[CF Lung Disease - a German S3 Guideline: Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal recessive genetic multisystemic disease. In Germany, it affects at least 8000 people. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the airway epithelial lining fluid which leads to reduction of the mucociliary clearance.Even if highly effective, CFTR modulator therapy has been available for some years and people with CF are getting much older than before, recurrent and chronic infections of the airways as well as pulmonary exacerbations still occur. In adult CF life, Pseudomonas aeruginosa (PA) is the most relevant pathogen in colonisation and chronic infection of the lung, leading to further loss of lung function. There are many possibilities to treat PA-infection.This is a S3-clinical guideline which implements a definition for chronic PA-infection and demonstrates evidence-based diagnostic methods and medical treatment in order to give guidance for individual treatment options.

Dynamics of abdominal symptoms during the start of a new therapy with elexacaftor/tezacaftor/ivacaftor using the novel CFAbd-day2day questionnaire.

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a novel, highly effective CFTR modulator combination proven to enhance lung function and body weight in people with cystic fibrosis (pwCF) carrying a F508del mutation. Recently, we revealed significant reductions in abdominal symptoms (AS) in German, British, and Irish pwCF after 24-26 weeks of ETI using the CFAbd-Score, the first patient-reported outcome measure (PROM) specifically developed and validated for pwCF following FDA guidelines. Notably, many pwCF reported marked changes in their AS during the first days of the new treatment. To capture these immediate effects, we developed the CFAbd-day2day, a CF-specific GI-diary, following FDA and COSMIN guidelines. Aim: To prospectively capture the immediate dynamics of AS using the CFAbd-day2day 14 days before and 14-28 days after ETI initiation. In addition, we aim to provide validation steps of the novel PROM concerning sensitivity to changes. Methods: To develop the CFAbd-day2day, focus groups (community voice = pwCF and their proxies and CF specialists from different fields) were repeatedly consulted. Before and during the new ETI therapy, pwCF prospectively scored AS on a daily basis with the CFAbd-day2day. Results: Altogether, 45 pwCF attended in five CF centers prospectively completed the CFAbd-day2day before (mean ± sd:14 ± 7 days) and after (mean ± sd: 28 ± 23 days) ETI initiation. On the one hand, cumulative scores significantly decreased during the 3-4-week time frame after ETI initiation, compared to 2 weeks prior to therapy. On the other hand, many patients who revealed a relatively stable level of AS before ETI reported changes during the first days of treatment with the highly effective CFTR modulators. Factors like pain and flatulence increased in up to 21% of patients during the first 14 days of therapy, but they improved during days 15-27. Conclusion: The CFAbd-day2day, specifically developed and in the process of validation to prospectively capture GI symptoms in pwCF, provides new substantial insights into the dynamics of AS in pwCF receiving a new treatment with ETI. This novel tool is also helpful in prospectively monitoring patients with specific GI problems. International implementation and further validation steps of the diary are ongoing.

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy.

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

Corrigendum: Elexacaftor-Tezacaftor-Ivacaftor treatment reduces abdominal symptoms in cystic fibrosis-early results obtained with the CF-specific CFAbd-Score.

[This corrects the article DOI: 10.3389/fphar.2022.877118.].

Antibiotic Therapy for Pulmonary Exacerbations in Cystic Fibrosis-A Single-Centre Prospective Observational Study.

