[Advances in the management of asthma]. / Asthma ­ was ist neu?

Asthma is a heterogeneous inflammatory airway disease that causes relevant morbidity across individuals of all age cohorts. In recent years, advances in the understanding of asthma pathophysiology have led to the development of treatments tailored to specific pheno- and endotypes of the disease. This has significantly changed asthma management, especially for patients with severe disease. These new treatment options offer individuals with asthma access to personalized and disease-modifying therapies. The present paper is a comprehensive overview of recent clinical studies and of German and international guideline updates on asthma management.

HEV-positive blood donations represent a relevant infection risk for immunosuppressed recipients.

BACKGROUND & AIMS: Routine HEV testing of blood products has recently been implemented in Great Britain and the Netherlands. The relevance of transfusion-transmitted HEV infections is still controversially discussed in Europe. METHODS: All blood donations at the University Medical Center Hamburg-Eppendorf were prospectively tested for HEV RNA by pooled PCR from October 2016 to May 2017. Reactive samples were individually retested. Additionally, stored samples from previous donations of positive donors were tested to determine the duration of HEV viraemia. HEV RNA-positive donors and a control cohort were asked to answer a questionnaire. RESULTS: Twenty-three out of 18,737 HEV RNA-positive donors were identified (0.12%). Only two of the positive donors (8.7%) presented with elevated aminotransferases at time of donation (alanine aminotransferase: 192 and 101 U/L). The retrospective analysis of all positive donors revealed that four asymptomatic donors had been HEV viraemic for up to three months with the longest duration of HEV viraemia exceeding four months. Despite the HEV-testing efforts, 14 HEV RNA-positive blood products were transfused into 12 immunocompromised and two immunocompetent patients. One recipient of these products developed fatal acute-on-chronic liver failure complicated by Pseudomonas septicemia. The questionnaire revealed that HEV RNA-positive donors significantly more often consumed raw pork meat (12 out of 18; 67%) than controls (89 out of 256; 35%; p = 0.01). In two donors, undercooked pork liver dishes were identified as the source of infection. HEV genotyping was possible in 7 out of 23 of HEV viraemic donors and six out of seven isolates belonged to HEV Genotype 3, Group 2. CONCLUSIONS: Prolonged HEV viraemia can be detected at a relatively high rate in Northern German blood donors, leading to transfusion-transmitted HEV infections in several patients with the risk of severe and fatal complications. Eating raw pork tartare represented a relevant risk for the acquisition of HEV infection. LAY SUMMARY: The relevance of transfusion-transmitted hepatitis E virus infections has been discussed controversially. Herein, we present the first report on routine hepatitis E virus screening of blood donations at a tertiary care centre in Germany. Hepatitis E viraemia was found at a relatively high rate of 0.12% among blood donors, which represents a relevant transfusion-related risk for vulnerable patient populations.

Hepatitis E seroprevalence in the Americas: A systematic review and meta-analysis.

BACKGROUND & AIMS: While hepatitis E virus infections are a relevant topic in Europe, knowledge about epidemiology of hepatitis E virus infections in the USA and Latin America is still limited. Aim of this study was to estimate anti-hepatitis E virus IgG seroprevalence in the Americas and to assess whether low socioeconomic status is associated with hepatitis E virus exposure. METHODS: We performed a systematic review and meta-analysis. Literature search was performed in PubMed for articles published 01/1994-12/2016. Prevalence was estimated using a mixed-effects model and reported in line with PRISMA reporting guidelines. RESULTS: Seroprevalence was significantly higher in the USA than in Latin America, independently of assay, patient cohort, methodological quality or study year (OR: 1.82 (1.06-3.08), P = .03). Patients in the USA had a more than doubled estimated seroprevalence (up to 9%, confidence interval 5%-15.6%) than those in Brazil (up to 4.2%, confidence interval 2.4%-7.1%; OR: 2.27 (1.25-4.13); P = .007) and Mixed Caribbean (up to 1%, OR: 8.33 (1.15-81.61); P = .04). A comparison with published data from Europe demonstrated that anti-hepatitis E virus seroprevalence in the USA and Europe did not differ significantly (OR: 1.33 (0.81-2.19), P = .25), while rate in South America was significantly lower than that in Europe (OR: 0.67 (0.45-0.98), P = .04). CONCLUSIONS: Hepatitis E virus is common in the USA. Surprisingly, the risk of hepatitis E virus exposure was low in many South American countries. Seroprevalence did not differ significantly between Europe and the USA. Hence, hepatitis E virus is not limited to countries with low sanitary standards, and a higher socioeconomic status does not protect populations from hepatitis E virus exposure.

