Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids.

Rationale: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure. Methods: Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study. Measurements and main results: The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were <5% of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high-dose ICS only, were more suppressed in females than males (p<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12-18 months. Conclusion: The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.

Developments in the Management of Severe Asthma in Children and Adolescents: Focus on Dupilumab and Tezepelumab.

Severe asthma in children and adolescents exerts a substantial health, financial, and societal burden. Severe asthma is a heterogeneous condition with multiple clinical phenotypes and underlying inflammatory patterns that might be different in individual patients. Various add-on treatments have been developed to treat severe asthma, including monoclonal antibodies (biologics) targeting inflammatory mediators. Biologics that are currently approved to treat children (≥ 6 years of age) or adolescents (≥ 12 years of age) with severe asthma include: anti-immunoglobulin E (omalizumab), anti-interleukin (IL)-5 (mepolizumab), anti-IL5 receptor (benralizumab), anti-IL4/IL13 receptor (dupilumab), and antithymic stromal lymphopoietin (TSLP) (tezepelumab). However, access to these targeted treatments varies across countries and relies on few and crude indicators. There is a need for better treatment stratification to guide which children might benefit from these treatments. In this narrative review we will assess the most recent developments in the treatment of severe pediatric asthma, as well as potential biomarkers to assess treatment efficacy for this patient population.

Real-World Effectiveness of IL-5/5Ra Targeted Biologics in Severe Eosinophilic Asthma With Comorbid Bronchiectasis.

BACKGROUND: Bronchiectasis is a common comorbidity in patients with asthma and is associated with increased disease severity. In patients with severe eosinophilic asthma, biologics targeting IL-5/5Ra have beneficial effects on oral corticosteroid (OCS) use and exacerbation frequency. However, how coexisting bronchiectasis affects the response to such treatments is unknown. OBJECTIVE: To evaluate the real-world effectiveness of anti-IL-5/5Ra therapy in patients with severe eosinophilic asthma and comorbid bronchiectasis on exacerbation frequency and daily maintenance and cumulative OCS dose. METHODS: This real-world study evaluated data from 97 adults with severe eosinophilic asthma and computed tomography-confirmed bronchiectasis from the Dutch Severe Asthma Registry, who initiated anti-IL5/5Ra biologics (mepolizumab, reslizumab, and benralizumab) and had follow-up data for 12 months or greater. The analysis was performed for the total population and subgroups with or without maintenance OCS use. RESULTS: Anti-IL-5/5Ra therapy significantly reduced exacerbation frequency in patients with maintenance OCS use as well as in those without it. In the year before biologic initiation, 74.5% of all patients had two or more exacerbations, which decreased to 22.1% in the follow-up year (P < .001). The proportion of patients on maintenance OCS decreased from 47% to 30% (P < .001), and in the OCS-dependent patients (n = 45) maintenance OCS dose decreased from median (interquartile range) of 10.0 mg/d (5-15 mg/d) to 2.5 mg/d (0-5 mg/d) after 1 year (P < .001). CONCLUSIONS: This real-world study shows that anti-IL-5/5Ra therapy reduces exacerbation frequency and daily maintenance as well as the cumulative OCS dose in patients with severe eosinophilic asthma and comorbid bronchiectasis. Although it is an exclusion criterion in phase 3 trials, comorbid bronchiectasis should not preclude anti-IL-5/5Ra therapy in patients with severe eosinophilic asthma.

Current and future developments in the pharmacology of asthma and COPD: ERS seminar, Naples 2022.

Pharmacological management of airway obstructive diseases is a fast-evolving field. Several advances in unravelling disease mechanisms as well as intracellular and molecular pathways of drug action have been accomplished. While the clinical translation and implementation of in vitro results to the bedside remains challenging, advances in comprehending the mechanisms of respiratory medication are expected to assist clinicians and scientists in identifying meaningful read-outs and designing clinical studies. This European Respiratory Society Research Seminar, held in Naples, Italy, 5-6 May 2022, focused on current and future developments of the drugs used to treat asthma and COPD; on mechanisms of drug action, steroid resistance, comorbidities and drug interactions; on prognostic and therapeutic biomarkers; on developing novel drug targets based on tissue remodelling and regeneration; and on pharmacogenomics and emerging biosimilars. Related European Medicines Agency regulations are also discussed, as well as the seminar's position on the above aspects.

