Initiation, response assessment, and switch of antibody therapies in patients with severe asthma - A survey among German specialists.

Background: For therapy of severe asthma 5 monoclonal antibodies have been available in Germany up to November 2022, but no clear rules exist on choice of initial therapy, assessment of response, and switch. Objective: To assess current practice on all aspects of biologic therapy by specialists in Germany. Methods: A questionnaire was created by specialists for severe asthma, which was tested and modified by further experts. We invited 119 pulmonologists of the German Asthma Net (GAN) to complete the survey and used SoSci Survey and SPSS for data collection and analysis. Results: Forty-seven pulmonologists took part in the survey with a median annual number of patients treated with biologics of 35, 55% worked in an outpatient practice, and 40% in a hospital. Exacerbations and oral steroid use were the most important factors for the decision to start a biologic therapy. Accordingly, these parameters were also the most relevant for assessment of response. Most participants considered type-2 inflammation biomarkers and comorbidities (foremost CRSwNP and AD) for choosing initial biologic. Asthma Control Test (ACT) was the most common instrument for assessing status of disease control. There was no consensus on thresholds for response of pulmonary function tests including FEV1, FVC, and RV. Eighty-five percent of participants distinguished between "responders", "partial responders" and "non-responders". Comorbidities played an important role for the decision to switch to another biologic, eg, when initial therapy had insufficient effectiveness on CRSwNP. Conclusion: This study provides a detailed insight into current opinions and practice of biologic use in severe asthma in Germany.

Biologics for severe asthma and beyond.

Advances in pathophysiological understanding and the elucidation of a type 2 inflammatory signature with interleukins 4, 5 and 13 at its center have led to the development of targeted antibody therapies that are now approved for the treatment of severe asthma. In suitable patients, these medications reduce asthma exacerbations and the necessity for oral corticosteroids, improve asthma control, quality of life and lung function. A proportion of patients with severe asthma may even achieve remission under ongoing biologic therapy. Type-2 inflammatory comorbidities are frequent in patients with severe asthma, sharing overlapping pathophysiology and may similarly respond to biologic treatment. Here, we give an overview of the six biologic therapies currently approved for severe asthma and review randomized clinical trials and real-life studies in asthma and other type-2 inflammatory diseases. We also discuss selection of biologics according to licensing criteria, asthma phenotype and biomarkers, monitoring of treatment response and proceedings in case of insufficient outcome under therapy.

Early mortality in German patients with lung cancer: risk factors associated with 30-and 60-day mortality.

Despite therapeutic advances, early mortality in lung cancer is still prevalent. In this study, we aimed to assess risk factors for 30- and 60-day mortality in German lung cancer patients. In this retrospective cross-sectional analysis, we used data of lung cancer patients treated at LMU Hospital Munich between 2015 and 2019. We categorized patients into 30-day mortality, 60 day-mortality, and longer survival. We used Student's t-test and ANOVA to compare means and Chi2-test to compare frequencies. We used logistic regression analysis to identify factors associated with a risk for early mortality. Of the 2454 lung cancer patients, 2.0% (n = 50) died within 30 and 1.7% (n = 41) within 30 to 60 days of diagnosis. Older age and advanced stage at diagnosis were significantly associated with early mortality in the univariate and the multivariate analysis. Patients in the 30-day mortality group significantly more often did not receive tumor-directed therapy. They were also more likely to die in an acute care setting compared to the 60-day mortality group. The group of patients who died unexpectedly (12.0%) was dominantly female, with a high proportion of patients with unintentional weight loss at the time of diagnosis. Our results suggest that in the treatment of patients with lung cancer there is a need for a greater focus on older patients. Moreover, physicians should pay special attention to females with recent weight loss and patients with a comorbidity of diabetes mellitus or renal impairment. Engaging a case manager focused on detecting patients with the above characteristics could help improve overall care.

Response to high-altitude triggers in seasonal asthmatics on and off inhaled corticosteroid treatment.

