[Diagnosis and treatment of asthma: a guideline for respiratory specialists 2023 - published by the German Respiratory Society (DGP) e. V.] / S2k-Leitlinie zur fachärztlichen Diagnostik und Therapie von Asthma 2023.

The management of asthma has fundamentally changed during the past decades. The present guideline for the diagnosis and treatment of asthma was developed for respiratory specialists who need detailed and evidence-based information on the new diagnostic and therapeutic options in asthma. The guideline shows the new role of biomarkers, especially blood eosinophils and fractional exhaled NO (FeNO), in diagnostic algorithms of asthma. Of note, this guideline is the first worldwide to announce symptom prevention and asthma remission as the ultimate goals of asthma treatment, which can be achieved by using individually tailored, disease-modifying anti-asthmatic drugs such as inhaled steroids, allergen immunotherapy or biologics. In addition, the central role of the treatment of comorbidities is emphasized. Finally, the document addresses several challenges in asthma management, including asthma treatment during pregnancy, treatment of severe asthma or the diagnosis and treatment of work-related asthma.

Skin Tests versus Serology: Specific IgE May Suffice for Diagnosis of Vespid Venom Allergy and Follow-Up of Allergen Immunotherapy.

INTRODUCTION: In adults, allergic reactions to insect stings are among the most frequent causes of anaphylaxis, a potentially life-threatening condition. Recurrent anaphylaxis following vespid stings may be prevented by allergen immunotherapy (AIT). The aim of this study was to evaluate the benefit of measuring venom-induced wheal area in intracutaneous skin tests (ICT), in comparison to various serological and clinical parameters, for the diagnosis of severe vespid venom allergy and during follow-up of AIT. METHODS: We conducted a monocentric, retrospective evaluation of 170 patients undergoing AIT against vespid venoms. We scanned ICT wheals at baseline and at three time points after AIT initiation and measured wheal area using objective data analysis software. RESULTS: We found that ICT histamine-induced and venom-induced wheal areas did not correlate. In addition, the venom-induced wheal area was independent from the minimal venom concentration required to elicit a wheal in an ICT and all other parameters. No correlation was found between wheal area and the severity of anaphylaxis. Wheal area standardized to the application of 0.1 µg/mL venom inversely correlated with anaphylaxis severity and positively correlated with venom-specific IgE levels. During AIT, mean areas of venom-induced wheals did not change. In contrast, venom-specific IgG and IgG4 levels, and the minimal venom concentration required to induce a positive ICT result increased, while the venom wheal area standardized to 0.1 µg/mL venom application and specific IgE levels decreased over time. CONCLUSION: Wheal area evaluation did not provide additional information over specific IgE analysis. We therefore recommend that ICTs are used only as a secondary measure for confirming serological test results.

Pathogen spectra in hospitalised and nonhospitalised children with community-acquired pneumonia.

Background: Paediatric community-acquired pneumonia (CAP) is a leading cause of paediatric morbidity. However, particularly for outpatients with paediatric CAP, data on aetiology and management are scarce. Methods: The prospective pedCAPNETZ study multicentrically enrols children and adolescents with outpatient-treated or hospitalised paediatric CAP in Germany. Blood and respiratory specimens were collected systematically, and comprehensive analyses of pathogen spectra were conducted. Follow-up evaluations were performed until day 90 after enrolment. Results: Between December 2014 and August 2020, we enrolled 486 children with paediatric CAP at eight study sites, 437 (89.9%) of whom had radiographic evidence of paediatric CAP. Median (interquartile range) age was 4.5 (1.6-6.6) years, and 345 (78.9%) children were hospitalised. The most prevalent symptoms at enrolment were cough (91.8%), fever (89.2%) and tachypnoea (62.0%). Outpatients were significantly older, displayed significantly lower C-reactive protein levels and were significantly more likely to be symptom-free at follow-up days 14 and 90. Pathogens were detected in 90.3% of all patients (one or more viral pathogens in 68.1%; one or more bacterial strains in 18.7%; combined bacterial/viral pathogens in 4.1%). Parainfluenza virus and Mycoplasma pneumoniae were significantly more frequent in outpatients. The proportion of patients with antibiotic therapy was comparably high in both groups (92.4% of outpatients versus 86.2% of hospitalised patients). Conclusion: We present first data on paediatric CAP with comprehensive analyses in outpatients and hospitalised cases and demonstrate high detection rates of viral pathogens in both groups. Particularly in young paediatric CAP patients with outpatient care, antibiotic therapy needs to be critically debated.

