The use of rhDNAse in severely ill, non-intubated adult asthmatics refractory to bronchodilators: a pilot study.
ABSTRACT Mucous plugging is associated with fatal asthma and may have a causative role for non-fatal cases of severe acute asthma. However, mucolytic agents have not been found effective in reversing the obstruction of acute asthma. We test the hypothesis that rhDNAse, an agent that reduces viscoelasticity of sputum in patients with cystic fibrosis, has a therapeutic role in acute asthma.
Symptomatic asthmatics aged 18-55 years presenting to an Emergency Department with an FEV(1) < 60% predicted after 2 nebulized albuterol and ipratropium treatments were included. Patients were randomized into one of three nebulized rhDNAse treatment groups of 2.5, 5.0 or 7.5 mg, or placebo. Standardized bronchodilator therapy was continued throughout the protocol and the FEV(1) at 6 h was the primary study endpoint.
50 patients were enrolled. There were no significant differences in FEV(1)% predicted between the rhDNAse and placebo patients at any of the post-randomization time points. The dose of rhDNAse administered did not influence response. In a post-hoc stratification, patients with the lowest pre-randomization FEV(1) tended to improve more from rhDNAse, particularly at times 60 and 120 min post-randomization.
In this pilot study rhDNAse did not cause clinical improvement among severely ill adults refractory to standardized care. The observed trend to higher FEV(1) among the most severely obstructed patients is an exploratory finding that may warrant further study. This clinical trial was registered as NCT00169962 under the name "Study of Pulmozyme to Treat Severe Asthma Episodes".
- BJA British Journal of Anaesthesia 06/2013; 110(6):1058-1059. · 4.24 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1β (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.The Journal of allergy and clinical immunology 02/2014; · 12.05 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The critical asthma syndrome (CAS) encompasses the most severe, persistent, refractory asthma patients for the clinician to manage. Personalized pharmacotherapy is necessary to prevent the next acute severe asthma exacerbation, not just the control of symptoms. The 2007 National Asthma Education and Prevention Program Expert Panel 3 provides guidelines for the treatment of uncontrolled asthma. The patient's response to recommended pharmacotherapy is highly variable which risks poor asthma control leading to frequent exacerbations that can deteriorate into CAS. Controlling asthma symptoms and preventing acute exacerbations may be two separate clinical activities with their own unique demands. Clinicians must be prepared to use the entire spectrum of asthma medications available but must concurrently be aware of potential drug toxicities some of which can paradoxically worsen asthma control. Medications normally prescribed for COPD can potentially be useful in the CAS patient, particularly those with asthma-COPD overlap syndrome. Immunomodulation with drugs like omalizumab in IgE-mediated asthma syndromes is one important approach. New and emerging drugs address unique aspects of airway inflammation and biology but at a significant financial cost. The pharmacology and toxicities of the agents that may be used in the treatment of CAS to control asthma symptoms and prevent severe exacerbations are reviewed.Clinical Reviews in Allergy & Immunology 11/2013; · 5.59 Impact Factor