Plasma levels of chemokines decrease during elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis.

Background: Cystic fibrosis (CF) is associated with dysregulated immune responses, exaggerated inflammation and chronic infection. CF transmembrane conductance regulator (CFTR) modulator therapies directly target the underlying protein defects and resulted in significant clinical benefits for people with CF (pwCF). This study analysed the effects of triple CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) on CF-associated inflammation, especially systemic chemokines. Methods: A bead-based immunoassay was used to quantify proinflammatory chemokines (IL-8, IP-10, Eotaxin, TARC, RANTES, MIP-1α, MIP-1ß, MIP-3α, MIG, ENA-78, GROα, I-TAC) in plasma samples from pwCF collected before, at three, and at six months after starting ETI therapy. Results: Fifty-one pwCF (47 % female; mean age 32 ± 10.4 years) were included. At baseline, 67 % were already receiving CFTR modulator therapy with tezacaftor/ivacaftor or lumacaftor/ivacaftor. After initiation of ETI therapy there was a significant improvement in percent predicted forced expiratory volume in 1 s (+12.7 points, p < 0.001) and a significant decrease in sweat chloride levels (-53.6 %, p < 0.001). After 6 months' treatment with ETI therapy there were significant decreases in plasma levels of MIP-3α (-68.2 %, p = 0.018), GROα (-17.7 %, p = 0.013), ENA-78 (-16.3 %, p = 0.034) and I-TAC (-3.4 %, p = 0.032). IL-8 exhibited a reduction that did not reach statistical significance (-17.8 %, p = 0.057); levels of other assessed cytokines did not change significantly from baseline. Conclusions: ETI appears to affect a distinct group of chemokines that are predominately associated with neutrophilic inflammation, demonstrating the anti-inflammatory properties of ETI therapy.

Low-dose high-resolution chest CT in adults with cystic fibrosis: intraindividual comparison between photon-counting and energy-integrating detector CT.

BACKGROUND: Regular disease monitoring with low-dose high-resolution (LD-HR) computed tomography (CT) scans is necessary for the clinical management of people with cystic fibrosis (pwCF). The aim of this study was to compare the image quality and radiation dose of LD-HR protocols between photon-counting CT (PCCT) and energy-integrating detector system CT (EID-CT) in pwCF. METHODS: This retrospective study included 23 pwCF undergoing LD-HR chest CT with PCCT who had previously undergone LD-HR chest CT with EID-CT. An intraindividual comparison of radiation dose and image quality was conducted. The study measured the dose-length product, volumetric CT dose index, effective dose and signal-to-noise ratio (SNR). Three blinded radiologists assessed the overall image quality, image sharpness, and image noise using a 5-point Likert scale ranging from 1 (deficient) to 5 (very good) for image quality and image sharpness and from 1 (very high) to 5 (very low) for image noise. RESULTS: PCCT used approximately 42% less radiation dose than EID-CT (median effective dose 0.54 versus 0.93 mSv, p < 0.001). PCCT was consistently rated higher than EID-CT for overall image quality and image sharpness. Additionally, image noise was lower with PCCT compared to EID-CT. The average SNR of the lung parenchyma was lower with PCCT compared to EID-CT (p < 0.001). CONCLUSION: In pwCF, LD-HR chest CT protocols using PCCT scans provided significantly better image quality and reduced radiation exposure compared to EID-CT. RELEVANCE STATEMENT: In pwCF, regular follow-up could be performed through photon-counting CT instead of EID-CT, with substantial advantages in terms of both lower radiation exposure and increased image quality. KEY POINTS: Photon-counting CT (PCCT) and energy-integrating detector system CT (EID-CT) were compared in 23 people with cystic fibrosis (pwCF). Image quality was rated higher for PCCT than for EID-CT. PCCT used approximately 42% less radiation dose and offered superior image quality than EID-CT.

Elexacaftor/tezacaftor/ivacaftor influences body composition in adults with cystic fibrosis: a fully automated CT-based analysis.

A poor nutritional status is associated with worse pulmonary function and survival in people with cystic fibrosis (pwCF). CF transmembrane conductance regulator modulators can improve pulmonary function and body weight, but more data is needed to evaluate its effects on body composition. In this retrospective study, a pre-trained deep-learning network was used to perform a fully automated body composition analysis on chest CTs from 66 adult pwCF before and after receiving elexacaftor/tezacaftor/ivacaftor (ETI) therapy. Muscle and adipose tissues were quantified and divided by bone volume to obtain body size-adjusted ratios. After receiving ETI therapy, marked increases were observed in all adipose tissue ratios among pwCF, including the total adipose tissue ratio (+ 46.21%, p < 0.001). In contrast, only small, but statistically significant increases of the muscle ratio were measured in the overall study population (+ 1.63%, p = 0.008). Study participants who were initially categorized as underweight experienced more pronounced effects on total adipose tissue ratio (p = 0.002), while gains in muscle ratio were equally distributed across BMI categories (p = 0.832). Our findings suggest that ETI therapy primarily affects adipose tissues, not muscle tissue, in adults with CF. These effects are primarily observed among pwCF who were initially underweight. Our findings may have implications for the future nutritional management of pwCF.

