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3.
N Engl J Med ; 385(9): 815-825, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34437784

RESUMO

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group. RESULTS: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).


Assuntos
Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Indóis/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolinas/uso terapêutico , Adolescente , Adulto , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/efeitos adversos , Suor/química
4.
Eur Respir J ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385272

RESUMO

BACKGROUND: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans. OBJECTIVE: We present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF. RESULTS: Initially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of -0.8% (95%CI -6.6, 4.9) in ppFEV1 and +2.1 units (95%CI -2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers. CONCLUSION: BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.

5.
Macromol Rapid Commun ; : e2100303, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34418212

RESUMO

The mucus layer is a hydrogel network that covers mucosal surfaces of the human body. Mucus has important protective properties that are related to its unique rheological properties, which are based on mucins being the main glycoprotein constituents. Mucin macromolecules entangle with one another and form a physical network that is instrumental for many important defense functions. Mucus derived from various human or animal sources is poorly defined and thus not suitable for many application purposes. Herein, a synthetic route is fabricated to afford a library of compositionally defined mucus-inspired hydrogels (MIHs). MIHs are synthesized by thiol oxidation to render disulfide bonds between the crosslinker ethoxylated trimethylolpropane tri(3-mercaptopropionate) (THIOCURE ETTMP 1300) and the linear precursors, dithiolated linear polyglycerol (LPG(SH)2 ) or polyethylene glycol (PEG(SH)2 ) of different molecular weights. The mixing ratio of linear polymers versus crosslinker and the length of the linear polymer are varied, thus delivering a library of compositionally defined mucin-inspired constructs. Their viscoelastic properties are determined by frequency sweeps at 25 and 37 °C and compared to the corresponding behavior of native human mucus. Here, MIHs composed of a 10:1 ratio of LPG(SH)2 and ETTMP 1300 are proved to be the best comparable to human airway mucus rheology.

6.
Allergy ; 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34460953

RESUMO

BACKGROUND: Children with asthma have impaired production of interleukin (IL) 37; in mice, IL-37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL-37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL-37 controls allergic inflammation. METHODS: IL-37 target cells were identified by single-cell RNA-seq of IL-1R5 and IL-1R8. Airway tissues were isolated by laser-capture microdissection and examined by microarray-based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL-1ß, or IL-33 together with recombinant human (rh) IL-37. Wild-type, IL-1R1- and IL-33-deficient mice with EAA were treated with rhIL-37. IL-1ß, IL-33, and IL-37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy. RESULTS: IL-37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL-37 led to differential expression of >90 genes induced by IL-1ß and IL-33. rhIL-37 reduced production of Th2 cytokines in allergen-activated MNCs from wild-type but not from IL-1R1-deficient mice and inhibited IL-33-induced Th2 cytokine release. Furthermore, rhIL-37 attenuated IL-1ß- and IL-33-induced pro-inflammatory mediator expression in murine AEC cultures. In contrast to wild-type mice, hIL-37 had no effect on EAA in IL-1R1- or IL-33-deficient mice. We also observed that expression/production ratios of both IL-1ß and IL-33 to IL-37 were dramatically increased in asthma patients compared to healthy controls. CONCLUSION: IL-37 downregulates allergic airway inflammation by counterbalancing the disease-amplifying effects of IL-1ß and IL-33.

7.
Euro Surveill ; 26(34)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34448448

RESUMO

BackgroundSchool attendance during the COVID-19 pandemic is intensely debated.AimIn November 2020, we assessed SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.MethodsWe collected oro-nasopharyngeal swabs and blood samples, examining SARS-CoV-2 infection and IgG antibodies by RT-PCR and ELISA. Household members self-swabbed. We assessed individual and institutional prevention measures. Classes with SARS-CoV-2 infection and connected households were retested after 1 week.ResultsWe examined 1,119 participants, including 177 primary and 175 secondary school students, 142 staff and 625 household members. SARS-CoV-2 infection occurred in eight classes, affecting each 1-2 individuals. Infection prevalence was 2.7% (95% confidence interval (CI): 1.2-5.0; 9/338), 1.4% (95% CI: 0.2-5.1; 2/140), and 2.3% (95% CI: 1.3-3.8; 14/611) among students, staff and household members. Six of nine infected students were asymptomatic at testing. We detected IgG antibodies in 2.0% (95%CI: 0.8-4.1; 7/347), 1.4% (95% CI: 0.2-5.0; 2/141) and 1.4% (95% CI: 0.6-2.7; 8/576). Prevalence increased with inconsistent facemask-use in school, walking to school, and case-contacts outside school. For three of nine households with infection(s), origin in school seemed possible. After 1 week, no school-related secondary infections appeared in affected classes; the attack rate in connected households was 1.1%.ConclusionSchool attendance under rigorously implemented preventive measures seems reasonable. Balancing risks and benefits of school closures need to consider possible spill-over infection into households. Deeper insight is required into the infection risks due to being a schoolchild vs attending school.