Characteristics of severe asthma patients on biologics: a real-life European registry study.

Background: The use of anti-interleukin-5 (IL5) for severe asthma is based on criteria from randomised controlled trials (RCTs), but in real-life patients might not fulfil the eligibility criteria but may benefit from biologics. We aimed to characterise patients starting anti-IL5(R) in Europe and evaluate the discrepancies between initiation of anti-IL5(R) in real life and in RCTs. Materials and methods: We performed a cross-sectional analysis with data from the severe asthma patients at the start of anti-IL5(R) in the Severe Heterogeneous Asthma Research collaboration Patient-centred (SHARP Central) registry. We compared the baseline characteristics of the patients starting anti-IL5(R) from 11 European countries within SHARP with the baseline characteristics of the severe asthma patients from 10 RCTs (four for mepolizumab, three for benralizumab and three for reslizumab). Patients were evaluated following eligibility criteria from the RCTs of anti-IL5 therapies. Results: Patients starting anti-IL5(R) in Europe (n=1231) differed in terms of smoking history, clinical characteristics and medication use. The characteristics of severe asthma patients in the SHARP registry differed from the characteristics of patients in RCTs. Only 327 (26.56%) patients fulfilled eligibility criteria of all the RCTs; 24 patients were eligible for mepolizumab, 100 for benralizumab and 52 reslizumab. The main characteristics of ineligibility were: ≥10 pack-years, respiratory diseases other than asthma, Asthma Control Questionnaire score ≤1.5 and low-dose inhaled corticosteroids. Conclusion: A large proportion of patients in the SHARP registry would not have been eligible for anti-IL5(R) treatment in RCTs, demonstrating the importance of real-life cohorts in describing the efficacy of biologics in a broader population of patients with severe asthma.

Identifying risk factors for COPD and adult-onset asthma: an umbrella review.

BACKGROUND: COPD and adult-onset asthma (AOA) are the most common noncommunicable respiratory diseases. To improve early identification and prevention, an overview of risk factors is needed. We therefore aimed to systematically summarise the nongenetic (exposome) risk factors for AOA and COPD. Additionally, we aimed to compare the risk factors for COPD and AOA. METHODS: In this umbrella review, we searched PubMed for articles from inception until 1 February 2023 and screened the references of relevant articles. We included systematic reviews and meta-analyses of observational epidemiological studies in humans that assessed a minimum of one lifestyle or environmental risk factor for AOA or COPD. RESULTS: In total, 75 reviews were included, of which 45 focused on risk factors for COPD, 28 on AOA and two examined both. For asthma, 43 different risk factors were identified while 45 were identified for COPD. For AOA, smoking, a high body mass index (BMI), wood dust exposure and residential chemical exposures, such as formaldehyde exposure or exposure to volatile organic compounds, were amongst the risk factors found. For COPD, smoking, ambient air pollution including nitrogen dioxide, a low BMI, indoor biomass burning, childhood asthma, occupational dust exposure and diet were amongst the risk factors found. CONCLUSIONS: Many different factors for COPD and asthma have been found, highlighting the differences and similarities. The results of this systematic review can be used to target and identify people at high risk for COPD or AOA.

Prospective Detection of Early Lung Cancer in Patients With COPD in Regular Care by Electronic Nose Analysis of Exhaled Breath.