People with cystic fibrosis experience bronchopulmonary exacerbations, leading to lung damage, lung function decline, increased mortality, and a poor health-related quality of life. To date, there are still open questions regarding the rationale for antibiotic use and the optimal duration of antibiotic therapy. This prospective single-center study (DRKS00012924) analyzes exacerbation treatment over 28 days in 96 pediatric and adult people with cystic fibrosis who started oral and/or intravenous antibiotic therapy in an inpatient or outpatient setting after clinician diagnosis of bronchopulmonary exacerbation. Biomarkers of exacerbation were examined in terms of their ability to predict response to treatment and the need for antibiotic therapy. The mean duration of antibiotic therapy was 14 days. Inpatient treatment was associated with a poorer health status, but no significant difference was found in the modified Fuchs exacerbation score between inpatients and outpatients. A significant increase of in-hospital FEV1, home spirometry FEV1, and body-mass index and a significant decrease of the modified Fuchs symptom score, C-reactive protein, and 8 out of the 12 domain scores of the revised cystic fibrosis questionnaire were demonstrated after 28 days. However, a trend towards a FEV1 decline in the inpatient group on day 28 could be demonstrated, while FEV1 was maintained in the outpatient group. Correlation analyses of changes between baseline and day 28 show a strong positive correlation between home spirometry and in-hospital FEV1, strong negative correlations between FEV1 and the modified Fuchs exacerbation score and between FEV1 and C-reactive protein, and a moderately negative correlation between FEV1 and the three domains of the revised cystic fibrosis questionnaire. Responders and non-responders to antibiotic therapy were defined in terms of FEV1 improvement after therapy. A higher baseline C-reactive protein, a greater decrease in C-reactive protein, a higher baseline modified Fuchs exacerbation score, and a greater decrease in the score after 28 days could be found in the responder group, while other baseline and follow-up parameters like FEV1 showed no significant differences. Our data show that the modified Fuchs exacerbation score is applicable in a clinical setting and can detect acute exacerbations regardless of health status. Home spirometry is a useful tool for outpatient exacerbation management. A change in C-reactive protein and a modified Fuchs score change are suitable follow-up markers of exacerbation due to their strong correlation with FEV1. Further studies are needed to assess which patients would benefit from a longer duration of antibiotic therapy. C-reactive protein at exacerbation onset and C-reactive protein decline during and after therapy better predict antibiotic therapy success than FEV1 at therapy onset, while the modified Fuchs score indicates exacerbation regardless of the need for antibiotic therapy, suggesting that antibiotic therapy is only part of exacerbation management.

Antigen specificity and cross-reactivity drive functionally diverse anti-Aspergillus fumigatus T cell responses in cystic fibrosis.

BACKGROUNDThe fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). Th cells orchestrate immune responses against fungi, but the types of A. fumigatus-specific Th cells in pwCF and their contribution to protective immunity or inflammation remain poorly characterized.METHODSWe used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls.RESULTSWe show that clonally expanded, high-avidity A. fumigatus-specific effector Th cells, which were absent in healthy donors, developed in pwCF. Individual patients were characterized by distinct Th1-, Th2-, or Th17-dominated responses that remained stable over several years. These different Th subsets target different A. fumigatus proteins, indicating that differential antigen uptake and presentation directs Th cell subset development. Patients with allergic bronchopulmonary aspergillosis (ABPA) are characterized by high frequencies of Th2 cells that cross-recognize various filamentous fungi.CONCLUSIONOur data highlight the development of heterogenous Th responses targeting different protein fractions of a single fungal pathogen and identify the development of multispecies cross-reactive Th2 cells as a potential risk factor for ABPA.FUNDINGGerman Research Foundation (DFG), under Germany's Excellence Strategy (EXC 2167-390884018 "Precision Medicine in Chronic Inflammation" and EXC 2051-390713860 "Balance of the Microverse"); Oskar Helene Heim Stiftung; Christiane Herzog Stiftung; Mukoviszidose Institut gGmb; German Cystic Fibrosis Association Mukoviszidose e.V; German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath (BMBF 03ZZ0838A+B).

Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score.

Background: The novel and highly effective CFTR modulator combination of elexacaftor-tezacaftor-ivacaftor (ETI) has been shown to improve lung function and body weight in people with Cystic Fibrosis (pwCF) carrying a F508del mutation. However, the impact of these modulators on gastrointestinal (GI) symptoms is relatively unknown. Therefore, the CFAbd-Score was developed and validated following FDA recommendations for development of a PROM including focus groups, multidisciplinary CF specialists, people with CF and their families. The aim of this study was to assess effects of ETI on GI symptoms using the CFAbd-Score. Methods: Gastrointestinal symptoms were prospectively assessed in pwCF using the CFAbd-Score before and up to 26 weeks during therapy. The CFAbd-Score was also administered to a healthy control (HC) group. The one-sided questionnaire includes 28 items grouped in five domains. Data analysis included calculation of scores with a weighting tool, developed according to FDA recommendations. Results: A total of 107 pwCF attended in four CF centres in Germany and four centres in the UK completed the CFAbd-Score on at least two occasions. Results were compared to those obtained from the questionnaire of 45 HCs. Despite differences in demographics, age and proportion of pancreatic insufficiency between German and UK patients, analyses based on linear mixed-effects models at week 24 of ETI therapy revealed that estimated marginal means (EMMs) of total CFAbd-Scores significantly reduced (mean ± SE: 14.9 ± 1.2→10.6 ± 1.4; p < 0.01). Also EMMs of all five domains significantly declined ("pain" 16.3 ± 1.6→10.2 ± 2.3, "GERD" 15.8 ± 1.8→8.2 ± 1.9, "disorders of bowel movement" 20.9 ± 1.5→16.0 ± 1.7, "disorders of appetite" 7.9 ± 1.1→2.6 ± 1.1 and "quality of life impairment" 10.1 ± 1.92→3.9 ± 1.9). However, during 24 weeks, CF participants' symptoms mostly still did not reach the reference levels of HCs. Discussion: Using the CFAbd-Score, the first PROM specifically developed for assessment of CF-related abdominal symptoms, we demonstrate comprehensive improvements in GI symptoms after initiation of the highly effective modulator therapy ETI.