Assuntos
COVID-19 , SARS-CoV-2 , Berlim , Estudos Transversais , Alemanha/epidemiologia , Humanos , Pandemias , Instituições Acadêmicas
8.
Artigo em Inglês | MEDLINE | ID: mdl-34283704

RESUMO

RATIONALE: Previous cross-sectional studies demonstrated that chest magnetic resonance imaging (MRI) is sensitive to detect early lung disease in infants and preschool children with cystic fibrosis (CF) without radiation exposure. However, the ability of MRI to detect progression of lung disease and the impact of early diagnosis in preschool children with CF remains unknown. OBJECTIVES: To investigate the potential of MRI to detect progression of early lung disease and impact of early diagnosis by CF newborn screening (NBS) in preschool children with CF. METHODS: Annual MRI was performed from diagnosis over four years in a cohort of 96 preschool children with CF (age 0-4 yr) that were concurrently diagnosed based on NBS (n=28) or clinical symptoms (n=68). MRI scans were evaluated using a dedicated morphofunctional score and the relationship between longitudinal MRI scores and respiratory symptoms, pulmonary exacerbations, upper airway microbiology and mode of diagnosis were determined. MEASUREMENTS AND MAIN RESULTS: The MRI global score increased in the total cohort of children with CF during preschool years (P<0.001) which was associated with cough, pulmonary exacerbations (P<0.0001), and detection of Staphylococcus aureus and Haemophilus influenzae (P<0.05). MRI-defined abnormalities in lung morphology, especially airway wall thickening/bronchiectasis, were lower in NBS compared to clinically diagnosed children with CF throughout the observation period (P<0.01). CONCLUSIONS: MRI detected progression of early lung disease and benefits of early diagnosis by NBS in preschool children with CF. These findings support MRI as sensitive outcome measure for diagnostic monitoring and early intervention trials in preschool children with CF.

9.
Int J Infect Dis ; 110: 261-266, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34302962

RESUMO

INTRODUCTION: Containing COVID-19 requires broad-scale testing. However, sample collection requires qualified personnel and protective equipment and may cause transmission. We assessed the sensitivity of SARS-CoV-2-rtPCR applying three self-sampling techniques as compared to professionally collected oro-nasopharyngeal samples (cOP/NP). METHODS: From 62 COVID-19 outpatients, we obtained: (i) multi-swab, MS; (ii) saliva sponge combined with nasal vestibula, SN; (iii) gargled water, GW; (iv) professionally collected cOP/NP (standard). We compared ct-values for E-gene and ORF1ab and analysed variables reducing sensitivity of self-collecting procedures. RESULTS: The median ct-values for E-gene and ORF1ab obtained in cOP/NP samples were 20.7 and 20.2, in MS samples 22.6 and 21.8, in SN samples 23.3 and 22.3, and in GW samples 30.3 and 29.8, respectively. MS and SN samples showed sensitivities of 95.2% (95%CI, 86.5-99.0) and GW samples of 88.7% (78.1-95.3). Sensitivity was inversely correlated with ct-values, and became <90% for samples obtained more than 8 days after symptom onset. For MS and SN samples, false negativity was associated with language problems, sampling errors, and symptom duration. CONCLUSION: Conclusions from this study are limited to the sensitivity of self-sampling in mildly to moderately symptomatic patients. Still, self-collected oral/nasal/saliva samples can facilitate up-scaling of testing in early symptomatic COVID-19 patients if operational errors are minimized.


Assuntos
COVID-19 , SARS-CoV-2 , Teste para COVID-19 , Humanos , Nasofaringe , Pacientes Ambulatoriais , Saliva , Manejo de Espécimes
10.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299227

RESUMO

Our previous study showed that in adult mice, conditional Nedd4-2-deficiency in club and alveolar epithelial type II (AE2) cells results in impaired mucociliary clearance, accumulation of Muc5b and progressive, terminal pulmonary fibrosis within 16 weeks. In the present study, we investigated ultrastructural alterations of the alveolar epithelium in relation to interstitial remodeling in alveolar septa as a function of disease progression. Two, eight and twelve weeks after induction of Nedd4-2 knockout, lungs were fixed and subjected to design-based stereological investigation at the light and electron microscopic level. Quantitative data did not show any abnormalities until 8 weeks compared to controls. At 12 weeks, however, volume of septal wall tissue increased while volume of acinar airspace and alveolar surface area significantly decreased. Volume and surface area of alveolar epithelial type I cells were reduced, which could not be compensated by a corresponding increase of AE2 cells. The volume of collagen fibrils in septal walls increased and was linked with an increase in blood-gas barrier thickness. A high correlation between parameters reflecting interstitial remodeling and abnormal AE2 cell ultrastructure could be established. Taken together, abnormal regeneration of the alveolar epithelium is correlated with interstitial septal wall remodeling.