[New interdisciplinary teaching concept for the cross-sectional subject of allergology in human medicine studies]. / Interdisziplinäre Neukonzeption der Lehre im Querschnittsfach "Allergologie" im Studiengang Humanmedizin.

BACKGROUND: Although allergic diseases are among the most important health disorders, allergology is not anchored as an independent subject in the clinical part of medical studies in Germany. OBJECTIVE: As all universities and institutes face the same challenge, the aim of our project was to establish exemplary coordination and networking of education in allergology at one location in agreement with all involved departments and institutes. Particularly, Comprehensive Allergy Centers (CAC) offer an established infrastructure via which the revised allergology education program can be transferred to other universities. MATERIALS AND METHODS: After an extensive inventory of the current allergological curriculum at the University Medical Center Göttingen, a new teaching concept was developed in interdisciplinary consensus, supplemented by first-time provision of additional digital contents ("blended learning"), and finally evaluated. RESULTS: Initially, we observed a high level of fragmentation in the teaching of allergology in the clinical study sections of human medicine, with no coordination between the 12 clinical departments/institutes involved and no coherent framework for the specific learning content. Within the established structure of the interdisciplinary CAC, we revised, coordinated, and defined key areas for improved student education in clinical allergology. The allocation of new interactive learning elements as well as supplementary materials for self-studies was welcomed by the students and positively evaluated. A survey among students after completing the former vs. current curricula showed significant improvements in achieving the desired educational objectives.

Intracutaneous Skin Tests and Serum IgE Levels Cannot Predict the Grade of Anaphylaxis in Patients with Insect Venom Allergies.

Background: Allergies against Hymenoptera venoms are a major cause of severe anaphylaxis. Risk assessment for subjects with suspected allergy is difficult because there are currently no biomarkers that predict the likelihood of high-grade anaphylaxis other than several associated comorbidities. Objective: We investigated the relationship between the severity of anaphylaxis and the results of intracutaneous skin tests (ICTs) together with serum levels of tryptase, total IgE, and venom-specific IgE, IgG, and IgG4. Methods: We performed a retrospective evaluation of 194 patients who presented to a single medical center with allergies to bee venoms (Apis mellifera, Bombus spp.; n=24, 12.4%), vespid venoms (Vespula spp., Vespa spp., Polistes spp.; n=169, 87.1%), or both (n=1, 0.5%). Results: Index bee stings occurred earlier in the year than vespid stings, although the latter were reported more frequently overall. On average, subjects who previously experienced grade IV anaphylaxis required higher dosages of venom to yield positive ICTs than those who exhibited lower grade responses. Patients diagnosed with grade IV anaphylaxis exhibited significantly lower levels of venom-specific IgE and IgG and trended toward elevated levels of tryptase. No significant differences in average levels of venom-specific IgG4 and total IgE were observed. Conclusion: Our findings reveal that intracutaneous skin testing and levels of venom-specific IgE do not predict the degree of anaphylaxis that develops in patients with venom allergy. Furthermore, the month of the index sting is not a reliable means to differentiate bee from vespid stings in patients presenting with an uncertain history.

Early priming of asthma and respiratory allergies: Future aspects of prevention: A statement by the European Forum for Education and Research in Allergy and Airway Disease (EUFOREA) and the EAACI-Clemens von Pirquet Foundation.

In order to summarize recent research on the prevention of allergies-particularly asthma-and stimulate new activities for future initiatives, a virtual workshop sponsored by the EAACI Clemens von Pirquet foundation and EUFOREA was held in October 2021. The determinants of the "allergic march" as well as the key messages from intervention studies were reviewed by an international faculty of experts. Several unmet needs were identified, and a number of priorities for future studies were proposed.

Clinical presentation and basic defect of the CFTR genotype p.Phe508del / p.Arg117His in a mother and her monozygous twin daughters.

A non-consanguineous two-generation family of parent and monozygous twins who all three share the same CFTR mutation genotype p.Phe508del / p.Arg117His, was examined in clinical features, sweat test, nasal potential difference and intestinal current measurements. As expected the twins were very much alike in anthropometry and appearance and shared the clinical manifestation of CFTR dysfunction albeit at different intensity but unexpectedly like in comparison to their mother they were discordant in their CFTR-mediated basic defect and the response thereof to CFTR potentiation by ivacaftor. This case report illustrates the strong impact of non-inherited factors on the electrophysiological phenotype of the most common CFTR mutation genotype of variable clinical significance.

