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Journal articleDobra R, Short C, Wong K, et al., 2025,
Utility and interpretation of multiple breath washout in children with cystic fibrosis
, Archives of Disease in Childhood: Education and Practice Edition, Vol: 110, Pages: 214-217, ISSN: 1743-0585Transformative changes in the health of children with cystic fibrosis (CF) mean that more sensitive outcome measures are needed to monitor paediatric CF lung disease. Multiple breath washout (MBW) and its primary readout lung clearance index are gaining increasing traction as an endpoint for clinical trials in the CF space and show promise as a clinical investigation. In this article, we use four clinically based questions to explore what MBW can and cannot (yet) do and highlight some of its strengths and weaknesses as an investigation. We end by discussing how we can increase the utility of MBW as an investigation in children with CF.
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Journal articleRowntree LC, Allen LF, Hagen RR, et al., 2025,
HLA-B*15:01-positive severe COVID-19 patients lack CD8+ T cell pools with highly expanded public clonotypes
, Proceedings of the National Academy of Sciences of USA, Vol: 122, ISSN: 0027-8424Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8+ T-cells directed against HLA-B*15:01-restricted Spike-derived S919-927 peptide (B15/S919+CD8+ T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8+ T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S919+CD8+ T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S919+CD8+ T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S919+CD8+ T-cell responses lacking a highly expanded key public B15/S919+CD8+ T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S919+CD8+ T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S919+CD8+ T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S919+CD8+ T-cells did not differ across disease severity. Moreover, B15/S919+CD8+ T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individua
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Journal articleBokobza I, Le Sayec M, Bossley C, et al., 2025,
Spirometry thresholds for clinical trial eligibility: time for urgent re-evaluation
, THORAX, ISSN: 0040-6376 -
Journal articleNakawesi J, Sow Tao Min T, Johansson C, 2025,
Natural killer cells are dispensable for virus control in Rag2-/- mice during primary RSV infection
, European Journal of Immunology, ISSN: 0014-2980Respiratory syncytial virus (RSV) is one of the major causes of severe lower respiratory tract infections, especially in children, the elderly and immunocompromised individuals. Complications arising from viral infections in these age groups can present therapeutic challenges as most of these individuals have impaired adaptive immunity. Using the T- and B cell-deficient Rag2-/- mice, the mechanisms that mediate protection in immunocompromised hosts during RSV infection can be investigated. RSV-infected Rag2-/- mice showed no symptoms of disease or chronic inflammation in the lungs and airways despite the presence of infectious virus in their lungs several months after infection. Interestingly, Natural Killer (NK) cells, the main innate cells with anti-viral cytotoxic effector functions, were recruited two days earlier in the lungs of Rag2-/- mice compared to wildtype mice, resulting in early production of IFN-. However, depletion of NK cells did not affect disease severity or viral load. Together, these results suggest that the NK cells are largely dispensable for virus control during primary RSV infection in Rag2-/- mice.
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Journal articleCarty L, Dobra R, Francis J, et al., 2025,
Qualitative Experiences and Depression/Anxiety Scores in Parents of Children With Cystic Fibrosis Transmembrane Conductance Regulator Related Metabolic Syndrome
, PEDIATRIC PULMONOLOGY, Vol: 60, ISSN: 8755-6863 -
Journal articleGuan S, Ogger P, Farias A, et al., 2025,
Sustained lung inflammation post SARS-CoV-2 infection in mice is associated with increased pulmonary T cells
, European Journal of Immunology, Vol: 55, ISSN: 0014-2980Many SARS-CoV-2 patients experience chronic pulmonary symptoms and long-term inflammation despite viral clearance. While these clinical manifestations have been linked to the dysregulation of the adaptive immune response, the underlying immunopathology remains poorly understood due to a lack of suitable animal models. To investigate long-term pulmonary consequences of SARS-CoV-2 infection, we used a genetic cross of 129 mice and C57BL/6 (B6)-K18-hACE2 transgene mice, a model previously shown to survive infection. 129xB6-K18-hACE2 mice or littermate controls were infected with a low dose (5 × 102 PFU) of ancestral SARS-CoV-2. Complete viral clearance and full recovery from weight loss occurred by day 8 post-infection. However, prolonged inflammation in the lung and airways persisted up to day 28 post-infection and was associated with the presence of CD4+ and CD8+ T cells, particularly CD8+ effector T cells. This model may therefore prove valuable for further understanding of drivers of long-term lung inflammation and for testing therapeutic strategies and clinically relevant interventions that can target long-term pulmonary inflammation following SARS-CoV-2 infection.