BACKGROUND: Patients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD. RESEARCH QUESTION: Can eNose technology be used for prospective detection of early lung cancer in patients with COPD? STUDY DESIGN AND METHODS: BreathCloud is a real-world multicenter prospective follow-up study using diagnostic and monitoring visits in day-to-day clinical care of patients with a standardized diagnosis of asthma, COPD, or lung cancer. Breath profiles were collected at inclusion in duplicate by a metal-oxide semiconductor eNose positioned at the rear end of a pneumotachograph (SpiroNose; Breathomix). All patients with COPD were managed according to standard clinical care, and the incidence of clinically diagnosed lung cancer was prospectively monitored for 2 years. Data analysis involved advanced signal processing, ambient air correction, and statistics based on principal component (PC) analysis, linear discriminant analysis, and receiver operating characteristic analysis. RESULTS: Exhaled breath data from 682 patients with COPD and 211 patients with lung cancer were available. Thirty-seven patients with COPD (5.4%) demonstrated clinically manifest lung cancer within 2 years after inclusion. Principal components 1, 2, and 3 were significantly different between patients with COPD and those with lung cancer in both training and validation sets with areas under the receiver operating characteristic curve of 0.89 (95% CI, 0.83-0.95) and 0.86 (95% CI, 0.81-0.89). The same three PCs showed significant differences (P < .01) at baseline between patients with COPD who did and did not subsequently demonstrate lung cancer within 2 years, with a cross-validation value of 87% and an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.84-0.95). INTERPRETATION: Exhaled breath analysis by eNose identified patients with COPD in whom lung cancer became clinically manifest within 2 years after inclusion. These results show that eNose assessment may detect early stages of lung cancer in patients with COPD.

Pulmonary Oxygen Toxicity Through Exhaled Breath Markers After Hyperbaric Oxygen Treatment Table 6.

Introduction: The hyperbaric oxygen treatment table 6 (TT6) is widely used to manage dysbaric illnesses in divers and iatrogenic gas emboli in patients after surgery and other interventional procedures. These treatment tables can have adverse effects, such as pulmonary oxygen toxicity (POT). It is caused by reactive oxygen species' damaging effect in lung tissue and is often experienced after multiple days of therapy. The subclinical pulmonary effects have not been determined. The primary aim of this study was to measure volatile organic compounds (VOCs) in breath, indicative of subclinical POT after a TT6. Since the exposure would be limited, the secondary aim of this study was to determine whether these VOCs decreased to baseline levels within a few hours. Methods: Fourteen healthy, non-smoking volunteers from the Royal Netherlands Navy underwent a TT6 at the Amsterdam University Medical Center-location AMC. Breath samples for GC-MS analysis were collected before the TT6 and 30 min, 2 and 4 h after finishing. The concentrations of ions before and after exposure were compared by Wilcoxon signed-rank tests. The VOCs were identified by comparing the chromatograms with the NIST library. Compound intensities over time were tested using Friedman tests, with Wilcoxon signed-rank tests and Bonferroni corrections used for post hoc analyses. Results: Univariate analyses identified 11 compounds. Five compounds, isoprene, decane, nonane, nonanal and dodecane, showed significant changes after the Friedman test. Isoprene demonstrated a significant increase at 30 min after exposure and a subsequent decrease at 2 h. Other compounds remained constant, but declined significantly 4 h after exposure. Discussion and Conclusion: The identified VOCs consisted mainly of (methyl) alkanes, which may be generated by peroxidation of cell membranes. Other compounds may be linked to inflammatory processes, oxidative stress responses or cellular metabolism. The hypothesis, that exhaled VOCs would increase after hyperbaric exposure as an indicator of subclinical POT, was not fulfilled, except for isoprene. Hence, no evident signs of POT or subclinical pulmonary damage were detected after a TT6. Further studies on individuals recently exposed to pulmonary irritants, such as divers and individuals exposed to other hyperbaric treatment regimens, are needed.

Persistence of parental-reported asthma at early ages: A longitudinal twin study.