Validation of the LEOSound® monitor for standardized detection of wheezing and cough in children.

BACKGROUND: A hallmark of many respiratory conditions is the presence of nocturnal symptoms. Nevertheless, especially in children there is currently still a huge diagnostic gap in detecting nighttime symptoms, which leads to an underestimation of the frequency in clinical practise. METHODS: We evaluated the clinical applicability and determined the formal test characteristics of the LEOSound ® system, a device for digital long-time recording and automated detection of acoustic airway events. Airway sounds were recorded overnight in 115 children and adolescents (1-17 years) with and without respiratory conditions. The automated classification for "cough" and "wheezing" was subsequently validated against the manual acoustic reassessment by an expert physician. RESULTS: The general acceptance was good across all age groups and a technically successful recording was obtained in 98 children, corresponding to 92,976 sound epochs (à 30 s) or a total of 774 h of lung sounds. We found a sensitivity of 89% and a specificity of 99% for the automated detection of cough. For detection of wheezing, sensitivity and specificity were both 98%. The cough index and the wheeze index (events per hour) of individual patients showed a strong positive correlation (cough: rS = 0.85, wheeze: rS = 0.95) and a sufficient agreement of the two assessment methods in the Bland-Altman analysis. CONCLUSION: Our data show that the LEOSound® is a suitable device for standardized detection of cough and wheezing and hence a promising diagnostic tool to detect nocturnal respiratory symptoms, especially in children. However, a validation process to reduce false positive classifications is essential in clinical routine use.

European Respiratory Society clinical practice guidelines for the diagnosis of asthma in children aged 5-16†years.

BACKGROUND: Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children. METHODS: A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework. CONCLUSION: Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future.

Wheeze and cough measurements at night in children with respiratory symptoms.

BACKGROUND: Nocturnal cough and wheeze are important symptoms when diagnosing any respiratory disease in a child, but objective measurements of these symptoms are not performed. METHODS: The aim of our study was to analyze the use of an automated detection system to assess breath sounds objectively in comparison to cough and wheeze questionnaires and to evaluate its feasibility in clinical practice. RESULTS: Forty-nine recordings of thirty-nine children were processed (asthma n = 13; cystic fibrosis n = 2; pneumonia n = 5; suspicion of habit cough n = 7; prolonged, recurrent or chronic cough n = 13), and cough and asthma scores were compared to the objective nocturnal recordings. Time for audio-validation of recordings took between 2 and 40 min (mean: 14.22 min, (SD): 10.72). Accuracy of the automated measurement was higher for cough than for wheezing sounds. Nocturnal cough readings but not wheeze readings correlated with some of the corresponding scores. CONCLUSION: To our knowledge this is the first study using a new device to assess nocturnal cough and obstructive breath sounds objectively in children with a wide variety of respiratory diseases. The assessment proved user friendly. We obtained additional information on nighttime symptoms, which would otherwise have remained obscure. Further studies to assess possible diagnostic and therapeutic benefits of this device are needed.

PedCAPNETZ - prospective observational study on community acquired pneumonia in children and adolescents.

BACKGROUND: Pediatric community acquired pneumonia (pedCAP) is one of the leading causes for childhood morbidity accounting for up to 20% of pediatric hospital admissions in high income countries. In spite of its high morbidity, updated epidemiological and pathogen data after introduction of preventive vaccination and novel pathogen screening strategies are limited. Moreover, there is a need for validated recommendations on diagnostic and treatment regimens in pedCAP. Through collection of patient data and analysis of pathogen and host factors in a large sample of unselected pedCAP patients in Germany, we aim to address and substantially improve this situation. METHODS: pedCAPNETZ is an observational, multi-center study on pedCAP. Thus far, nine study centers in hospitals, outpatient clinics and practices have been initiated and more than 400 patients with radiologically confirmed pneumonia have been enrolled, aiming at a total of 1000 study participants. Employing an online data base, information on disease course, treatment as well as demographical and socioeconomical data is recorded. Patients are followed up until day 90 after enrollment; Comprehensive biosample collection and a central pedCAPNETZ biobank allow for in-depth analyses of pathogen and host factors. Standardized workflows to assure sample logistics and data management in more than fifteen future study centers have been established. DISCUSSION: Through comprehensive epidemiological, clinical and biological analyses, pedCAPNETZ fills an important gap in pediatric and infection research. To secure dissemination of the registry, we will raise clinical and scientific awareness at all levels. We aim at participating in decision making processes for guidelines and prevention strategies. Ultimately, we hope the results of the pedCAPNETZ registry will help to improve care and quality of life in pedCAP patients in the future.