Clinician variability in the diagnosis and treatment of aspergillus fumigatus-related conditions in cystic fibrosis: An international survey.

BACKGROUND: The diagnosis and treatment of Aspergillus fumigatus (Af)-related conditions remain a challenge in cystic fibrosis (CF) due to overlapping features of disease and absence of clinical guidelines for Af-related conditions outside of ABPA. OBJECTIVE: To investigate the differences of clinical practice in the diagnosis and management of Af-related conditions in CF. METHODS: We conducted an international survey to CF clinicians to ascertain the screening, diagnostic, and treatment practices for Af-related conditions in CF. Respondents were grouped into geographical regions and regional comparisons using chi-square tests of independence or Fisher's tests were performed. RESULTS: A total of 319 survey responses from 35 countries were analyzed. We observed differences in use and frequency of fungus culture, Aspergillus-specific IgE and IgG, skin prick testing, and pulmonary function testing as screening for Af-related conditions between the geographical regions. ABPA and Aspergillus bronchitis diagnostic criteria selection differed by region; significantly greater proportion of United States (US) and Canadian clinicians were unable to define Aspergillus bronchitis compared to Europe and other regions. Decision to treat ABPA was uniform across regions, but the consideration of Aspergillus bronchitis as a clinical disease warranting therapy differed between regions. The use of glucocorticoid and itraconazole was the first-line treatment of ABPA among clinicians; however, prednisone monotherapy was more common in US and Canada. CONCLUSIONS: Significant variability in the diagnosis and management of Aspergillus-related conditions in CF was observed. Future studies are necessary to better harmonize the approach to Af-related disease in CF.

Genetic diversification of persistent Mycobacterium abscessus within cystic fibrosis patients.

Mycobacterium (M.) abscessus infections in Cystic Fibrosis (CF) patients cause a deterioration of lung function. Treatment of these multidrug-resistant pathogens is associated with severe side-effects, while frequently unsuccessful. Insight on M. abscessus genomic evolvement during chronic lung infection would be beneficial for improving treatment strategies. A longitudinal study enrolling 42 CF patients was performed at a CF center in Berlin, Germany, to elaborate phylogeny and genomic diversification of in-patient M. abscessus. Eleven of the 42 CF patients were infected with M. abscessus. Five of these 11 patients were infected with global human-transmissible M. abscessus cluster strains. Phylogenetic analysis of 88 genomes from isolates of the 11 patients excluded occurrence of M. abscessus transmission among members of the study group. Genome sequencing and variant analysis of 30 isolates from 11 serial respiratory samples collected over 4.5 years from a chronically infected patient demonstrated accumulation of gene mutations. In total, 53 genes exhibiting non-synonymous variations were identified. Enrichment analysis emphasized genes involved in synthesis of glycopeptidolipids, genes from the embABC (arabinosyltransferase) operon, betA (glucose-methanol-choline oxidoreductase) and choD (cholesterol oxidase). Genetic diversity evolved in a variety of virulence- and resistance-associated genes. The strategy of M. abscessus populations in chronic lung infection is not clonal expansion of dominant variants, but to sustain simultaneously a wide range of genetic variants facilitating adaptation of the population to changing living conditions in the lung. Genomic diversification during chronic infection requires increased attention when new control strategies against M. abscessus infections are explored.

Clinical impact of levofloxacin inhalation solution in cystic fibrosis patients in a real-world setting.

