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The 4th Davos Declaration was developed during the Global Allergy Forum in Davos which aimed to elevate the care of patients with atopic dermatitis (AD) by uniting experts and stakeholders. The forum addressed the high prevalence of AD, with a strategic focus on advancing research, treatment, and management to meet the evolving challenges in the field. This multidisciplinary forum brought together top leaders from research, clinical practice, policy, and patient advocacy to discuss the critical aspects of AD, including neuroimmunology, environmental factors, comorbidities, and breakthroughs in prevention, diagnosis, and treatment. The discussions were geared towards fostering a collaborative approach to integrate these advancements into practical, patient-centric care. The forum underlined the mounting burden of AD, attributing it to significant environmental and lifestyle changes. It acknowledged the progress in understanding AD and in developing targeted therapies but recognized a gap in translating these innovations into clinical practice. Emphasis was placed on the need for enhanced awareness, education, and stakeholder engagement to address this gap effectively and to consider environmental and lifestyle factors in a comprehensive disease management strategy. The 4th Davos Declaration marks a significant milestone in the journey to improve care for people with AD. By promoting a holistic approach that combines research, education, and clinical application, the Forum sets a roadmap for stakeholders to collaborate to improve patient outcomes in AD, reflecting a commitment to adapt and respond to the dynamic challenges of AD in a changing world.
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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.
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Antibacterianos , Fibrose Cística , Guias de Prática Clínica como Assunto , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/tratamento farmacológico , Fibrose Cística/microbiologia , Fibrose Cística/terapia , Alemanha , Antibacterianos/uso terapêutico , Pneumologia/normas , Medicina Baseada em EvidênciasRESUMO
Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity. Mechanistic studies involving cryoelectron microscopy identified a surface-exposed C-terminal PcrV epitope as the target of highly neutralizing mAbs with broad activity against drug-resistant PA isolates. These anti-PcrV mAbs were as effective as treatment with conventional antibiotics in vivo. Our study reveals that chronically infected patients represent a source of neutralizing antibodies, which can be exploited as therapeutics against PA.
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Anticorpos Antibacterianos , Anticorpos Neutralizantes , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Anticorpos Antibacterianos/farmacologia , Microscopia Crioeletrônica , Imunoglobulinas/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Infecções por Pseudomonas/tratamento farmacológicoRESUMO
Across the lifespan, the human body and brain endure the impact of a plethora of exogenous and endogenous factors that determine the health outcome in old age. The overwhelming inter-individual variance spans between progressive frailty with loss of autonomy to largely preserved physical, cognitive, and social functions. Understanding the mechanisms underlying the diverse aging trajectories can inform future strategies to maintain a healthy body and brain. Here we provide a comprehensive overview of the current literature on lifetime factors governing brain health. We present the growing body of evidence that unhealthy alimentary regime, sedentary behaviour, sleep pathologies, cardio-vascular risk factors, and chronic inflammation exert their harmful effects in a cumulative and gradual manner, and that timely and efficient intervention could promote healthy and successful aging. We discuss the main effects and interactions between these risk factors and the resulting brain health outcomes to follow with a description of current strategies aiming to eliminate, treat, or counteract the risk factors. We conclude that the detailed insights about modifiable risk factors could inform personalized multi-domain strategies for brain health maintenance on the background of increased longevity.