Asthma control in children: Body plethysmography in addition to spirometry.

BACKGROUND: There is a lack of agreement among measures of asthma control in children. In Central Europe, body plethysmography is additionally used for asthma monitoring. However, its value is still unclear. OBJECTIVES: We investigated the possible additional value of body plethysmographic measures (specific resistance, residual volume-total lung capacity ratio [RV/TLC]) compared with spirometric measures forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC, forced expiratory flow at 25% to 75% of forced vital capacity (FEF 25-75 ), and fraction of exhaled nitric oxide (FeNO) for assessment of asthma control. METHODS: One hundred and forty-five asthmatic children aged 5 to 17 were included. All children performed measurements of FeNO, spirometry, and body plethymography. Asthma control was assessed by the asthma control test (c-ACT/ACT) and a doctor's assessment of asthma control. RESULTS: Investigating single lung function parameters, FEV1 , FEV 1 /FVC, FEF 25-75 and RV/TLC differed between controlled and partly controlled asthma. However, we found no differences between controlled and uncontrolled asthma with regard to single lung function parameters or for any parameter if investigated in a multivariable approach. This was also true if we combined obtained parameters from spirometry (comparing pathologic vs normal spirometry). Investigating the combination of body plethysmography and doctor's assessment of asthma control a significant association was found ( P = 0.02). Furthermore, combined spirometry and body plethysmography showed a significant association with both doctor's assessed asthma control ( P = 0.009) and the c-ACT/ACT ( P = 0.04). The addition of FeNO did not improve the results. CONCLUSIONS: The combination of body plethysmography and spirometry shows best agreement with asthma control in children compared with spirometry or body plethysmography alone. Further studies are needed to find out whether additional measurements of body plethysmography improve the outcome of children in asthma monitoring.

Functional analysis of the p.[Arg74Trp;Val201Met;Asp1270Asn]/p.Phe508del CFTR mutation genotype in human native colon.

BACKGROUND: The impact of complex alleles on CFTR processing and function has yet not been investigated in native human tissue. METHODS: Intestinal current measurements (ICM) followed by CFTR immunoblot were performed on rectal biopsies taken from two siblings who are compound heterozygous for the CFTR mutations p.Phe508del and the complex allele p.[Arg74Trp;Val201Met;Asp1270Asn]. RESULTS: Normal and subnormal chloride secretory responses in the ICM were associated with normal and fourfold reduced amounts of the mature glycoform band C CFTR, respectively, consistent with the unequal clinical phenotype of the siblings. CONCLUSION: The combined use of bioassay and protein analysis is particularly meaningful to resolve the CFTR phenotype of "indeterminate" borderline CFTR genotypes on a case-to-case basis.

What does lung function tell us about respiratory multimorbidity in childhood and early adulthood? Results from the MAS birth cohort study.

BACKGROUND: Interaction between respiratory multimorbidity and lung function has not been examined in longitudinal population studies. We aimed to assess the association of multimorbidity of asthma and rhinitis with lung function and bronchial hyperresponsiveness in comparison with single and no allergies from early school age to young adulthood. METHODS: In 1990, the Multicenter Allergy Study birth cohort recruited 1314 newborns from 5 German cities. At 7, 13, and 20 years, we performed lung function and bronchial challenge tests. We assessed symptoms, medications, and doctor's diagnoses for asthma and rhinitis for 3 outcomes: current multimorbidity (both coexisting), asthma only, and rhinitis only. RESULTS: From 7 to 20 years, multimorbidity prevalence more than doubled from 3.5% to 7.7%, current asthma only (without rhinitis co-occurring) decreased by half from 2.8% to 1.3%, and current rhinitis only (without asthma co-occurring) increased from 14.3% to 41.6%. Resting lung function parameters differed between allergic and asymptomatic participants but showed no considerable differences between the allergic phenotypes. Frequency and severity of bronchial hyperresponsiveness were particularly associated with multimorbidity. At the age of 20 years, participants with multimorbidity showed a clearly higher severity in hyperresponsiveness compared to participants who suffered only asthma (P = .049) or rhinitis (P = .008) or were asymptomatic (P < .001). CONCLUSION: Single lung function measurements from childhood ongoing do not seem to discriminate between subjects with multimorbidity, single allergies, and no allergy. Our results show that multimorbidity is associated with more severe symptoms compared to those suffering only a single allergic disease.

