Infrared molecular fingerprinting of blood-based liquid biopsies for the detection of cancer

Recent omics analyses of human biofluids provide opportunities to probe selected species of biomolecules for disease diagnostics. Fourier-transform infrared (FTIR) spectroscopy investigates the full repertoire of molecular species within a sample at once. Here, we present a multi-institutional study in which we analysed infrared fingerprints of plasma and serum samples from 1639 individuals with different solid tumours and carefully matched symptomatic and non-symptomatic reference individuals. Focusing on breast, bladder, prostate, and lung cancer, we find that infrared molecular fingerprinting is capable of detecting cancer: training a support vector machine algorithm allowed us to obtain binary classification performance in the range of 0.78–0.89 (area under the receiver operating characteristic curve [AUC]), with a clear correlation between AUC and tumour load. Intriguingly, we find that the spectral signatures differ between different cancer types. This study lays the foundation for high-throughput onco-IR-phenotyping of four common cancers, providing a cost-effective, complementary analytical tool for disease recognition

Identification of a novel SERPINA-1 mutation causing alpha-1 antitrypsin deficiency in a patient with severe bronchiectasis and pulmonary embolism

Katrin Milger,1 Lesca Miriam Holdt,2 Daniel Teupser,2 Rudolf Maria Huber,1 Jürgen Behr,1 Nikolaus Kneidinger1 1Department of Internal Medicine V, University of Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, 2Institute of Laboratory Medicine, University of Munich, Munich, Germany Abstract: Deficiency in the serine protease inhibitor, alpha-1 antitrypsin (AAT), is known to cause emphysema and liver disease. Other manifestations, including airway disease or skin disorders, have also been described. A 44-year-old woman presented to our emergency department with dyspnea and respiratory insufficiency. She had never smoked, and had been diagnosed with COPD 9 years earlier. Three months previously, she had suffered a pulmonary embolism. Chest computed tomography scan revealed severe cystic bronchiectasis with destruction of the lung parenchyma. The sweat test was normal and there was no evidence of the cystic fibrosis transmembrane conductance regulator (CFTR) mutation. Capillary zone electrophoresis showed a decrease of alpha-1 globin band and AAT levels were below the quantification limit (<25 mg/dL). No S or Z mutation was identified, but sequencing analysis found a homozygous cytosine and adenine (CA) insertion in exon 2 of the SERPINA-1 gene, probably leading to a dysfunctional protein (PI Null/Null). This mutation has not been previously identified. The atypical presentation of the patient, with severe cystic bronchiectasis, highlights AAT deficiency as a differential diagnosis in bronchiectasis. Further, awareness should be raised regarding a possible increased risk of thromboembolism associated with AAT deficiency. Keywords: alpha-1 antitrypsin deficiency, bronchiectasis, SERPINA-1 mutation, pulmonary embolis

Dupilumab improves asthma control and lung function in patients with insufficient outcome during previous antibody therapy.

Background: Biological treatments directed against IgE and IL-5 have largely improved outcomes for patients with severe type 2–high asthma. However, a fraction of patients with severe asthma show insufficient treatment outcome under anti-IgE and anti–IL-5/IL-5 receptor α antibodies. Objective: To evaluate whether switching to dupilumab was of benefit in patients with insufficient outcome under previous anti-IgE or anti–IL-5/IL-5 receptor α therapy. Methods: We retrospectively analyzed 38 patients who were switched to dupilumab from a previous anti-IgE or anti–IL-5/IL-5 receptor α medication because of insufficient outcome. We defined response criteria after 3 to 6 months as an improvement in at least 1 of the following criteria without deterioration in the other criteria, comparing values under dupilumab with values under previous antibody therapy: (1) increase of 3 or more in Asthma Control Test score, (2) 50% or more reduction in oral corticosteroid dose, and (3) FEV1 improvement greater than or equal to 150 mL, and classified patients as responders and nonresponders. Results: Switch to dupilumab led to a response in 76% of patients. In the total cohort, Asthma Control Test score increased by a mean of 2.9 (P < .0001), whereas exacerbations decreased significantly (P < .0001) and number of oral corticosteroid–dependent patients decreased from 15 to 12. Mean FEV1 improved by 305 mL (P < .0001). Median fractional exhaled nitric oxide decreased by −30 ppb (P < .0001), whereas eosinophil counts increased by 0.17 G/L (P < .01). There were no significant differences in clinical characteristics between responders and nonresponders to dupilumab. However, patients with increased fractional exhaled nitric oxide (≥25 ppb) during previous antibody therapy were more often responders than patients with low fractional exhaled nitric oxide (<25 ppb) (P < .05). Conclusions: Altogether, we show that a switch to dupilumab in patients with insufficient outcome under previous biological therapy was effective in most patients

Real-life effectiveness of biological therapies on symptoms in severe asthma with comorbid CRSwNP.