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Encéfalo , Longevidade , Humanos , Envelhecimento , Fatores de Risco , Comportamento SedentárioRESUMO
Inhalation therapy represents the standard of care in children, adolescents as well as in young, middle-aged and geriatric adults with asthma or chronic obstructive pulmonary disease. However, there are only few recommendations for the choice of inhalation devices, which consider both, age-specific limitations in young and geriatric patients. Transition concepts are lacking. In this narrative review, the available device technologies and the evidence for age-specific problems are discussed. Pressurized metered-dose inhalers may be favoured in patients who fulfill all cognitive, coordinative and manual power requirements. Breath-actuated metered-dose inhalers, soft-mist inhalers or the use of add-on devices such as spacers, face masks and valved holding chambers may be suitable for patients with mild to moderate impairments of these variables. In these cases, available resources of personal assistance by educated family members or caregivers should be used to allow metered-dose inhaler therapy. Dry powder inhalers may be reserved for patients with a sufficient peak inspiratory flow and good cognitive and manual abilities. Nebulizers may be indicated in persons who are either unwilling or unable to use handheld inhaler devices. After initiation of a specific inhalation therapy, close monitoring is essential to reduce handling mistakes. An algorithm is developed that considers age and relevant comorbidities to support the decision-making process for the choice of an inhaler device.
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Asma , Doença Pulmonar Obstrutiva Crônica , Adulto , Criança , Pessoa de Meia-Idade , Adolescente , Humanos , Lactente , Idoso , Asma/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Nebulizadores e Vaporizadores , Terapia Respiratória , Administração por Inalação , Inaladores Dosimetrados , Inaladores de Pó Seco , Desenho de EquipamentoRESUMO
BACKGROUND: The Asthma Severity Scoring System (ASSESS) quantifies asthma severity in adolescents and adults. Scale performance in children younger than 12 years is unknown. OBJECTIVE: To validate the ASSESS score in the All Age Asthma Cohort and explore its use in children younger than 12 years. METHODS: Scale properties, responsiveness, and known-group validity were assessed in 247 children (median age, 11 years; interquartile range, 8-13 years) and 206 adults (median age, 52 years; interquartile range, 43-63 years). RESULTS: Overall, measures of internal test consistency and test-retest reliability were similar to the original data of the Severe Asthma Research Program. Cronbach α was 0.59 in children aged 12 to 18 years and 0.73 in adults, reflecting the inclusion of multiple and not-always congruent dimensions to the ASSESS score, especially in children. Analysis of known-group validity confirmed the discriminatory power, because the ASSESS score was significantly worse in patients with poor asthma control, exacerbations, and increased salbutamol use. In children aged 6 to 11 years, test-retest reliability was inferior compared with that in adults and adolescents (Cronbach α, 0.27) mostly because of a less lung function impairment in children with asthma of this age group. Known-group validity, however, confirmed good discriminative power regarding severity-associated variables similar to adolescents and adults. CONCLUSIONS: Test-retest reliability and validity of the ASSESS score was confirmed in the All Age Asthma Cohort. In children aged 6 to 11 years, internal consistency was inferior compared with that in older patients with asthma; however, test validity was good and thus encourages age-spanning usage of the ASSESS score in all patients 6 years or older.
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Asma , Criança , Adulto , Adolescente , Humanos , Idoso , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Inquéritos e Questionários , Asma/diagnósticoRESUMO
RATIONALE: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children. OBJECTIVES: To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages. METHODS: In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2â years (1â year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28. MEASUREMENTS AND MAIN RESULTS: Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: "atopy-only", "eosinophils-only", "T2-high" (eosinophilia + atopy) and "T2-low" (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2â years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood. CONCLUSIONS: Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.
