Management der Primären Ciliären Dyskinesie

Die Primäre Ciliäre Dyskinesie (PCD, MIM 242650) ist eine seltene hereditäre Multisystemerkrankung mit klinisch heterogenem Phänotyp. Leitsymptom ist eine chronische Sekretretention der oberen und unteren Atemwege, welche durch die Dysfunktion motiler respiratorischer Zilien entsteht. In der Folge kommt es zur Ausbildung von Bronchiektasen, häufig zu einer Infektion durch Pseudomonas aeruginosa sowie einer abnehmenden Lungenfunktion bis hin zum Lungenversagen. Bislang gibt es kaum evidenzbasierte Therapieempfehlungen, da randomisierte Langzeitstudien zur Behandlung der PCD fehlten. In diesem Jahr wurden die Daten einer ersten placebokontrollierten Medikamentenstudie bei PCD veröffentlicht. Anlässlich dieses Meilensteins im Management der PCD wurde der vorliegende Übersichtsartikel als Konsens von Patientenvertretern sowie Klinikern, die langjährige Erfahrung in der Behandlung der PCD haben, verfasst. Diese Arbeit bietet eine Zusammenfassung aktuell eingesetzter Behandlungsverfahren, die überwiegend auf persönlichen Erfahrungen und Expertenmeinungen beruhen oder von anderen Atemwegserkrankungen wie der Cystischen Fibrose (CF), COPD oder Bronchiektasen-Erkrankung abgeleitet werden. Da es derzeit keine kurative Therapie für PCD gibt, stehen symptomatische Maßnahmen wie die regelmäßige Reinigung der Atemwege und die Behandlung von rezidivierenden Atemwegsinfektionen im Fokus. Nicht respiratorische Manifestationen werden organspezifisch behandelt. Um neben der ersten Medikamentenstudie mehr evidenzbasiertes Wissen zu generieren, werden weitere Projekte etabliert, u. a. ein internationales PCD-Register. Hierüber wird Patienten der Zugang zu klinischen und wissenschaftlichen Studien erleichtert und die Vernetzung behandelnder Zentren gefördert. Des Weiteren können Erkenntnisse über eine Genotyp-spezifische Erkrankungsschwere erlangt werden, um folglich die therapeutische Versorgung der Patienten zu verbessern und somit zu individualisieren. = Primary Ciliary Dyskinesia (PCD, MIM 242650) is a rare, hereditary multiorgan disease characterized by malfunction of motile cilia. Hallmark symptom is a chronic airway infection due to mucostasis leading to irreversible lung damage that may progress to respiratory failure. There is no cure for this genetic disease and evidence-based treatment is limited. Until recently, there were no randomized controlled trials performed in PCD, but this year, data of the first placebo-controlled trial on pharmacotherapy in PCD were published. This cornerstone in the management of PCD was decisive for reviewing currently used treatment strategies. This article is a consensus of patient representatives and clinicians, which are highly experienced in care of PCD-patients and provides an overview of the management of PCD. Treatments are mainly based on expert opinions, personal experiences, or are deduced from other lung diseases, notably cystic fibrosis (CF), COPD or bronchiectasis. Most strategies focus on routine airway clearance and treatment of recurrent respiratory tract infections. Non-respiratory symptoms are treated organ specific. To generate further evidence-based knowledge, other projects are under way, e. g. the International PCD-Registry. Participating in patient registries facilitates access to clinical and research studies and strengthens networks between centers. In addition, knowledge of genotype-specific course of the disease will offer the opportunity to further improve and individualize patient care

The international primary ciliary dyskinesia cohort (iPCD Cohort): methods and first results

