Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease.

BACKGROUND: Allergic diseases caused by fungi are common. The best understood conditions are allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Our knowledge of the fungal microbiome (mycobiome) is limited to a few studies involving healthy individuals, asthmatics, and smokers. No study has yet examined the mycobiome in fungal lung disease. OBJECTIVES: The main aim of this study was to determine the mycobiome in lungs of individuals with well-characterized fungal disease. A secondary objective was to determine possible effects of treatment on the mycobiome. METHODS: After bronchoscopy, ribosomal internal transcribed spacer region 1 DNA was amplified and sequenced and fungal load determined by real-time PCR. Clinical and treatment variables were correlated with the main species identified. Bronchopulmonary aspergillosis (n = 16), severe asthma with fungal sensitization (n = 16), severe asthma not sensitized to fungi (n = 9), mild asthma patients (n = 7), and 10 healthy control subjects were studied. RESULTS: The mycobiome was highly varied with severe asthmatics carrying higher loads of fungus. Healthy individuals had low fungal loads, mostly poorly characterized Malasezziales. The most common fungus in asthmatics was Aspergillus fumigatus complex and this taxon accounted for the increased burden of fungus in the high-level samples. Corticosteroid treatment was significantly associated with increased fungal load (P < .01). CONCLUSIONS: The mycobiome is highly variable. Highest loads of fungus are observed in severe asthmatics and the most common fungus is Aspergillus fumigatus complex. Individuals receiving steroid therapy had significantly higher levels of Aspergillus and total fungus in their bronchoalveolar lavage.

Development of chronic pulmonary aspergillosis in adult asthmatics with ABPA.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is an occasional complication of allergic bronchopulmonaryaspergillosis (ABPA) but the transition is poorly understood. METHODS: All patients referred to the UK's National Aspergillosis Centre with CPA between May 2009 and June 2012 were screened with serum total IgE and anti-Aspergillus IgE for a dual diagnosis of ABPA and CPA. Those patients suspected of having both conditions were re-evaluated and their imaging reviewed. RESULTS: Of 407 referred patients, 42 screened positive and 22 were confirmed as having both ABPA and CPA. Asthma was present from early childhood in 19 (86%), the median interval between ABPA and onset of CPA was 7.5 years; one patient developed ABPA and CPA simultaneously. Aspergillus IgG levels varied from 23 to 771 mg/L, median 82 mg/L. All 22 patients had bronchiectasis. In patients with ABPA, CT typically demonstrated varicose or cystic bronchiectasis primarily affecting segmental and proximal subsegmental upper lobe bronchi. Other findings included mucoid impaction and centrilobular nodules. Radiological changes associated with CPA included pleural thickening which was often bilateral and accentuated by adjacent hypertrophied extrapleural fat, upper lobe volume loss, thick walled apical cavities, some of which contained aspergillomas, and cavitating pulmonary nodules. CPA secondary to ABPA has more subtle radiological appearances than when due to other underlying diseases. CONCLUSIONS: CPA may complicate ABPA and have distinct radiology features, in addition to bronchiectasis. A novel biomarker is required to anticipate this serious complication, as current serology is not specific enough.

Efficacy and safety of nebulised amphotericin B (NAB) in severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA).

BACKGROUND AND RATIONALE: Antifungal therapy for severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) remains poorly studied. We assessed the efficacy and safety of NAB as second and third line therapy in SAFS and ABPA. METHODS: 21 adult asthmatics with SAFS (n = 11) and ABPA (n = 10) who had either failed itraconazole (n = 8), voriconazole proceeded by itraconazole (n = 5) or developed adverse events (AEs) to either agent (n = 7) were treated with 10mg of NAB (Fungizone) twice daily. We audited clinical and immunological response, using the Asthma Quality of Life Questionnaire (AQLQ-J) scores, asthma control, FEV1, healthcare utilisation and IgE. Patients were followed up for 12 months. RESULTS: Twenty-one patients were treated (SAFS, n = 11) and (ABPA, n = 10), M: F = 8:12, median age 65 years (range, 24-78). The median duration of therapy was 30 days (0-1825). Clinical benefit was observed in three (14.3 %) in which overall mean AQLQ-J score improved by + 2.9, mean FEV1 improved by 0.5 L and there was improvement in overall asthma control. Seven (33%) failed initial dose (bronchospasm). Eleven (52.4%) discontinued within 12 months of therapy due to delayed bronchospasm (n = 3, within 4 weeks), equipment problems (n = 2, within 4 weeks) and lack of clinical benefit (n = 4, within 16 weeks). CONCLUSION: Our data suggest that the overall efficacy of NAB in this group of patients is poor and associated with bronchospasm. However, the excellent response in 3 patients, suggest it may be considered when other alternatives have been exhausted. Overcoming the initial bronchospasm may improve tolerability.

Voriconazole and posaconazole improve asthma severity in allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization.

Rationale and objectives. Severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) are progressive allergic fungal lung diseases whose effective treatment remains to be established. Current treatment with itraconazole is associated with a 40% failure rate and adverse events (AEs). We assessed the effect of voriconazole or posaconazole as second- and third-line therapies. Methods. We conducted a retrospective review of adult asthmatic patients with either ABPA or SAFS receiving voriconazole or posaconazole. Clinical, radiological, and immunological evaluation was used to assess response. Results. There were 25 patients, ABPA (n = 20) or SAFS (n = 5), 10 males, median age = 58 years. All patients had failed itraconazole (n = 14) or developed AEs (n = 11). There were 33 courses of therapy analyzed, 24 with voriconazole and 9 with posaconazole. Clinical response to voriconazole was observed in 17/24 (70%) patients at 3 months, 15/20 (75%) at 6 months, and 12/16 (75%) at 12 months compared with 7/9 (78%) at 3, 6, and 12 months for posaconazole. Eighteen of 24 (75%) patients discontinued oral corticosteroids (OCS), 12 of them within 3 months of therapy. Asthma severity was downgraded from severe to moderate (n = 8) and moderate to mild (n = 1) asthma in 9 of 24 (38%) asthmatic patients. There was a marked reduction in OCS and short-acting beta-2 agonist use, health-care utilization due to asthma, and improvement in overall health status. Furthermore, there was a statistically significant reduction in immunological markers appearing at 9 months (p = .008) for total IgE and at 12 months for radioallergosorbent test IgE for Aspergillus fumigatus (p = .0056). Six of 23 (26%) patients on voriconazole had AEs requiring discontinuation before 6 months compared with none on posaconazole (p = .15). Four relapsed (57%), one at 3 months and three at 12 months after discontinuation. Conclusion. Both voriconazole and posaconazole are potentially effective alternative treatment options for SAFS and ABPA and may improve asthma control and reduce severity, though larger prospective studies are required to support these retrospective study findings.