Body composition impacts outcome of bronchoscopic lung volume reduction in patients with severe emphysema: a fully automated CT-based analysis.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive and irreversible airflow limitation, with individual body composition influencing disease severity. Severe emphysema worsens symptoms through hyperinflation, which can be relieved by bronchoscopic lung volume reduction (BLVR). To investigate how body composition, assessed through CT scans, impacts outcomes in emphysema patients undergoing BLVR. Fully automated CT-based body composition analysis (BCA) was performed in patients with end-stage emphysema receiving BLVR with valves. Post-interventional muscle and adipose tissues were quantified, body size-adjusted, and compared to baseline parameters. Between January 2015 and December 2022, 300 patients with severe emphysema underwent endobronchial valve treatment. Significant improvements were seen in outcome parameters, which were defined as changes in pulmonary function, physical performance, and quality of life (QoL) post-treatment. Muscle volume remained stable (1.632 vs. 1.635 for muscle bone adjusted ratio (BAR) at baseline and after 6 months respectively), while bone adjusted adipose tissue volumes, especially total and pericardial adipose tissue, showed significant increase (2.86 vs. 3.00 and 0.16 vs. 0.17, respectively). Moderate to strong correlations between bone adjusted muscle volume and weaker correlations between adipose tissue volumes and outcome parameters (pulmonary function, QoL and physical performance) were observed. Particularly after 6-month, bone adjusted muscle volume changes positively corresponded to improved outcomes (ΔForced expiratory volume in 1 s [FEV1], r = 0.440; ΔInspiratory vital capacity [IVC], r = 0.397; Δ6Minute walking distance [6MWD], r = 0.509 and ΔCOPD assessment test [CAT], r = -0.324; all p < 0.001). Group stratification by bone adjusted muscle volume changes revealed that groups with substantial muscle gain experienced a greater clinical benefit in pulmonary function improvements, QoL and physical performance (ΔFEV1%, 5.5 vs. 39.5; ΔIVC%, 4.3 vs. 28.4; Δ6MWDm, 14 vs. 110; ΔCATpts, -2 vs. -3.5 for groups with ΔMuscle, BAR% < -10 vs. > 10, respectively). BCA results among patients divided by the minimal clinically important difference for forced expiratory volume of the first second (FEV1) showed significant differences in bone-adjusted muscle and intramuscular adipose tissue (IMAT) volumes and their respective changes after 6 months (ΔMuscle, BAR% -5 vs. 3.4 and ΔIMAT, BAR% -0.62 vs. 0.60 for groups with ΔFEV1 ≤ 100 mL vs > 100 mL). Altered body composition, especially increased muscle volume, is associated with functional improvements in BLVR-treated patients.

[Advances in the management of asthma]. / Asthma ­ was ist neu?

Asthma is a heterogeneous inflammatory airway disease that causes relevant morbidity across individuals of all age cohorts. In recent years, advances in the understanding of asthma pathophysiology have led to the development of treatments tailored to specific pheno- and endotypes of the disease. This has significantly changed asthma management, especially for patients with severe disease. These new treatment options offer individuals with asthma access to personalized and disease-modifying therapies. The present paper is a comprehensive overview of recent clinical studies and of German and international guideline updates on asthma management.

Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy.

Introduction: Cystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF. Methods: Peripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry. Results: Elexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (p<0.001) at 3 months. During elexacaftor/tezacaftor/ivacaftor therapy, percentages of Tregs were enhanced (+18.7%, p<0.001), with an increased proportion of Tregs expressing CD39 as a marker of stability (+14.4%, p<0.001). Treg enhancement was more pronounced in PwCF clearing Pseudomonas aeruginosa infection. Only minor, non-significant shifts were observed among Th1-, Th2- and Th17-expressing effector T helper cells. These results were stable at 3- and 6-month follow-up. Cytokine measurements showed a significant decrease in interleukin-6 levels during treatment with elexacaftor/tezacaftor/ivacaftor (-50.2%, p<0.001). Conclusion: Treatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.