Background: Due to the effects of climate change, winter sport enthusiasts will be increasingly forced to stay at higher altitudes. High altitude (HA) environmental factors such as cold temperature, physical exertion, and hypoxia with subsequent hypocapnia due to hyperventilation have been shown to induce bronchoconstriction. With bronchial asthma being highly prevalent, asthmatics also will be increasingly exposed to HA environment and might experience increasing symptoms. Methods: We analysed the effects of HA factors at around 2600 m a.s.l. (metres above sea level) on lung function in mild seasonal asthmatics while they were routinely off (January) and on (March, after start of lowland pollen season) low-dose inhaled corticosteroid (ICS) treatment (n = 10), and matched healthy controls (n = 11). Results: Without inhaled corticosteroid (ICS) treatment mean FEV1 in asthmatics was 230 ml lower after exercise at HA compared to low altitude (LA, p < 0.05), while in healthy controls there was no significant difference. This decrease was mainly induced by cold and exercise at HA. During ICS treatment, this decrease was prevented. Methacholine response was reduced at HA compared to LA. Conclusions: The decrease of FEV1 in response to a combination of hypoxia, cold, and exercise is prevented by ICS treatment in mild, seasonal asthmatics. However, the FEV1 response to high altitude factors was overall small.

Overall Response to Anti-IL-5/Anti-IL5-Rα Treatment in Severe Asthma Does Not Depend on Initial Bronchodilator Responsiveness.

BACKGROUND: Positive bronchodilator responsiveness (BDR) (change in forced expiratory volume in 1 second [ΔFEV1] ≥ +200 mL and ≥ +12%) after inhalation of a short-acting beta-2 agonist has been an inclusion criterion in licensing trials of anti-interleukin 5/anti-interleukin 5 receptor alpha (anti-IL-5/anti-IL-5Rα) 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-IL-5/anti-IL-5Rα stratified for baseline BDR. RESULTS: Of 133 patients included, 37 had a positive and 96 had a negative BDR at baseline. Following anti-IL-5/anti-IL-5Rα treatment, FEV1 improved significantly in both groups compared with baseline (P < .0001), with no significant difference between patients with positive and negative BDR (ΔFEV1 +493 mL vs +306 mL; P = .06). Forced vital capacity (FVC) increased (ΔFVC: +85 mL vs +650 mL; P < .01) and residual volume (RV) decreased (ΔRV +113 mL vs -307 mL; P < .01) significantly in patients with negative BDR. Median annualized exacerbations (0 vs 0; P = .7), reduction of exacerbation rate (Δexacerbations 0 vs -2; P = .07), continuous oral corticosteroids (OCS) use (Δpatients on OCS -35% vs -39%; P = .99) and improvement of Asthma Control Test (ACT) score (ΔACT 6 vs 5; P = .7) were similar in both groups. Multivariate logistic regression analysis showed no significant correlations of positive versus 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-IL-5/anti-IL-5Rα treatment, with differences in response patterns noted.

Pulmonary function impairment of asymptomatic and persistently symptomatic patients 4 months after COVID-19 according to disease severity.

