mind whenever a patient has treatment-refractory asthma, and also the anticipation of biphasic reaction that warrants adequate observation period especially those who are likely to have developed it.

Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice.

Patients with severe, treatment-refractory asthma are at risk for death from acute exacerbations. The cytokine IL17A has been associated with airway inflammation in severe asthma, and novel therapeutic targets within this pathway are urgently needed. We recently showed that IL17A increases airway contractility by activating the procontractile GTPase RhoA. Here, we explore the therapeutic potential of targeting the RhoA pathway activated by IL17A by inhibiting RhoA guanine nucleotide exchange factors (RhoGEFs), intracellular activators of RhoA. We first used a ribosomal pulldown approach to profile mouse airway smooth muscle by qPCR and identified Arhgef12 as highly expressed among a panel of RhoGEFs. ARHGEF12 was also the most highly expressed RhoGEF in patients with asthma, as found by RNA sequencing. Tracheal rings from Arhgef12-KO mice and WT rings treated with a RhoGEF inhibitor had evidence of decreased contractility and RhoA activation in response to IL17A treatment. In a house dust mite model of allergic sensitization, Arhgef12-KO mice had decreased airway hyperresponsiveness without effects on airway inflammation. Taken together, our results show that Arhgef12 is necessary for IL17A-induced airway contractility and identify a therapeutic target for severe asthma.

Models of care for severe asthma: the role of primary care.

Severe asthma encompasses treatment-refractory asthma and difficult-to-treat asthma. There are a number of barriers in primary, secondary and tertiary settings which compromise optimal care for severe asthma in Australia. Guidelines recommend a multidimensional assessment of severe asthma, which includes confirming the diagnosis, severity and phenotype and identifying and treating comorbidities and risk factors. This approach has been found to improve severe asthma symptoms and quality of life and reduce exacerbations. Primary care providers can contribute significantly to the multidimensional approach for severe asthma by performing spirometry, optimising therapy and addressing risk factors such as non-adherence and smoking before referring the patient to a respiratory physician for review. Primary care practitioners are encouraged to remain engaged with the management of a patient with severe asthma following specialist review by assisting with community-based allied health referrals, managing general medical comorbidities and administering prescribed biological therapies. Specialists can support primary care by providing advice to individuals with indeterminate diagnosis, streamlining investigation and management of unrecognised risk factors and complex comorbidities, optimising treatment for severe or difficult asthma including assessment of suitability for and, if appropriate, initiating advanced therapies such as biological therapies. When discharging patients back to primary care, specialists should provide clear recommendations regarding ongoing management and should specify the indications requiring further specialist review, ideally offering a streamlined re-referral pathway.

IL-5Rα expression on airway neutrophils in children with treatment-refractory asthma

IL-5Rα expression on airway neutrophils in children with treatment-refractory asthma

TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status

The pathogenesis of severe asthma in childhood remains poorly understood. We sought to construct the immunologic landscape in the airways of children with severe asthma. Comprehensive analysis of multiple cell types and mediators was performed by using flow cytometry and a multiplex assay with bronchoalveolar lavage (BAL) specimens (n=68) from 52 highly characterized allergic and nonallergic children (0.5-17years) with severe treatment-refractory asthma. Multiple relationships were tested by using linear mixed-effects modeling. Memory CCR5+ TH1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ+IL-17+ and IFN-γ-IL-17+ subsets constituted secondary TH types, and BAL fluid CD8+ T cells were almost exclusively IFN-γ+. The TH17-associated mediators IL-23 and macrophage inflammatory protein 3α/CCL20 were highly expressed. Despite low TH2 numbers, TH2 cytokines were detected, and TH2 skewing correlated with total IgE levels. Type 2 innate lymphoid cells and basophils were scarce in BAL fluid. Levels of IL-5, IL-33, and IL-28A/IFN-λ2 were increased in multisensitized children and correlated with IgE levels to dust mite, ryegrass, and fungi but not cat, ragweed, or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE+FcεRI+ myeloid dendritic cells were present in BAL fluid. The lower airways of children with severe asthma display a dominant TH1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of TH1 cells in patients with severe asthma.