BACKGROUND: We aimed to evaluate the effectiveness of different antibody therapies on nasal polyp symptoms in patients treated for severe asthma. METHODS: We performed a retrospective analysis of patients with severe asthma and comorbid CRSwNP who were treated with anti-IgE, anti-IL-5/R or anti-IL-4R. CRSwNP symptom burden was evaluated before and after 6 months of therapy. RESULTS: Fifty patients were included hereof treated with anti-IgE: 9, anti-IL-5/R: 26 and anti-IL-4R: 15 patients. At baseline median SNOT-20 was similar among groups (anti-IgE: 55, anti-IL-5/R: 52 and anti-IL-4R: 56, p = 0.76), median visual analogue scale (VAS) for nasal symptoms was 4, 7 and 8 (p = 0.14) and VAS for total symptoms was higher in the anti-IL-4R group (4, 5 and 8, p = 0.002). After 6 months SNOT-20 improved significantly in all patient groups with median improvement of anti-IgE: -8 (p < 0.01), anti-IL-5/R: -13 (p < 0.001) and anti-IL-4R: -18 (p < 0.001), with larger improvement in the anti-IL-4R group than in anti-IgE (p < 0.001) and anti-IL-5/R (p < 0.001) groups. VAS nasal symptoms improved by median anti-IgE: 0 (n.s.), anti-IL-5/R: -1 (p < 0.01) and anti-IL-4R: -3 (p < 0.001), VAS total symptoms by anti-IgE: -1 (n.s.), anti-IL-5/R: -2 (p < 0.001) and anti-IL-4R: -2 (p < 0.001). CONCLUSIONS: Treatment by all antibodies showed effectiveness in reducing symptoms of CRSwNP in patients with severe asthma, with the largest reduction observed in anti-IL-4R-treated patients

The German Asthma Net: Anti-IL5(R) therapy reduces disease burden in a real-life severe asthma cohort in comparison to patients on maintenance OCS therapy

Bal C, Korn S, Milger-Kneidinger K, et al. The German Asthma Net: Anti-IL5(R) therapy reduces disease burden in a real-life severe asthma cohort in comparison to patients on maintenance OCS therapy. Pneumologie. 2023;77(S 01):S45

Overall response to anti-IL5/anti-IL5Rα treatment in severe asthma does not depend on initial bronchodilator responsiveness.

BACKGROUND: Positive bronchodilator responsiveness (BDR) (ΔFEV1≥+200ml and ≥+12%) after inhalation of short-acting beta-agonist (SABA) has been an inclusion criterion in licensing trials of anti-IL5/anti-IL5Rα biologics in severe asthma. However, in clinical practice patients with severe uncontrolled asthma frequently show a negative BDR. OBJECTIVE: To investigate whether the response to anti-IL5/anti-IL5Rα therapies differs between patients with positive and negative BDR at baseline. METHODS: Retrospective multicenter analysis of treatment outcomes in patients with severe asthma receiving anti-IL5/anti-IL5Rα stratified for baseline BDR. RESULTS: Of 133 patients included, 37 had a positive and 96 had a negative BDR at baseline. Following anti-IL5/anti-IL5Rα treatment FEV1 improved significantly in both groups compared to baseline (p<0.0001), with no significant difference between patients with positive and negative BDR (ΔFEV1 +493ml vs +306ml, p=0.06). FVC increased (ΔFVC: +85ml vs +650ml, p<0.01) and RV decreased (ΔRV +113ml vs -307ml, p<0.01) significantly in patients with negative BDR. Median annualized exacerbations (0 vs 0; p=0.7), reduction of exacerbation rate (Δexacerbations: 0 vs -2, p=0.07), continuous oral corticosteroid (OCS) use (Δpatients on OCS: -35% vs -39%, p=0.99) and improvement of asthma control test (ACT) score (ΔACT: 6 vs 5, p=0.7) were similar in both groups. Multivariate logistic regression analysis showed no significant correlations of positive vs negative BDR with response parameters. CONCLUSIONS: Both groups improved following treatment with similar responses concerning reduction of OCS therapy, exacerbations and improvement of symptom control. Pulmonary function also improved in both groups during anti-IL5/anti-IL5Rα treatment, with differences in response patterns noted