BACKGROUND: Currently, we cannot predict whether a pre-school child with asthma-like symptoms will have asthma at school age. Whether genetic information can help in this prediction depends on the role of genetic factors in persistence of pre-school to school-age asthma. We examined to what extent genetic and environmental factors contribute to persistence of asthma-like symptoms at ages 3 to asthma at age 7 using a bivariate genetic model for longitudinal twin data. METHODS: We performed a cohort study in monozygotic and dizygotic twins from the Netherlands Twin Register (NTR, n = 21,541 twin pairs). Bivariate genetic models were fitted to longitudinal data on asthma-like symptoms reported by parents at age 3 and 7 years to estimate the contribution of genetic and environmental factors. RESULTS: Bivariate genetic modeling showed a correlation on the liability scale between asthma-like symptoms at age 3 and asthma at age 7 of 0.746 and the contribution of genetics was estimated to be 0.917. The genetic analyses indicated a substantial influence of genetic factors on asthma-like symptoms at ages 3 and 7 (heritability 80% and 90%, respectively); hence, contribution of environmental factors was low. Persistence was explained by a high (rg = 0.807) genetic correlation. CONCLUSION: Parental-reported asthma-like symptoms at age 3 and asthma at age 7 are highly heritably. The phenotype of asthma-like symptoms at age 3 and 7 was highly correlated and mainly due to heritable factors, indicating high persistence of asthma development over ages 3 and 7.

Expert meeting report: towards a joint European roadmap to address the unmet needs and priorities of paediatric asthma patients on biologic therapy.

A digital multidisciplinary European expert meeting took place on the 9 July 2020 to identify the unmet needs of paediatric severe asthma patients, and set the priorities for clinical and research activities ahead https://bit.ly/3CeLBHB.

LTA4H rs2660845 association with montelukast response in early and late-onset asthma.

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04-8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61-4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.

Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response.

The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate lymphoid cells (IL-10+ ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1+ but not KLRG1- ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10+ ILC2s in the disease-modifying effect by allergen immunotherapy.

Exhaled breath analysis by use of eNose technology: a novel diagnostic tool for interstitial lung disease.

INTRODUCTION: Early and accurate diagnosis of interstitial lung diseases (ILDs) remains a major challenge. Better noninvasive diagnostic tools are much needed. We aimed to assess the accuracy of exhaled breath analysis using eNose technology to discriminate between ILD patients and healthy controls, and to distinguish ILD subgroups. METHODS: In this cross-sectional study, exhaled breath of consecutive ILD patients and healthy controls was analysed using eNose technology (SpiroNose). Statistical analyses were done using partial least square discriminant analysis and receiver operating characteristic analysis. Independent training and validation sets (2:1) were used in larger subgroups. RESULTS: A total of 322 ILD patients and 48 healthy controls were included: sarcoidosis (n=141), idiopathic pulmonary fibrosis (IPF) (n=85), connective tissue disease-associated ILD (n=33), chronic hypersensitivity pneumonitis (n=25), idiopathic nonspecific interstitial pneumonia (n=10), interstitial pneumonia with autoimmune features (n=11) and other ILDs (n=17). eNose sensors discriminated between ILD and healthy controls, with an area under the curve (AUC) of 1.00 in the training and validation sets. Comparison of patients with IPF and patients with other ILDs yielded an AUC of 0.91 (95% CI 0.85-0.96) in the training set and an AUC of 0.87 (95% CI 0.77-0.96) in the validation set. The eNose reliably distinguished between individual diseases, with AUC values ranging from 0.85 to 0.99. CONCLUSIONS: eNose technology can completely distinguish ILD patients from healthy controls and can accurately discriminate between different ILD subgroups. Hence, exhaled breath analysis using eNose technology could be a novel biomarker in ILD, enabling timely diagnosis in the future.

Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens.

Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P = 9.4 × 10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.

Quantitative Method for the Analysis of Ivacaftor, Hydroxymethyl Ivacaftor, Ivacaftor Carboxylate, Lumacaftor, and Tezacaftor in Plasma and Sputum Using Liquid Chromatography With Tandem Mass Spectrometry and Its Clinical Applicability.