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Journal articleKrishnan JA, Cao B, Chotirmall SH, et al., 2025,
Using the 2024 National Academies of Science, Engineering, and Medicine Definition of Long COVID Implications for Pulmonary and Critical Care Medicine
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 211, Pages: 1391-1396, ISSN: 1073-449X- Cite
- Citations: 1
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Journal articleJohansson C, 2025,
RORing for oral tolerance
, Science -
Journal articleHigham S, Wang Z, Murugaiah V, et al., 2025,
Intranasal delivery of mRNA expressing newly identified Acinetobacter baumannii antigens protects against bacterial lung disease
, npj Vaccines, Vol: 10, ISSN: 2059-0105Vaccines are central to the strategy to control antimicrobial resistant (AMR) bacterial infections; one multidrug resistant pathogen of particular concern is Acinetobacter baumannii. In this study we identified two novel A. baumannii antigens using mass spectrometry and phage expression: Oxa23 and PAL. These genes are highly conserved between different isolates of A. baumannii and recognised by convalescent human sera. We explored their protective immunity using two different vaccine platforms, recombinant outer membrane vesicles (rOMV) and mRNA. RNA vaccine immunised mice had significantly reduced bacterial load in their lower airways following challenge with carbapenem resistant A. baumannii, with Oxa23 providing better protection than PAL. We then compared routes of delivery and RNA vaccine platforms, demonstrating that intranasally delivery of mRNA encoding OXA-23 (formulated with GL67A) significantly reduced disease severity and enhanced bacterial clearance. These studies validate in silico identified antigens through challenge studies and novel mucosal vaccine delivery approaches.
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Journal articleLee T, Hill K, Caudri D, et al., 2025,
Pulmonary endpoints in clinical trials for children with cystic fibrosis under two years of age
, Journal of Cystic Fibrosis, Vol: 24, Pages: 669-683, ISSN: 1569-1993Cystic fibrosis is a lifelong progressive disease in which lung disease is the main prognostic factor, where starting early treatment is crucial for improving long-term outcomes. Therefore, new treatment should be available as early as possible. However, choosing appropriate and feasible clinical trial endpoints in children under 2 years of age presents significant challenges. Most studies in this age group have extrapolated pulmonary efficacy from older age groups, focusing on safety, pharmacokinetics, and biomarker response. As lung health is near normal in infants, demonstrating absence of pulmonary decline requires large sample sizes and extended study duration, which may not be feasible for standard regulatory trials. To address this gap, the European Cystic Fibrosis Society Clinical Trials Network developed a consensus document evaluating direct pulmonary endpoints for therapeutic pulmonary studies in this young age group. The pulmonary endpoints evaluated include multiple-breath washout (MBW); chest computed tomography (CT); chest magnetic resonance imaging (MRI); airway infection and inflammation. Relevant literature, pitfalls, practice guidelines, and recommendations are presented. None of the pulmonary endpoints evaluated are currently suitable to serve as a primary efficacy endpoint in children below 2 years of age, as this will require large numbers and long follow-up. For clinical trials in infants with CF, pharmacokinetics, pharmacodynamics, safety and tolerability should remain the primary endpoints, with pulmonary endpoints as secondary or exploratory outcomes. Post authorization studies are essential to evaluate long-term pulmonary benefits, including MBW, structural lung assessment (e.g. CT and MRI), and markers of pulmonary inflammation to fully understand the impact of early therapy initiation in this young population.
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