BACKGROUND: Levofloxacin inhalation solution is the most recently approved inhaled antibiotic in Europe and Canada for adult cystic fibrosis patients. Its efficacy and safety have been assessed in randomized controlled trials. Our aim was to evaluate real life experience and outcomes in our treatment centre. METHODS: We evaluated the efficacy of inhaled levofloxacin solution in 86 patients with cystic fibrosis in terms of the following outcome parameters: changes in %-predicted forced expiratory volume in one second (FEV1), body-mass index (BMI), and exacerbation rate. We conducted an intraindividual analysis of patients who received levofloxacin inhalation solution twice daily 240 mg for at least 4 weeks. RESULTS: Change in FEV1% predicted for the treatment period was +2.27% (p=0.0027) after 4 weeks. There was no change in BMI for overall group, but exacerbation rate compared to one year before initiation of inhaled levofloxacin decreased significantly (p=0.0024) after 1 year of treatment (3.23 ± 1.39 versus 2.71 ± 1.58). CONCLUSIONS: In patients with cystic fibrosis, inhaled levofloxacin solution has the potential to improve FEV1 and to reduce the number of bronchopulmonary exacerbations.

Risk factors for respiratory Aspergillus fumigatus in German Cystic Fibrosis patients and impact on lung function.

Airway inflammation and chronic lung infections in cystic fibrosis (CF) patients are mostly caused by bacteria, e.g. Pseudomonas aeruginosa (PA). The role of fungi in the CF lung is still not well elucidated, but evidence for a harmful and complex role is getting stronger. The most common filamentous fungus in CF is Aspergillus fumigatus (AF). Age and continuous antibiotic treatment have been discussed as risk factors for AF colonisation but did not differentiate between transient and persistent AF colonisation. Also, the impact of co-colonisation of PA and AF on lung function is still under investigation. Data from patients with CF registered in the German Cystic Fibrosis Registry database in 2016 and 2017 were retrospectively analysed, involving descriptive and multivariate analysis to assess risk factors for transient or persistent AF colonisation. Age represented an independent risk factor for persistent AF colonisation. Prevalence was low in children less than ten years, highest in the middle age and getting lower in higher age (≥ 50 years). Continuous antibiotic lung treatment was significantly associated with AF prevalence in all age groups. CF patients with chronic PA infection had a lower lung function (FEV1%predicted), which was not influenced by an additional AF colonisation. AF colonisation without chronic PA infection, however, was significantly associated with a lower function, too. Older age up to 49 years and continuous antibiotic use were found to be the main risk factors for AF permanent colonisation. AF might be associated with decrease of lung function if not disguised by chronic PA infection.

Urban Life as Risk Factor for Aspergillosis.

Aspergillus fumigatus (Af) frequently colonizes the airways of patients with cystic fibrosis (CF) and can cause severe diseases, such as allergic bronchopulmonary aspergillosis, Af bronchitis or even Af pneumonia. However, risk factors, including environmental factors, for acquiring Af in the respiratory tract of patients with CF are rarely studied and described. The aim of this study was to investigate whether urban or rural life could affect colonization with Af in the respiratory tract of patients with CF. Due to privacy policy, registry data are usually not linked to patients´ home addresses. It is therefore very difficult to analyze the influence of the patient´s residential environment. This prospective questionnaire survey was carried out in 31 German CF centers in 2018. Only completed surveys, including a clearly assigned type of residential area were included. Statistical analysis was performed by chi-squared test and logistic regression models. A total of 1016 questionnaires were analyzed (Patients` age: 23 ± 13; 0-88 years; female gender: n=492; 48%). The majority of patients with CF live in large cities (n =314; 30.9%) or urban districts (n=461; 45.4%). Prevalence of 30.2% was found for Af, within the 12 months of investigation period. Af colonization was significantly associated with urban life (p=0.004). Urban live should be considered as possible new risk factor for colonization with Af in the respiratory tract of patients with CF. These new results may raise the awareness of the influence of environmental factors on patient outcomes and should be included in patient guidance and preventive measures.

[Therapy of cystic fibrosis - new drugs give hope]. / Therapie der Mukoviszidose ­ neue Medikamente geben Hoffnung.