BACKGROUND: The novel cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, and tezacaftor, are the first drugs directly targeting the underlying pathophysiological mechanism in cystic fibrosis (CF); however, independent studies describing their pharmacokinetics are lacking. The aim of this study was to develop a quantification method for ivacaftor and its 2 main metabolites, lumacaftor and tezacaftor, in plasma and sputum using liquid chromatography with tandem mass spectrometry. METHODS: The developed method used a small sample volume (20 µL) and simple pretreatment method; protein precipitation solution and internal standard were added in one step to each sample. Liquid chromatography with tandem mass spectrometry was performed for a total run time of 6 minutes. The method was validated by assessing selectivity, carryover, linearity, accuracy and precision, dilution, matrix effects, and stability. RESULTS: The selectivity was good as no interference from matrices was observed. In the concentration range from 0.01 to 10.0 mg/L, calibration curves were linear with a correlation coefficient >0.9997 for all compounds. The within-run and between-run accuracy were between 99.7% and 116% at the lower limit of quantitation (LLOQ) and between 95.8% and 112.9% for all concentrations above LLOQ for all analytes in plasma and sputum. Within-run and between-run precisions were <12.7% for LLOQ and <6.7% for the higher limit of quantitation. Samples were stable, with no significant degradation at examined temperatures and time points. Clinical applicability was revealed by analyzing samples from 2 patients with CF. CONCLUSIONS: The presented method enables simultaneous quantification of ivacaftor, lumacaftor, and tezacaftor in plasma and sputum and is an improvement over previous methods because it uses smaller sample volumes, a simple pretreatment protocol, and includes tezacaftor. In future studies, it can be applied for examining pharmacokinetics characteristics of new CF transmembrane conductance regulator modulators.

Bronchiectasis in Severe Asthma: Does It Make a Difference?

BACKGROUND: Asthma and bronchiectasis are 2 heterogeneous diseases that frequently coexist, particularly in severe asthma. Recognition of this co-diagnosis may importantly affect treatment decisions and outcome. Previous studies in asthma with bronchiectasis show inconsistent outcomes, probably due to the heterogeneity of the included asthma cohorts. OBJECTIVES: We hypothesized that bronchiectasis contributes to asthma severity and that patients with severe asthma and bronchiectasis present with distinct characteristics resulting in different treatable traits. In addition, we explored whether bronchiectasis in severe asthma is more common in a specific phenotype. METHODS: This is a single-center study consecutively including patients with severe asthma from a tertiary referral center. Severe asthma was diagnosed according to the ATS/ERS guidelines. Asthma and infectious exacerbations were defined by the attending specialist as respiratory symptoms requiring treatment with systemic steroids or antibiotics, respectively. Two independent blinded radiologists evaluated each CT. RESULTS: 19% of patients with severe asthma showed bronchiectasis on CT. Patients with bronchiectasis had a lower FEV1% predicted (p = 0.02) and FEV1/FVC (p = 0.004) and more infectious exacerbations (p = 0.003) compared to patients without bronchiectasis. Bronchiectasis is more common in patients with a longer duration of asthma, sensitization to A. fumigatus or a positive sputum culture. Sputum cultures of patients with severe asthma and bronchiectasis revealed more P. aeruginosa, S. maltophilia, H. parainfluenzae, and A. fumigates compared to the non-bronchiectasis group. The adult-onset, eosinophilic asthma phenotype showed the highest prevalence of bronchiectasis (29.4%). CONCLUSIONS: Patients with severe asthma and coexisting bronchiectasis were found to represent a distinct group, in terms of disease severity, microbiology, and asthma phenotype. Performing (HR)CT and sputum cultures can help to identify these patients. These results can possibly contribute to early recognition and targeted treatment of this patient group.

Comparison of Myelotoxicity and Nephrotoxicity Between Daily Low-Dose Cisplatin With Concurrent Radiation and Cyclic High-Dose Cisplatin in Non-Small Cell Lung Cancer Patients.