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Asma , Eosinofilia , Alérgenos , Biomarcadores , Antígenos CD28/genética , Eosinófilos , Humanos , Imunoglobulina E , Interleucina-13 , Interleucina-5 , Lipopolissacarídeos , Longevidade , FenótipoRESUMO
RESEARCH QUESTION: Pulmonary disease progression in patients with cystic fibrosis (CF) is characterised by inflammation and fibrosis and aggravated by Pseudomonas aeruginosa (Pa). We investigated the impact of Pa specifically on: 1) protease/antiprotease balance; 2) inflammation; and 3) the link of both parameters to clinical parameters of CF patients. METHODS: Transforming growth factor-ß1 (TGF-ß1), interleukin (IL)-1ß, IL-8, neutrophil elastase (NE) and elastase inhibitor elafin were measured (ELISA assays), and gene expression of the NF-κB pathway was assessed (reverse transcriptase PCR) in the sputum of 60 CF patients with a minimum age of 5â years. Spirometry was assessed according to American Thoracic Society guidelines. RESULTS: Our results demonstrated the following: 1) NE was markedly increased in Pa-positive sputum, whereas elafin was significantly decreased; 2) increased IL-1ß/IL-8 levels were associated with both Pa infection and reduced forced expiratory volume in 1â s, and sputum TGF-ß1 was elevated in Pa-infected CF patients and linked to an impaired lung function; and 3) gene expression of NF-κB signalling components was increased in sputum of Pa-infected patients, and these findings were positively correlated with IL-8. CONCLUSION: Our study links Pa infection to an imbalance of NE and NE inhibitor elafin and increased inflammatory mediators. Moreover, our data demonstrate an association between high TGF-ß1 sputum levels and a progress in chronic lung inflammation and pulmonary fibrosis in CF. Controlling the excessive airway inflammation by inhibition of NE and TGF-ß1 might be promising therapeutic strategies in future CF therapy and a possible complement to cystic fibrosis transmembrane conductance regulator (CFTR) modulators.
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OBJECTIVES: Pediatric lymphocytic interstitial pneumonia (LIP) and follicular bronchiolitis (FB) are poorly characterized lymphoproliferative disorders. We present and quantify demographics, radiological and histopathologic patterns, treatments and their responses, and outcomes in non-HIV-infected children with LIP and FB. METHODS: This structured registry-based study included a retrospective chart review, blinded analysis of imaging studies and lung biopsies, genetic testing, and evaluation of treatments and outcomes. RESULTS: Of the 13 patients (eight females) studied, eight had FB, four had combined LIP/FB, and one had isolated LIP; diagnoses were highly concordant between the pathologists. Most patients became symptomatic during the first 2 years of life, with a mean lag time to diagnosis of 4 years. The most common symptoms were coughing and respiratory infections (11 out of 13 each), dyspnea (10 out of 13), and wheezing (eight out of 13). Autoantibodies were found in eight out of 13 patients. In three patients, disease-causing mutations in the COPA gene were identified. CT revealed hilar lymphadenopathy (five out of 12), ground-glass opacity (eight out of 12), consolidation (five out of 12), and cysts (four out of 13). Systemic steroids as intravenous pulses (11 out of 13) or oral intake (10 out of 13) were the main treatments and showed high response rates of 100% and 90%, respectively. Within the mean observation period of 68 months, all children had chronic courses, eight out of 13 had severe diseases, two died, and one worsened. CONCLUSIONS: Children with LIP/FB have chronic diseases that occurred in early childhood and were commonly associated with immune dysregulation as well as high morbidity and mortality. Early diagnosis and treatment may be crucial to improve the outcome.