Data on primary ciliary dyskinesia (PCD) epidemiology is scarce and published studies are characterised by low numbers. In the framework of the European Union project BESTCILIA we aimed to combine all available datasets in a retrospective international PCD cohort (iPCD Cohort). We identified eligible datasets by performing a systematic review of published studies containing clinical information on PCD, and by contacting members of past and current European Respiratory Society Task Forces on PCD. We compared the contents of the datasets, clarified definitions and pooled them in a standardised format. As of April 2016 the iPCD Cohort includes data on 3013 patients from 18 countries. It includes data on diagnostic evaluations, symptoms, lung function, growth and treatments. Longitudinal data are currently available for 542 patients. The extent of clinical details per patient varies between centres. More than 50% of patients have a definite PCD diagnosis based on recent guidelines. Children aged 10–19 years are the largest age group, followed by younger children (⩽9 years) and young adults (20–29 years). This is the largest observational PCD dataset available to date. It will allow us to answer pertinent questions on clinical phenotype, disease severity, prognosis and effect of treatments, and to investigate genotype–phenotype correlations

Factors associated with worse lung function in cystic fibrosis patients with persistent staphylococcus aureus

Background Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. Results 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). Conclusions In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia

ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function

Anaphylaxis in Elderly Patients-Data From the European Anaphylaxis Registry

Background: Elicitors and symptoms of anaphylaxis are age dependent. However, little is known about typical features of anaphylaxis in patients aged 65 years or more. Methods: The data from the Network for Online Registration of Anaphylaxis (NORA) considering patients aged ≥65 (elderly) in comparison to data from adults (18–64 years) regarding elicitors, symptoms, comorbidities, and treatment measures were analyzed. Results: We identified 1,123 elderly anaphylactic patients. Insect venoms were the most frequent elicitor in this group (p < 0.001), followed by drugs like analgesics and antibiotics. Food allergens elicited less frequently anaphylaxis (p < 0.001). Skin symptoms occurred less frequently in elderly patients (77%, p < 0.001). The clinical symptoms were more severe in the elderly (51% experiencing grade III/IV reactions), in particular when skin symptoms (p < 0.001) were absent. Most strikingly, a loss of consciousness (33%, p < 0.001) and preexisting cardiovascular comorbidity (59%, p < 0.001) were more prevalent in the elderly. Finally, adrenaline was used in 30% of the elderly (vs. 26% in the comparator group, p < 0.001) and hospitalization was more often required (60 vs. 50%, p < 0.001). Discussion and Conclusion: Anaphylaxis in the elderly is often caused by insect venoms and drugs. These patients suffer more often from cardiovascular symptoms, receive more frequently adrenaline and require more often hospitalization. The data indicate that anaphylaxis in the elderly tends to be more frequently life threatening and patients require intensified medical intervention. The data support the need to recognize anaphylaxis in this patient group, which is prone to be at a higher risk for a fatal outcome

Diagnostik der primären ziliären Dyskinesie

Characteristics: Primary ciliary dyskinesia (PCD) is a rare congenital disease of the cilia which is mostly manifested in the respiratory system. Diagnostics: When there is a clinical suspicion of the presence of PCD and/or a positive screening result with reduced nasal nitrogen oxide (NO) values, further diagnostic measures should be initiated as soon as possible. In centers where high-frequency video microscopy analyses (HVMA) of beating of cilia are available, an initial nasal NO measurement for screening must not necessarily be carried out. As the first diagnostic measure for confirmation or exclusion of PCD, HVMA should be carried out. If the findings are conspicuous transmission electron microscopic analysis (TEM) of the ciliary structure and high-resolution immunofluorescence (IF) microscopic analysis of the cilia should follow. Mandatory for diagnosis are at least two congruent pathological findings from HVMA, TEM or IF. When a PCD variant with no evidence of ultrastructural defects is present, an identical pathological beating of cilia must be demonstrated with HVMA on three independent occasions. Following that a targeted genetic clarification should be attempted based on the findings for HVMA, TEM and IF. A clear genetic result can also confirm the diagnosis. Approach: When PCD is suspected contact with a diagnostic center should be made. A reference center for PCD diagnostics will evaluate uncertain findings

Type 2 biomarker expression according to age of asthma onset: an analysis of the German severe asthma registry (GAN)

