[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.

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.

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.

[New therapeutic strategies in HIV infection-immune reconstitution and virus suppression]. / Immunrekonstitution und Virussuppression durch neue Therapiestrategie bei HIV-Infektion.

BACKGROUND: In the last years, highly active antiretroviral therapy has decreased AIDS-associated mortality of patients dramatically. Due to this prolonged lifetime, the emergence of resistance against antiretroviral therapy has increased. Additionally, cross-resistance within the classes of nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) complicates HIV therapy. Development of new classes of therapeutic agents can help avoiding cross-resistance. Fuzeon, the first agent in the new class of fusion inhibitors, should be combined with as many effective antiretroviral agents as possible. CASE REPORT: The course of a 106-week therapy in a patient infected with a multiresistant virus is described. CONCLUSION: Fusion inhibitor Fuzeon represents a new option for patients having multiple resistance against HAART.

Cell activation by synthetic lipopeptides of the hepatitis C virus (HCV)--core protein is mediated by toll like receptors (TLRs) 2 and 4.

T cell epitopes coupled to a lipid moiety (lipopeptides) may be superior immunostimulants compared to peptide antigens and are currently studied as potential vaccines. The cause of enhanced immunogenicity of lipopeptides is largely unknown but members of the novel family of Toll like receptors (TLR) such as TLR2 and TLR4 have been shown to mediate activation of cells in response to bacterial lipopolysaccharide (LPS) and other lipidated bacterial or viral components. We studied TLR-mediated activation by 14 synthetic lipopeptides corresponding to T cell epitopes on hepatitis C virus (HCV) core in human embryonic kidney cells (HEK293) transiently over-expressing TLR2 and in Ba/F3 mouse bone marrow cells stably transfected with TLR4 and the adaptor molecule MD-2. Stimulation of transfected HEK293 or Ba/F3 cells was measured via luciferase activity as a reporter of nuclear factor kappaB activation. Free peptides, a non-HCV-related lipopeptide as well as LPS and the lipopeptide SK4 were used as controls. Ten of the 14 HCV core lipopeptides stimulated luciferase activity in TLR2-transfected HEK293 cells but not in mock-transfected control cells. Nine of the 14 lipopeptides also stimulated luciferase activity in the TLR4/MD-2 double-transfected Ba/F3 cells but not Ba/F3 control cells. Overall, there was a close statistical correlation between TLR2 and TLR4/MD-2-mediated cell activation by the lipopeptides. In contrast, the corresponding free peptides had no stimulatory effect on TLR2 nor on TLR4/MD-2 transfected cells. Thus, lipopeptides but not their corresponding free peptides can activate cells via TLRs 2 and 4. This activation is apparently affected by the amino acid sequence of the peptide moiety.