Novel assessment tool to detect breathing pattern disorder in patients with refractory asthma.

Breathing pattern disorder (BPD) can co-exist with and mimic asthma, acting to amplify symptoms and confound assessment of disease control, resulting in inappropriate treatment escalation. The aim of this research was to report the utility of a novel breathing pattern assessment tool (BPAT) to detect BPD in treatment-refractory asthma. As a component of a multidisciplinary assessment, adult patients referred with treatment-refractory asthma underwent respiratory physiotherapy assessment to diagnose BPD. Based on this assessment, patients were classified as having asthma, asthma + BPD or BPD alone. BPAT data were collected in addition to questionnaire data (Asthma Quality of Life Questionnaire (AQLQ) and Nijmegen Questionnaire (NQ)), pulmonary function and an assessment of exercise capacity. Data were retrospectively analysed for 150 (female; 69%) patients, mean (SD) age of 43 (14) years; characterized as asthma-only (n = 54, 36%), asthma + BPD (n = 63, 42%) and BPD-only (n = 33, 22%). Of the total population, 113 (76%) had an NQ score ≥23, but of these only 68% had physiotherapy evidence of BPD. Exercise capacity and AQLQ were lower in the asthma + BPD group than in the asthma-only group (P < 0.05), whilst lung function was similar between groups. Sensitivity analysis indicated that a BPAT score of ≥4 corresponded to a sensitivity of 0.92 and a specificity of 0.75 for diagnosis of BPD in this cohort. Breathing pattern irregularities are highly prevalent in individuals referred with treatment-refractory asthma and can be characterized using the BPAT. Further work is needed to determine inter-observer and within-subject variability and ensure the BPAT is a robust clinical tool. Watch the video abstract.

Biologics in practice: A unique opportunity for allergist/immunologist expertise

Biologics in practice: A unique opportunity for allergist/immunologist expertise

Diagnostic challenges of adult asthma.

Bronchial asthma is a common disorder that affects about 300 million people worldwide. Its signs and symptoms however, can be present in other pulmonary and/or airway diseases and therefore a careful workup of patients with respiratory symptoms that might be due to asthma is required to a) keep a broad differential diagnosis, especially in cases that do not respond well to standard antiasthmatic therapy and b) attempt to subphenotype patients within the syndrome of asthma to diagnose e.g. precipitating factors, inflammatory subtypes and comorbidities. The syndrome of asthma contains a number of different phenotypes that offer the possibility of personalized medicine based on the respective asthma phenotype. There are attempts to combine asthma and COPD in newly postulated overlap syndromes which this review discourages to do but instead, based on new and old information concerning asthma phenotyping, suggests to rule in comorbidities and rule out a number of other diseases that can mimick asthma clinically. Bronchial asthma, although one of the most common respiratory diseases, can be mimicked by a number of other pulmonary and airway diseases, and especially patients with so called severe or treatment refractory asthma should receive a detailed diagnostic workup with a rather broad differential diagnosis.

P47 Continuous Laryngoscopy During Exercise (cle): A Practical And Valuable Test In A Respiratory Service?

Introduction and rationale Exertional wheeze and dyspnoea are most frequently attributed to exercise induced bronchoconstriction (EIB), yet may arise secondarily to a temporary closure of the larynx. This condition, termed Exercise induced laryngeal obstruction (EILO), is best characterised by the gold standard technique of direct and continuous laryngoscopy during exercise (CLE). To date most descriptions of the utility of CLE are in young highly athletic populations. Objectives Assessment of the safety, utility and application of CLE in subjects with unexplained and/or disproportionate exertional dyspnoea in a general respiratory population (i.e. not confined to athletes). Methods and measurements Patients referred for CLE with unexplained breathlessness and other respiratory diagnosis including treatment refractory asthma and COPD were identified. Thereafter clinical and physiological assessments were reviewed. Results In total 83 referrals (October 2012–February 2014) for CLE studies were analysed. The overall median (range) age was 43 (17–71) years. The majority of subjects were female (n = 56). Only a total of 4 (5%) subjects were athletes. We made a diagnosis of EILO in 30 (36%) of subjects studied. Prior to CLE 32 (39%) had been given a diagnosis of EIB, and of these we identified 17 (53%) actually had a diagnosis of EILO. Only one minor complication (pre-syncopal episode) was encountered during the procedure. Conclusion CLE is a safe effective method for the assessment of disproportionate exercise induced dyspnoea. It is a sensitive diagnostic tool and should not be reserved for use in a highly athletic population. It appears to be particularly useful in patients diagnosed with EIB who are not responding to treatment. Therapeutic intervention in the form of physiotherapy once the diagnosis is made offers the potential for symptomatic improvement and the withdrawal of unneeded pharmacological agents.