Lommatzsch M, Taube C, Hamelmann E, et al. Type 2 biomarker expression according to age of asthma onset: an analysis of the German severe asthma registry (GAN). In: ERS International Congress 2022 abstracts. European Respiratory Journal. Vol 60. Sheffield: European Respiratory Society; 2022.Background: The relevance of the age of asthma onset for type 2 biomarker expression in severe asthma is incompletely understood. Methods: Data of 1512 patients documented in the German severe asthma registry (GAN) were analysed according to age of asthma onset (severe early-onset asthma, SEA: age of onset <18 years of age; severe adult-onset asthma, SAA: age of onset ≥18 years of age). Results: There were 456 patients with SEA (30.2%, median age: 38 years, median age at asthma onset: 5 years) and 1056 patients with SAA (69.8%, median age: 56 years, median age at asthma onset: 40 years). There was no significant difference in the gender distribution (SEA: 59%, SAA: 56.2% females). SAA was characterised by a higher percentage of ever-smokers (SEA: 24.6%, SAA: 48.9%), a higher median BMI (SEA: 24.9 kg/m2, SAA: 26.7 kg/m2), a higher number of very frequent exacerbators (SEA: 4.7%, SAA: 8.3%) and a higher percentage of patients with chronic sinusitis (SEA: 39%, SAA: 56.5%), nasal polyps (SEA: 22.3%, SAA: 45.2%) and Aspirin-exacerbated respiratory disease (SEA: 17.8%, SAA: 23.8%) than SEA. In contrast, there was a lower median FEV1 (SEA: 70%, SAA: 66% predicted), a lower median total serum immunoglobulin E (IgE, SEA: 201 IU/ml, SAA: 169 IU/ml) and a lower prevalence of allergic co-morbidities (SEA: 81.5%, SAA: 57.5%) in SAA than in SEA. Patients with SAA displayed higher median exhaled FeNO values (SEA: 23 ppb, SAA: 41 ppb) and higher median blood eosinophil counts (SEA: 200 cells/µl, SAA: 251 cells/µl) than patients with SEA. Conclusion: Severe adult-onset asthma is characterised by a stronger expression of type 2 biomarkers than severe early-onset asthma

Die induzierbare laryngeale Obstruktion (ILO) – Ursachen, klinische Präsentation, Diagnostik und Therapie

&lt;jats:title&gt;Zusammenfassung&lt;/jats:title&gt;&lt;jats:p&gt;Wiederholt episodenhaft auftretende Atemnot ist im Kindes- und Jugendalter ein häufiges Symptom. Neben anstrengungsinduzierter Bronchialobstruktion im Rahmen eines Asthma bronchiale ist eine funktionelle Genese eine sehr häufige Differenzialdiagnose. Dennoch wird diese Diagnose häufig nicht oder mit langer Latenz gestellt. Unter dem Oberbegriff „ILO“ („inducible laryngeal obstruction“) werden sowohl funktionelle supraglottische Obstruktionen durch Kollaps der Knorpelstrukturen als auch Dysfunktionen auf Glottisebene wie „vocal cord dysfunction“ (VCD) subsumiert. Körperliche Anstrengung ist ein häufiger Auslöser; es werden jedoch auch Beschwerdebilder ohne Anstrengungsbezug beobachtet. Es wird der Erkenntnisstand zur Pathophysiologie referiert und die klinische Präsentation beschrieben. Ein wesentlicher Fokus des Artikels liegt im Folgenden auf der Darstellung eines sinnvollen und Ressourcen-orientierten diagnostischen Vorgehens. Der CLE-Test („continuous laryngoscopy exercise test“) als Provokationsmethode unter Wach-Videolaryngoskopie ist der Goldstandard, jedoch wird diese Diagnostik im deutschsprachigen Raum nicht flächendeckend vorgehalten. Dieses Positionspapier stellt daher die diagnostische Wertigkeit verschiedener anderer Diagnostik-Algorithmen und anamnestischer Informationen heraus. Ein weiterer Schwerpunkt des Papiers besteht in der detaillierten Vorstellung geeigneter atemphysiotherapeutischer Interventionen.&lt;/jats:p&gt