Bronchodilator reversibility in patients with severe asthma included in the GAN registry

Milger-Kneidinger K, Muemmler C, Skowasch D, et al. Bronchodilator reversibility in patients with severe asthma included in the GAN registry. Pneumologie. 2022;76(S01):S27.Background Bronchodilator reversibility is a diagnostic criterion for asthma. However, patients with asthma may exhibit irreversible obstruction for various reasons including long-standing uncontrolled disease with airway remodeling or beta-2 receptor down-regulation caused by frequent use of inhaled short acting beta2-agonist (SABA). Aim This study aims to describe frequency of negative bronchodilator reversibility in patients with severe asthma and associations with other phenotypic characteristics. Methods Bronchodilator testing was performed according to guideline recommendations, with patients being advised to pause asthma and other interfering treatments before testing. Significant bronchodilator reversibility was defined as FEV1 increase > 200ml AND > 12% upon testing with SABA and/or short-acting muscarinic antagonist (SAMA). Results Bronchodilator reversibility results were available from 793 of the 2013 patients included in the GAN registry. Hereof, 250 (31.5%) had significant reversibility, while 543 (68.5%) were classified irreversible. Comparing patients with reversible and irreversible obstruction, sex (52% vs 56%), mean age (49.6 vs 50.0 years), smoking history (non: 57.2% vs 56.1%; active: 2.8% vs 2.2%; ex: 40% vs 41.7%), COPD comorbidity (5.2% vs 7.2%) and BMI (27.2 vs 27.5kg/m2) were similar in both groups. Comorbidities significantly associated with irreversible obstruction were: gastro-esophageal reflux (GERD), eosinophilic granulomatosis and polyangiitis (EGPA) and history of sinus surgery (p<0.05). Patients with reversible obstruction reported dyspnea at rest (27% vs 16%) and chest tightness (36% vs 26%) more frequently, had more severe obstruction at baseline (FEV1: 56% pred. vs. 64% pred.) and higher median FeNO levels (41ppb vs 33ppb, all p<0.05), while diffusion capacity did not differ (70% vs 71%). Conclusion In this real-life setting the majority of patients with severe asthma exhibited negative bronchodilator reversibility. Irreversible obstruction was associated with lower FeNO levels and history of GERD, EGPA and sinus surgery

Lung volumes predict survival in patients with chronic lung allograft dysfunction.

Identification of disease phenotypes might improve the understanding of patients with chronic lung allograft dysfunction (CLAD). The aim of the study was to assess the impact of pulmonary restriction and air trapping by lung volume measurements at the onset of CLAD.A total of 396 bilateral lung transplant recipients were analysed. At onset, CLAD was further categorised based on plethysmography. A restrictive CLAD (R-CLAD) was defined as a loss of total lung capacity from baseline. CLAD with air trapping (AT-CLAD) was defined as an increased ratio of residual volume to total lung capacity. Outcome was survival after CLAD onset. Patients with insufficient clinical information were excluded (n=95).Of 301 lung transplant recipients, 94 (31.2%) developed CLAD. Patients with R-CLAD (n=20) and AT-CLAD (n=21), respectively, had a significantly worse survival (p&lt;0.001) than patients with non-R/AT-CLAD. Both R-CLAD and AT-CLAD were associated with increased mortality when controlling for multiple confounding variables (hazard ratio (HR) 3.57, 95% CI 1.39-9.18; p=0.008; and HR 2.65, 95% CI 1.05-6.68; p=0.039). Furthermore, measurement of lung volumes was useful to identify patients with combined phenotypes.Measurement of lung volumes in the long-term follow-up of lung transplant recipients allows the identification of patients who are at risk for worse outcome and warrant special consideration