Assuntos
Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/ultraestrutura , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Remodelação das Vias Aéreas/fisiologia , Células Epiteliais Alveolares/fisiologia , Animais , Células Epiteliais/metabolismo , Feminino , Fibrose/metabolismo , Fibrose/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Ubiquitina-Proteína Ligases Nedd4/genética , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Surfactantes Pulmonares , Mucosa Respiratória/metabolismo
11.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200296

RESUMO

Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4-2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na+ channel (ENaC), TGFß signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4-2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4-2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4-2fl/fl/CCSP-rtTA2S-M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of Nedd4-2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4-2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4-2 may support studies of the pathogenesis and preclinical development of therapies for chILD.


Assuntos
Células Epiteliais/patologia , Pulmão/patologia , Ubiquitina-Proteína Ligases Nedd4/fisiologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/patologia , Animais , Animais Recém-Nascidos , Células Epiteliais/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/metabolismo , Fibrose Pulmonar/etiologia
12.
J Vis Exp ; (171)2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34096915

RESUMO

Proteases are regulators of countless physiological processes and the precise investigation of their activities remains an intriguing biomedical challenge. Among the ~600 proteases encoded by the human genome, neutrophil serine proteases (NSPs) are thoroughly investigated for their involvement in the onset and progression of inflammatory conditions including respiratory diseases. Uniquely, secreted NSPs not only diffuse within extracellular fluids but also localize to plasma membranes. During neutrophil extracellular trap (NETs) formation, NSPs become an integral part of the secreted chromatin. Such complex behavior renders the understanding of NSPs pathophysiology a challenging task. Here, detailed protocols are shown to visualize, quantify and discriminate free and membrane-bound neutrophil elastase (NE) and cathepsin G (CG) activities in sputum samples. NE and CG are NSPs whose activities have pleiotropic roles in the pathogenesis of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD): they promote tissue remodeling, regulate downstream immune responses and correlate with lung disease severity. The protocols show how to separate fluid and cellular fraction, as well as the isolation of neutrophils from human sputum for enzymatic activity quantification via small-molecule Förster resonance energy transfer-based (FRET) reporters. To gather specific insights into the relative role of NE and CG activities, a FRET readout can be measured by different technologies: i) in vitro plate reader measurements allow for high-throughput and bulk detection of protease activity; ii) confocal microscopy spatiotemporally resolves membrane-bound activity at the cell surface; iii) small-molecule FRET flow cytometry enables for the rapid evaluation of anti-inflammatory treatments via single-cell protease activity quantification and phenotyping. The implementation of such methods opens the doors to explore NSPs pathobiology and their potential as biomarkers of disease severity for CF and COPD. Given their standardization potential, their robust readout and simplicity of transfer, the described techniques are immediately shareable for implementation across research and diagnostic laboratories.


Assuntos
Catepsina G , Fibrose Cística , Elastase de Leucócito , Doença Pulmonar Obstrutiva Crônica , Fibrose Cística/enzimologia , Humanos , Neutrófilos/enzimologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Serina Proteases , Escarro/enzimologia
13.
Genes (Basel) ; 12(6)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070354

RESUMO

Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.

14.
Int J Mol Sci ; 22(9)2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-34065111

RESUMO

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.


Assuntos
Imunidade nas Mucosas , Pneumopatias/etiologia , Pneumopatias/metabolismo , Muco/metabolismo , Peptídeo Hidrolases/metabolismo , Animais , Doença Crônica , Cílios/imunologia , Cílios/metabolismo , Suscetibilidade a Doenças , Humanos , Transporte de Íons , Pneumopatias/diagnóstico , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais
15.
J Clin Invest ; 131(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34061776

RESUMO

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients' sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.


Assuntos
Autoanticorpos/imunologia , COVID-19/complicações , COVID-19/imunologia , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , SARS-CoV-2 , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Autoanticorpos/sangue , Feminino , Humanos , Técnicas In Vitro , Interferon-alfa/antagonistas & inibidores , Interferon-alfa/imunologia , Masculino , Poliendocrinopatias Autoimunes/genética , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Fatores de Transcrição/genética , Replicação Viral/imunologia , Adulto Jovem
16.
Eur J Public Health ; 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33956945

RESUMO

Actual surveys in kindergartens on SARS-CoV-2 infections are rare. At the beginning of the second pandemic wave, we screened twelve randomly selected kindergartens in Berlin, Germany. A total of 720 participants (pre-school children, staff, and connected household members) were briefly examined and interviewed, and SARS-CoV-2 infections and anti-SARS-Cov-2 IgG antibodies were assessed. About a quarter of the participants showed common cold-resembling symptoms. However, no SARS-CoV-2 infection was detected, and only one childcare worker showed IgG seroreactivity. Against a backdrop of increased pandemic activity in the community, this cross-sectional study does not suggest that kindergartens are silent transmission reservoirs.