Treatment of severe asthma: expert opinion

Severe asthmatics account 10% of the all asthmatic population. Those asthmatics whose disease is inadequately controlled account for up to half of the cost for asthma, because they have more emergency room visits, more hospital admission and greater absenteeism from work. New therapeutic options were tried in those patients whose asthma was uncontrolled with standart high dose inhaled corticosteroid and long acting beta-2 agonsit combination therapy. In this paper taking into account the conditions of our country, current literature was reviewed and treatment options was discussed and graded recommendations are made for daily clinical practice in patients with severe treatment-refractory asthma.

Unusual asthma syndromes and their management.

Asthma usually presents with symptoms of wheeze, dyspnoea and cough. However, clinicians should be aware of atypical presentation of this disorder when cough is the main or only symptom in conditions such as cough-variant asthma, nonasthmatic eosinophilic bronchitis and atopic cough. Early diagnosis and treatment of these conditions with inhaled corticosteroids improves symptoms in the majority of patients. Up to 10% of patients with asthma remain poorly controlled in spite of optimal standard therapy. These patients have been encompassed under the term 'treatment-refractory asthma' (TRA), have the greatest morbidity and are responsible for more than 50% of healthcare costs. In this review we discuss investigations, management and pathophysiology of the various phenotypes of atypical presentations of asthma as well as novel biological agents licensed and those that have been reported in clinical trials in terms of their efficacy and safety in TRA.

Psychogenic Respiratory Distress: A Case of Paradoxical Vocal Cord Dysfunction and Literature Review.

BACKGROUND: Pulmonary disease such as asthma is a psychosomatic disorder vulnerable to exacerbations precipitated by psychological factors. A case is described in which a patient thought to have treatment-refractory asthma was discovered to have a conversion reaction, specifically paradoxical vocal cord dysfunction (PVCD), characterized by abnormal vocal cord adduction during inspiration. DATA SOURCES: Reports of PVCD were located using a MEDLINE search and review of bibliographies. MEDLINE (English language only) was searched from 1966 through December 1998 using the terms functional asthma, functional upper airway obstruction, laryngeal diseases, Munchausen's stridor, paradoxical vocal cord dysfunction, psychogenic stridor, respiratory stridor, vocal cord dysfunction, and vocal cord paralysis. A total of 170 cases of PVCD were reviewed. STUDY FINDINGS: PVCD appears to be significantly more common among females. PVCD spans all age groups, including pediatric, adolescent, and adult patients. PVCD was most often misdiagnosed as asthma or upper airway disease. Because patients present with atypical and/or refractory symptoms, several diagnostic tests are employed to evaluate patients with PVCD; laryngoscopy is the most common. Direct visualization of abnormal vocal cord movement is the most definitive means of establishing the diagnosis of PVCD. A number of psychiatric disturbances are related to PVCD, including conversion and anxiety disorders. PVCD is associated with severe psychosocial stress and difficulties with modulation of intense emotional states. CONCLUSIONS: Psychogenic respiratory distress produced by PVCD can be easily misdiagnosed as severe or refractory asthma or other pulmonary disease states. Recognition of PVCD is important to avoid unnecessary medications and invasive treatments. Primary care physicians can detect cases of PVCD by attending to clinical symptoms, implementing appropriate laboratory investigations, and examining the psychological covariates of the disorder. Psychotherapy and speech therapy are effective in treating most cases of PVCD.