[New international reference values for spirometry: implications for clinical issues using a comparative analysis of a paediatric population]. / Neue internationale Referenzwerte für die Spirometrie--Implikation für die Praxis anhand einer vergleichenden Analyse eines pädiatrischen Patientenkollektivs.

BACKGROUND: The new lung function reference values of the global lung initiative (GLI) are recommended by most health societies. The aim of this study was to analyze FEV1- and FEV1/FVC-values from a German and Austrian patient group applying old and new reference values. RESULTS: A total of 215 Caucasian children (aged 5-17 years) were included. FEV1-values were significantly lower applying GLI reference values compared to Zapletal values (median 96.9 % pred. (87.3-105.2) versus 100.6 % pred. (quartile 91.5-111.4), p = 0.000), the median difference was 4.9 % (range -12.9 to 27.5) % pred. Differences correlated significantly with age and FEV1 in % predicted (Zapletal), p = 0.000 17/70 (24 %) patients with cystic fibrosis had FEV1-values <80% pred. applying Zapletal, in 25 (36 %) patients FEV1 was abnormal (z-score <1645) using GLI values; 3/145 asthmatics (2 %) had FEV1-Werte <80 % d.S. (Zapletal), 7/145 (5 %) z-scores <1645 (GLI). CONCLUSION: Differences between GLI-and Zapletal-reference values were considerable in pediatric asthma and CF-patients.

Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation.

This review focuses on the methods available for measuring reversible airways obstruction, bronchial hyperresponsiveness (BHR) and inflammation as hallmarks of asthma, and their role in monitoring children with asthma. Persistent bronchial obstruction may occur in asymptomatic children and is considered a risk factor for severe asthma episodes and is associated with poor asthma outcome. Annual measurement of forced expiratory volume in 1 s using office based spirometry is considered useful. Other lung function measurements including the assessment of BHR may be reserved for children with possible exercise limitations, poor symptom perception and those not responding to their current treatment or with atypical asthma symptoms, and performed on a higher specialty level. To date, for most methods of measuring lung function there are no proper randomised controlled or large longitudinal studies available to establish their role in asthma management in children. Noninvasive biomarkers for monitoring inflammation in children are available, for example the measurement of exhaled nitric oxide fraction, and the assessment of induced sputum cytology or inflammatory mediators in the exhaled breath condensate. However, their role and usefulness in routine clinical practice to monitor and guide therapy remains unclear, and therefore, their use should be reserved for selected cases.

Monitoring asthma in children.

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence.

Elevated exhaled leukotriene B4 in the small airway compartment in children with asthma.

BACKGROUND: Inflammatory processes in the asthmatic lung involve the large and small airway and alveolar sites. Leukotriene B4 (LTB4) is an important disease marker, but its role in inflammation of the small airways in asthma has not been established yet. OBJECTIVE: To distinguish between large and small airway or alveolar LTB4 concentrations in children with asthma using the new technique of fractionated exhaled breath condensate sampling. METHODS: Sixty-eight children (9-17 years old, 33 children with asthma and 35 controls) underwent fractional exhaled nitric oxide (FeNO) measurements, lung function testing, and collection of fractionated exhaled breath condensate using a capnograph-based approach. The LTB4 concentrations in the small airway or alveolar and large airway fractions were correlated to disease status, lung function impairment, and clinical parameters. RESULTS: Children with asthma had significantly higher LTB4 concentrations in the small airway or alveolar fraction than controls (5.58 pg/mL; 95% interquartile range [IQR], 2.0-11.77 pg/mL; vs 2.0 pg/mL; 95% IQR, 2.0-6.2 pg/mL; P = .003). No difference was found between the groups in the large airway fraction. Children with obstructive lung function impairment (forced expiratory volume in 1 second z score <-1.65) had increased small airway or alveolar LTB4 concentrations compared with children without impairment (2.0 pg/mL; 95% IQR, 2.0-9.21 pg/mL; vs 18.32 pg/mL; 95% IQR, 3.7-23.02 pg/mL; P = .04). Children with asthma but without pathologic obstructive lung function still had higher LTB4 concentrations than controls (5.57 pg/mL; 95% IQR, 2.00-10.60 pg/mL; vs 2.00 pg/mL; 95% IQR, 2.00-6.20 pg/mL; P = .01). CONCLUSION: LTB4 is detectable and elevated in the small airway or alveolar fraction of exhaled breath condensate in pediatric asthma. Because of the possibility of detecting elevated levels in patients without lung function impairment in controlled disease, it may be used as a noninvasive marker of small airways disease; however, future long-term studies are needed.