For decades there were only symptom-oriented therapies for the monogenetic disease cystic fibrosis. With the new modulator therapies there are new hopes to better influence the course of the disease, which has its manifestation in several organs such as the lungs, the liver or pancreas.In addition to ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor, a triple combination with elexacaftor/tezacaftor/ivacaftor was developed. Studies in F508del homozygous and heterozygous patients with cystic fibrosis have resulted in significant clinical improvement and have therefore been approved by the FDA for the first time in the USA.The results are very promising as already after 4 weeks a significant improvement of FEV1 and a significant decrease of the sweat chloride content could be detected. In the USA all patients with at least one F508del mutation can be prescribed the drug. This corresponds to approximately 90 % of all patients with cystic fibrosis and has the potential to change the landscape of cystic fibrosis.

Gene-Dose Effect of MEFV Gain-of-Function Mutations Determines ex vivo Neutrophil Activation in Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. Disease severity depends on genotype and gene dose with most serious clinical courses observed in patients with M694V homozygosity. Neutrophils are thought to play an important role in the initiation and perpetuation of inflammatory processes in FMF, but little is known about the specific characteristics of these cells in FMF patients. To further characterize neutrophilic inflammatory responses in FMF and to delineate gene-dose effects on a cellular level, we analyzed cytokine production and activation levels of isolated neutrophils derived from patients and subjects with distinct MEFV genotypes, as well as healthy and disease controls. Serum levels of interleukin-18 (IL-18) (median 11,485 pg/ml), S100A12 (median 9,726 ng/ml), and caspase-1 (median 394 pg/ml) were significantly increased in patients with homozygous M694V mutations. Spontaneous release of S100A12, caspase-1, proteinase 3, and myeloperoxidase (MPO) was restricted to ex vivo cultured neutrophils derived from patients with two pathogenic MEFV mutations. IL-18 secretion was highest in patients with two mutations but also increased in neutrophils from healthy heterozygous MEFV mutation carriers, exhibiting an ex vivo gene-dose effect, which was formerly described by us in patients' serum. CD62L (l-selectin) was spontaneously shed from the surface of ex vivo cultured neutrophils [median of geometric mean fluorescence intensity (gMFI) after 5 h: 28.8% of the initial level]. While neutrophils derived from healthy heterozygous mutation carriers again showed a gene-dose effect (median gMFI: 67.1%), healthy and disease controls had significant lower shedding rates (median gMFI: 83.6 and 82.9%, respectively). Co-culture with colchicine and/or stimulation with adenosine triphosphate (ATP) and lipopolysaccharide (LPS) led to a significant increase in receptor shedding. Neutrophils were not prevented from spontaneous shedding by blocking IL-1 or the NLRP3 inflammasome. In summary, the data demonstrate that ex vivo cultured neutrophils derived from FMF patients display a unique phenotype with spontaneous release of high amounts of IL-18, S100A12, MPO, caspase-1, and proteinase 3 and spontaneous activation as demonstrated by the loss of CD62L. Neutrophilic activation seems to be independent from IL-1 activation and displays a gene-dose effect that may be responsible for genotype-dependent phenotypes.

Frequent Pet Contact as Risk Factor for Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis.

Aspergillus fumigatus (Af) frequently colonizes the respiratory tract of patients with cystic fibrosis (CF). Af is associated with loss of pulmonary function and allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity fungal lung disease. Environmental factors have impact on CF patients' lung function variation. The aim of this nationwide questionnaire survey was to investigate the amount of CF patients with frequent pet contact including pet species and to examine the potential impact of frequent pet contact on the occurrence of Af colonization and ABPA diagnosis in these patients. The survey was carried out in 31 German CF centers in 2018. A total of 1232 who completed the surveys were included, and statistical analysis was performed by chi-squared test. Within the study cohort 49.8% of subjects (n = 614; CF patients < 18years: 49.4%, n = 234; ≥ 18years: 50.1%, n = 380) reported frequent contact to pets, of which 60.7% reported frequent contact to dogs, 42.3% to cats and other animals. Of those with frequent pet contact, 71.8% (n = 441) had contact to one pet or more pets from the same family. Af colonization was not significantly associated with frequent pet contact. ABPA diagnosis was documented in 16.7% (n = 206) of all included CF patients and was significantly associated with frequent pet contact (18.9%, n = 116, p = 0.042), confirming previous single center examinations. Particularly, patients with frequent contact to dogs showed an increased ABPA prevalence of 21.3%. Frequent pet contact might be a risk factor for ABPA. CF patients who are sensitized to Af should be informed about the increased risk to develop an ABPA by frequent pet contact. Patients with recurrent onset of ABPA should be evaluated in terms of frequent pet contact.