AIM: Antineoplastic effect of cisplatin, the first line treatment in non-small cell lung cancer (NSCLC), is hindered by its nephrotoxicity and myelotoxicity. Both low-dose and high-dose regimens are used in the management of NSCLC. The aim of this study is to assess the risk on myelotoxicity and nephrotoxicity from the daily low-dose cisplatin (DLD) treatment as compared to cyclic high-dose cisplatin (CHD). METHODS: A retrospective cohort study was conducted. NSCLC patients treated with cisplatin between 2011 and 2018 in the Amsterdam UMC or Antoni van Leeuwenhoek cancer hospital were studied. Myelotoxicity and nephrotoxicity were defined based on common terminology criteria (CTCAE v4.03) and categorized as ≥grade 1 and ≥grade 2. Modified Poisson regression and Cox proportional hazards model were used to estimate relative risks and cumulative hazard respectively. RESULTS: Of the 115 NSCLC patients receiving DLD (N=62) and CHD (N=53), 60% had ≥grade 1 anemia, 33.9% leukopenia, 31.3% neutropenia, 27.8% thrombocytopenia, 32.2% acute nephrotoxicity with combined definition (Cr-electrolyte nephrotoxicity), and 58.3% chronic nephrotoxicity. The DLD group was older, had an earlier cancer stage, had more comorbidities, and had higher baseline albumin levels. In the DLD group less ≥grade 2 toxicities were reported compared to the CHD group except for Cr-electrolyte nephrotoxicity. However, there was a stronger association in the DLD group with ≥grade 1 leukopenia, thrombocytopenia, and Cr-electrolyte nephrotoxicity. The DLD group developed significantly more ≥grade 1 leukopenia [adjusted relative risk (adjRR)=1.83, 95% CI 1.02-3.27], thrombocytopenia (adjRR=3.43, 95% CI 1.64-7.15), and ≥grade 2 Cr-electrolyte nephrotoxicity (adjRR=3.02, 95% CI 1.20-7.56). The DLD group had a lower adjusted cumulative hazard for developing ≥grade 2 myelotoxicity and chronic nephrotoxicity but not for Cr-electrolyte nephrotoxicity [adjusted hazard ratio (adjHR)=3.90, 95% CI 1.35-11.23]. In contrast, DLD showed protective effect to ≥grade 2 nephrotoxicity when definition was restricted to the traditional creatinine-based definition (adjRR=0.07, 95% CI 0.01-0.86; adjHR=0.05, 95% CI 0.01-0.56). CONCLUSIONS: Overall, the DLD regimen was safer than the CHD regimen when assessing the risk of ≥grade 2 myelotoxicity and nephrotoxicity. However, this might not be the case in patients with a higher risk of electrolyte abnormalities.

Treatment Eligibility of Real-Life Mepolizumab-Treated Severe Asthma Patients.

BACKGROUND: Patients with severe asthma not meeting the strict trial eligibility criteria for mepolizumab are now routinely treated with this biological in clinical practice, but it remains unclear whether these ineligible patients respond differently to mepolizumab treatment. OBJECTIVE: This study investigated the extent and reasons for trial ineligibility of real-life, mepolizumab-treated patients with severe asthma and compared the characteristics of these patients with trial populations. Subsequently, therapeutic response in ineligible patients was assessed on the basis of oral corticosteroid (OCS) reduction. METHODS: Trial eligibility, population differences, and therapeutic response were assessed using the baseline characteristics of mepolizumab-receiving patients with severe asthma treated in the Amsterdam University Medical Centres and OCS dose at 6 months for OCS-dependent patients extracted from patients' electronic health records. Eligibility criteria and population characteristics from trials investigating mepolizumab were extracted from their original publications. RESULTS: A total of 82.4% of 119 mepolizumab-receiving, real-life patients with severe asthma were ineligible for trial inclusion, wherein 42.9% and 39.5% were excluded on the basis of inclusion and exclusion criteria, respectively. The clinical care population was older, more often male and demonstrating a better lung function under lower OCS maintenance dosages in comparison with trial populations. A total of 50% of 66 ineligible, OCS-dependent mepolizumab-treated patients were able to reduce their maintenance OCS dosage to ≤5 mg prednisone/day. CONCLUSIONS: A large proportion of the real-life, mepolizumab-treated population with severe asthma would be excluded from trial participation, and significant differences in population characteristics exist. Regardless, a large fraction of ineligible patients in clinical care can reduce maintenance OCS dosage under mepolizumab therapy.