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Bronquite/complicações , Doenças Pulmonares Intersticiais/complicações , Adolescente , Idade de Início , Biópsia , Bronquite/diagnóstico , Bronquite/tratamento farmacológico , Bronquite/patologia , Criança , Pré-Escolar , Doença Crônica , Tosse/etiologia , Diagnóstico Diferencial , Dispneia/etiologia , Feminino , Testes Genéticos , Humanos , Lactente , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumopatias/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Masculino , Sistema de Registros , Sons Respiratórios/etiologia , Infecções Respiratórias/etiologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Balanced composition of a well-functioning pulmonary surfactant is crucial and essential for normal breathing. Here, we explored whether the composition of lipids recovered by broncho-alveolar lavage (BAL) in children with cystic fibrosis (CF) differ from children with protracted bacterial bronchitis (PBB) and controls. We wanted to differentiate, if alterations are primarily caused by the disease process or secondary due to an increased amount of cell-membrane lipids derived from inflammatory cells. METHODS: Comprehensive lipidomics profiles of BAL fluid from children diagnosed with CF, PBB and controls were generated by electrospray ionization tandem mass spectrometry analysis. BAL cell differential and numbers were examined. RESULTS: 55 children (37 patients with CF, 8 children with PBB and 10 controls) were included in this study. Results showed comparable total quantities of lipids in all groups. Phospholipids were the major lipid fraction and similar in all groups, whereas the fractions of cholesteryl esters were less and of free cholesterol were increased in children with CF. Among the phospholipids, patients with CF had higher proportion of the non-surfactant membrane-lipids in the classes phosphatidylethanolamine based plasmalogens (PE P), phosphatidylethanolmine (PE) and phosphatidylserine (PS), but a lower proportion of phosphatidylcholine (PC) compared to healthy controls. No such changes were identified in the BAL fluid of children diagnosed with PBB. No differences were observed for the surfactant lipids dipalmitoyl-phosphatidylcholin (PC 32:0) and phosphatidylglycerol (PG). CONCLUSIONS: In CF patients with neutrophilic airway inflammation the lipid composition for surfactant phospholipid components were unchanged, whereas alteration in lipid profile were characteristic for those found in membranes of inflammatory cells. We suspect that the changes in CF were caused by the prolonged inflammation in contrast to a relatively short standing process in PBB.
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Líquido da Lavagem Broncoalveolar/imunologia , Ésteres do Colesterol/metabolismo , Colesterol/metabolismo , Fibrose Cística , Lipidômica/métodos , Fosfolipídeos/metabolismo , Bronquite/diagnóstico , Bronquite/metabolismo , Bronquite/microbiologia , Criança , Fibrose Cística/diagnóstico , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Inflamação/metabolismo , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Lipídeos de Membrana/análise , Lipídeos de Membrana/classificação , Lipídeos de Membrana/metabolismo , Depuração Mucociliar/imunologiaRESUMO
BACKGROUND: Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes. METHODS: Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N = 723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N = 1646). RESULTS: RORA* NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth. CONCLUSION: RORA* NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.
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Asma/genética , Ritmo Circadiano , Predisposição Genética para Doença , Hipersensibilidade/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores Acoplados a Proteínas G/genética , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/metabolismo , Fatores de RiscoRESUMO
Injections of a crude fetal sheep liver extract (FSLE) containing fetal hemoglobin, MPLA, and glutathione (GSSH) reversed cytokine changes in aged mice. To investigate the role of fetal hemoglobin we derived mice with homzygous deletions for either of the two major ßchains, HgbßmaKO or HgbßmiKO. Hgbßmi is the most prominent fetal Hgbß chain, with Hgbßma more prominent in adult mice. Mice lacking another fetal Hgb chain, HgbεKO, died in utero. CHO cells transfected with cloned Hgb chains were used to produce proteins for preparation of rabbit heteroantibodes. Splenocytes from HgbßmaKO mice stimulated in vitro with Conconavalin A showed a higher IL-2:IL-4 ratio than cells from HgbßmiKO mice. Following immunization in vivo with ovalbumin in alum, HgbßmaKO mice produced less IgE than HgbßmiKO mice, suggesting that in the absence of HgbßmiKO mice had a predeliction to heightened allergic-type responses. Using CHO cells transfected with cloned Hgb chains, we found that only the fetal Hgb chain, Hgbε, was secreted at high levels. Secretion of Hgbßma or Hgbßmi chains was seen only after genetic mutation to introduce the two N-linked glycosylation sites present in Hgbε, but absent in the Hgbß chains. We speculated that a previously unanticipated biological function of a naturally secreted fetal Hgb chain may be partly responsible for the effects reported following injection of animals with fetal, not adult, Hgb. Mice receiving injections of rabbit anti-Hgbε but not either anti-Hgbßma or anti-Hgbßmi from day 14 gestation also showed a bias towards the higher IL-2:IL-4 ratios seen in HgbßmiKO mice.