Prospective Evaluation of Aspergillus fumigatus-Specific IgG in Patients With Cystic Fibrosis.

Background: In Cystic Fibrosis (CF), the airways are often colonized by opportunistic fungi. The most frequently detected mold is Aspergillus fumigatus (Af). Af diseases are associated with significant morbidity and mortality. The most common clinical picture caused by Af is allergic bronchopulmonary aspergillosis (ABPA), triggered by an immunological reaction against Af. Af bronchitis and invasive aspergillosis rarely occur in CF as a result of spore colonization and germination. Since pulmonary mycoses and exacerbations by other pathogens overlap in clinical, radiological, and immunological characteristics, diagnosis still remains a challenge. The search for reliable, widely available biomarkers for Af diseases is therefore still an important task today. Objectives: Af-specific IgG m3 is broadly available. Sensitivity and specificity data are contradictory and differ depending on the study population. In our prospective study on pulmonary Af diseases in CF, we determined specific IgG m3 in order to test its suitability as a biomarker for acute Af diseases and as a follow-up parameter. Methods: In this prospective single center study, 109 patients with CF were screened from 2016 to 2019 for Af-associated diseases. According to diagnostic criteria, they were divided into four groups (control, bronchitis, ABPA, pneumonia). The groups were compared with respect to the level of Af-specific IgG (ImmunoCAP Gm3). We performed a receiver operating characteristic (ROC) curve analysis to determine cut-off, sensitivity and specificity. Twenty-one patients could be enrolled for a follow-up examination. Results: Of the 109 patients, 36 were classified as acute Af-disease (Af bronchitis, ABPA, Af pneumonia). Of these, 21 patients completed follow up-screening. The median Af-specific Gm3 was higher in the acute Af-disease groups. There was a significant difference in Af-specific IgG m3 compared to the control group without acute Af-disease. Overall, there was a large interindividual distribution of Gm3. A cut-off value of 78.05 mg/L for Gm3 was calculated to discriminate controls and patients with ABPA/pneumonia with a specificity of 75% and a sensitivity of 74.6%. The follow up examination of 21 patients showed a decrease of Gm3 in most patients without statistical significance due to the small number of follow up patients. Conclusion: Af specific IgG may be a useful biomarker for acute ABPA and Af pneumonia, but not for Af bronchitis in CF. However, due to the large interindividual variability of Gm3, it should only be interpreted alongside other biomarkers. Therefore, due to its broad availability, it could be suitable as a biomarker for ABPA and Af pneumonia in CF, if the results can be supported by a larger multicenter cohort.

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans.

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human anti-fungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.

[Patients with cystic fibrosis become adults : Treatment hopes and disappointments]. / Patienten mit zystischer Fibrose werden erwachsen : Therapeutische Hoffnungen und Enttäuschungen.

Mucoviscidosis or cystic fibrosis (CF) is one of the most frequent monogenetic diseases in middle Europe. It is inherited in an autosomal recessive manner. A defect in the cystic fibrosis transmembrane conductance regulator (CFTR) channel reduces chloride ion transport to the cell membrane, which leads to malfunctions in all exocrine glands. This results in a progressive multiorgan disease, which leads to chronic inflammation and infections of the lungs. The progressive destruction of lung tissue with respiratory insufficiency is the most common cause of death in CF. Progress in symptomatic treatment over the past decades has led to a dramatic improvement in life expectation and quality of life for those affected, so that nowadays in nearly all industrial countries the majority of patients are adults. In 2012 the era of causal therapy of the CFTR protein defects was opened with the approval of ivacaftor. Long-term data now confirm the benefits. There is reason to hope that the success story of CF treatment will be continued, particularly by further CFTR modulators with innovative modes of action and improved efficacy; however, so far these are not available for all mutation classes, so that not all patients can reap the benefits. Therefore, the further development of symptomatic treatment becomes of great importance due to the complications that have already occurred before the implementation of the CFTR modulators. The implementation of modulators in early childhood can attenuate or prevent early irreversible complications. Therefore, in this article special emphasis is placed on new developments in symptomatic treatment and on new treatment options.