OBJECTIVE: Evaluation of pulmonary function impairment after COVID-19 in persistently symptomatic and asymptomatic patients of all disease severities and characterisation of risk factors. METHODS: Patients with confirmed SARS-CoV-2 infection underwent prospective follow-up with pulmonary function testing and blood gas analysis during steady-state cycle exercise 4 months after acute illness. Pulmonary function impairment (PFI) was defined as reduction below 80% predicted of DLCOcSB, TLC, FVC, or FEV1. Clinical data were analyzed to identify risk factors for impaired pulmonary function. RESULTS: 76 patients were included, hereof 35 outpatients with mild disease and 41 patients hospitalized due to COVID-19. Sixteen patients had critical disease requiring mechanical ventilation, 25 patients had moderate-severe disease. After 4 months, 44 patients reported persisting respiratory symptoms. Significant PFI was prevalent in 40 patients (52.6%) occurring among all disease severities. The most common cause for PFI was reduced DLCOcSB (n = 39, 51.3%), followed by reduced TLC and FVC. The severity of PFI was significantly associated with mechanical ventilation (p < 0.001). Further risk factors for DLCO impairment were COPD (p < 0.001), SARS-CoV-2 antibody-Titer (p = 0.014) and in hospitalized patients CT score. A decrease of paO2 > 3 mmHg during cycle exercise occurred in 1/5 of patients after mild disease course. CONCLUSION: We characterized pulmonary function impairment in asymptomatic and persistently symptomatic patients of different severity groups of COVID-19 and identified further risk factors associated with persistently decreased pulmonary function. Remarkably, gas exchange abnormalities were revealed upon cycle exercise in some patients with mild disease courses and no preexisting pulmonary condition.

Polyomavirus exerts detrimental effects on renal function in patients after lung transplantation.

INTRODUCTION: Chronic kidney disease (CKD) is associated with significant morbidity and mortality after lung transplantation (LTX). Calcineurin inhibitor (CNI) nephrotoxicity is the leading cause of CKD. After kidney transplantation, polyomavirus-associated nephropathy (PyVAN) is a well-recognized problem. This study aims to evaluate the role of polyomavirus in patients after LTX. METHODS: From January 2017 to January 2020, all lung transplant recipients who performed follow-up visits in our center were included in the study and retrospectively assessed. We measured renal function (creatinine levels before and after transplantation), JCPyV, and BKPyV load by polymerase chain reaction (PCR) in serum and urine samples after transplantation. RESULTS: In total, 104 consecutive patients (59 males, 56.7%) with a mean age of 49.6 ± 11.1 years were identified. JCPyV was found in urine of 36 patients (34.6%) and serum of 3 patients (2.9%). BKPyV was found in urine of 40 patients (38.5%) and serum of 4 patients (3.8%), respectively. Urine evidence for JCPyV (p < 0.001, coefficient: +21.44) and BKPyV (p < 0.001, coefficient: +29.65) correlated highly with further kidney function decline. CONCLUSION: Kidney function deterioration is associated with JCPyV and BKPyV viruria in patients after LTX. This might indicate a role of PyVAN in lung transplant recipients.

Rituximab Treatment of Hairy Cell Leukemia in a Patient with Mycobacterium kansasii Infection: A Case Report.

INTRODUCTION: Infectious complications represent a major cause of morbidity and mortality in hairy cell leukemia (HCL) patients. Due to the immunosuppressive nature of the disease, these patients are frequently affected by opportunistic infections and rare pathogens. Furthermore, cytotoxic chemotherapy might lead to poor or even fatal outcomes in the setting of an active infection. CASE PRESENTATION: We report the case of a 62-year-old HCL patient who presented with recurrent fever episodes, pancytopenia, and mediastinal lymphadenopathy. A treatment decision against purine analogs and for rituximab mono was made as lymph node tissue revealed disseminated Mycobacterium kansasii infection. Together with specific antimycobacterial treatment, rituximab mono led to complete hematologic remission after 6 months without aggravating the accompanying infection. CONCLUSION: Here, we demonstrate successful treatment of HCL with rituximab in a patient with concomitant disseminated M. kansasii infection.

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.

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.

Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a severe hypersensitivity reaction to aspergillus species colonizing the airways of patients with asthma or cystic fibrosis. Biologics including anti-IgE and anti-IL5 antibodies have strongly changed the treatment of severe asthmatics and have partly been reported to be effective in the treatment of ABPA. Recently, dupilumab, an anti-IL4-Rα antibody which inhibits signaling by the Th2-cytokines IL4 and IL13, has been approved for the treatment of severe asthma. CASE PRESENTATION: Here, we report the case of a 49-year-old woman with severe asthma and ABPA, who was uncontrolled despite maximum inhalative therapy, anti-IL5-Rα antibody and continuous oral steroid therapy. Moreover, trials of itraconazole as well as omalizumab showed insufficient efficacy. Lung function revealed peripheral obstruction. FeNO and IgE were increased, eosinophils were suppressed under treatment while marked increases had been documented previously. Switching to dupilumab led to a complete resolution of pulmonary symptoms, resolution of exacerbations and complete withdrawal of oral steroids. A drastic improvement in lung function was noted, with an increase in FEV1 of almost 1 l. FeNO was normalized and IgE strongly reduced. CONCLUSION: Our case highlights that a patient may exhibit differential treatment responses to the currently available asthma biologics and suggests switching treatment if outcome is insufficient. A potential role for dupilumab in the treatment of ABPA warrants future studies.

High prevalence of falsely declaring nicotine abstinence in lung transplant candidates.

Tobacco use after lung transplantation is associated with adverse outcome. Therefore, active smoking is regarded as a contraindication for lung transplantation and should be excluded prior to placement on the waiting list. The aim of the study was to compare self-reporting with a systematic cotinine based screening approach to identify patients with active nicotine abuse. Nicotine use was systematically assessed by interviews and cotinine test in all lung transplant candidates at every visit in our center. Patients were classified according to the stage prior to transplantation and cotinine test results were compared to self-reports and retrospectively analyzed until June 2019. Of 620 lung transplant candidates, 92 patients (14.8%) had at least one positive cotinine test. COPD as underlying disease (OR 2.102, CI 1.110-3.981; p = 0.023), number of pack years (OR 1.014, CI 1.000-1.028; p = 0.047) and a time of cessation less than one year (OR 2.413, CI 1.410-4.128; p = 0.001) were associated with a positive cotinine test in multivariable regression analysis. The majority of non-COPD patients (n = 13, 72.2%) with a positive test had a cessation time of less than one year. 78 patients (84.7%) falsely declared not consuming any nicotine-based products prior to the test. Finally, all never smokers were test negative. In conclusion, our data demonstrate that active nicotine use is prevalent in transplant candidates with a high prevalence of falsely declaring nicotine abstinence. COPD was the main diagnosis in affected patients. Short cessation time and a high number of pack years are risk factors for continued nicotine abuse.

Cell-specific expression of runt-related transcription factor 2 contributes to pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited therapeutic options and unknown etiology. IPF is characterized by epithelial cell injury, impaired cellular crosstalk between epithelial cells and fibroblasts, and the formation of fibroblast foci with increased extracellular matrix deposition (ECM). We investigated the role of runt-related transcription factor 2 (RUNX2), a master regulator of bone development that has been linked to profibrotic signaling. RUNX2 expression was up-regulated in lung homogenates from patients with IPF and in experimental bleomycin-induced lung fibrosis. The RUNX2 level correlated with disease severity as measured by decreased diffusing capacity and increased levels of the IPF biomarker, matrix metalloproteinase 7. Nuclear RUNX2 was observed in prosurfactant protein C-positive hyperplastic epithelial cells and was rarely found in myofibroblasts. We discovered an up-regulation of RUNX2 in fibrotic alveolar epithelial type II (ATII) cells as well as an increase of RUNX2-negative fibroblasts in experimental and human pulmonary fibrosis. Functionally, small interfering RNA-mediated RUNX2 knockdown decreased profibrotic ATII cell function, such as proliferation and migration, whereas fibroblasts displayed activation markers and increased ECM expression after RUNX2 knockdown. This study reveals that RUNX2 is differentially expressed in ATII cells vs. fibroblasts in lung fibrosis, which contributes to profibrotic cell function. Cell-specific targeting of RUNX2 pathways may represent a therapeutic approach for IPF.-Mümmler, C., Burgy, O., Hermann, S., Mutze, K., Günther, A., Königshoff, M. Cell-specific expression of runt-related transcription factor 2 contributes to pulmonary fibrosis.