17.
Antioxidants (Basel) ; 10(3)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808590

RESUMO

RATIONALE: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to impaired pancreatic function and therefore reduced intestinal absorption of lipids and fat-soluble vitamins especially in patients with CF developing pancreatic insufficiency (PI). Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown. OBJECTIVES: To investigate the course of plasma vitamin A and E in patients with CF under LUM/IVA therapy. METHODS: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy. RESULTS: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p < 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p < 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p < 0.01). CONCLUSIONS: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33800392

RESUMO

Briefly before the first peak of the COVID-19 pandemic in Berlin, Germany, schools closed in mid-March 2020. Following re-opening, schools resumed operation at a reduced level for nine weeks. During this phase, we aimed at assessing, among students and teachers, infection status, symptoms, individual behaviour, and institutional infection prevention measures. Twenty-four primary and secondary school classes, randomly selected across Berlin, were examined. Oro-nasopharyngeal swabs and capillary blood samples were collected to determine SARS-CoV-2 infection (PCR) and specific IgG (ELISA), respectively. Medical history, household characteristics, leisure activities, fear of infection, risk perception, hand hygiene, facemask wearing, and institutional preventive measures were assessed. Descriptive analysis was performed. Among 535 participants (385 students, 150 staff), one teenager was found to be infected with SARS-CoV-2 (0.2%), and seven individuals exhibited specific IgG (1.3%). Compared to pre-pandemic times, screen time (e.g., TV, gaming, social media) increased, and the majority of primary school students reported reduced physical activity (42.2%). Fear of infection and risk perception were relatively low, acceptance of adapted health behaviors was high. In this post-lockdown period of low SARS-CoV-2 incidence in Berlin, individual and school-level infection prevention measures were largely adhered to. Nevertheless, vigilance and continued preventive measures are essential to cope with future pandemic activity.


Assuntos
COVID-19 , SARS-CoV-2 , Adolescente , Berlim , Controle de Doenças Transmissíveis , Estudos Transversais , Alemanha/epidemiologia , Humanos , Pandemias , Percepção , Instituições Acadêmicas
19.
Mediators Inflamm ; 2021: 6682657, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33828414

RESUMO

Background: Elevated levels of the cysteine protease cathepsin S (CatS) are associated with chronic mucoobstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). We have previously demonstrated that prophylactic treatment with a CatS inhibitor from birth reduces inflammation, mucus plugging, and lung tissue damage in juvenile ß-epithelial Na+ channel-overexpressing transgenic (ßENaC-Tg) mice with chronic inflammatory mucoobstructive lung disease. In this study, we build upon this work to examine the effects of therapeutic intervention with a CatS inhibitor in adult ßENaC-Tg mice with established disease. Methods: ßENaC-Tg mice and wild-type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS-/- ßENaC-Tg mice were analysed at 6 weeks of age. Bronchoalveolar lavage (BAL) fluid inflammatory cell counts were quantified, and lung tissue destruction and mucus obstruction were analysed histologically. Results: At 6 weeks of age, ßENaC-Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS-/- ßENaC-Tg mice and ßENaC-Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS-/- ßENaC-Tg mice, therapeutic inhibition of CatS in ßENaC-Tg mice had no effect on established emphysema-like lung tissue damage. Conclusions: These results suggest that while early CatS targeting may be required to prevent the onset and progression of lung tissue damage, therapeutic CatS targeting effectively inhibited airway inflammation and mucus obstruction. These results indicate the important role CatS may play in the pathogenesis and progression of mucoobstructive lung disease.

20.
Am J Respir Crit Care Med ; 203(12): 1522-1532, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33734030

RESUMO

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes. Methods: In this 24-week open-label phase 3 study, children (N = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).


Assuntos
Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Indóis/uso terapêutico , Pirazóis/uso terapêutico , Quinolonas/uso terapêutico , Alelos , Criança , Agonistas dos Canais de Cloreto/farmacocinética , Combinação de Medicamentos , Feminino , Variação Genética , Genótipo , Humanos , Indóis/farmacocinética , Masculino , Pirazóis/farmacocinética , Quinolonas/farmacocinética
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