NIHR Southampton Respiratory Biomedical Research Unit

Cyclical epidemics of pertussis, also known as whooping cough, continue to occur despite vaccination, because current vaccines fail to suppress colonisation by, and transmission of, the causative agent Bordetella pertussis. We aimed to show the safety of B pertussis controlled human infection delivered in an outpatient setting, as well as identify immunological correlates of protection against B pertussis colonisation, to guide the future development of pertussis vaccines. This open-label, phase 1, controlled human infection study was conducted at University Hospital Southampton, Southampton, UK. Healthy volunteers aged 18-55 years who had received a whole-cell pertussis vaccine in childhood were inoculated intranasally with 105 colony-forming units of wild-type B pertussis strain B1917. Volunteers were monitored as outpatients for 28 days to assess safety, colonisation, and B pertussis-specific immunological parameters. Individuals who shared a bedroom with inoculated volunteers were enrolled to measure transmission to close contacts. After approximately 90 days, volunteers who agreed to participate in a rechallenge phase of the study were re-inoculated with the same dose of B pertussis. Volunteers received azithromycin 14 days after each inoculation. The primary objective was to assess the safety of delivering this controlled human infection model on an outpatient basis; safety endpoints were the occurrence of possible or confirmed pertussis and unsolicited or serious adverse events. Secondary objectives were the assessment of immunological biomarkers of protection from colonisation and the assessment of transmission from volunteers to close contacts. All volunteers who received the inoculum were included in the safety analysis, and all participants who completed follow-up to day 14 were included in the per-protocol population for colonisation and immunological analysis. This trial is registered at ClinicalTrials.gov, NCT03751514, and is ongoing. Between Aug 29, 2019 and March 6, 2023, 77 volunteers were screened and 51 were enrolled and inoculated, of whom 50 completed follow-up to day 14 post-inoculation. 20 (40%) of these 50 volunteers became colonised with B pertussis. One volunteer developed symptoms suggestive of possible pertussis after initial inoculation; this volunteer tested negative for B pertussis throughout the study and all symptoms resolved within 4 days. Adverse events were mostly mild to moderate, with no significant increase in the reporting of any individual symptom by colonised volunteers. All unsolicited adverse events were assessed as either unlikely to be related or unrelated to B pertussis infection, with no increase in the frequency of these events seen in colonised volunteers. There were no serious adverse events and no treatment-related deaths. Compared with those who became colonised with B pertussis, non-colonised volunteers had significantly higher pre-inoculation serum IgG antibody concentrations against several acellular pertussis vaccine antigens (pertussis toxin [p=0·028], pertactin [p=0·037], and filamentous haemagglutinin [p=0·024]); higher nasal (p=0·022) and serum (p=0·044) IgA antibody concentrations against whole B pertussis; higher serum IgA antibody concentrations specific to filamentous haemagglutinin (p=0·024); and higher peripheral T-helper (Th)-22-cell responses to pertussis toxin (p=0·0045) and filamentous haemagglutinin (p=0·029). After inoculation, only colonised volunteers showed seroconversion, IgA and IgG binding to B pertussis, and increases in B pertussis-specific IgG-secreting memory B-cell frequencies by day 28. Th17 responses to pertussis toxin were increased (p=0·039) and Th22 responses to filamentous haemagglutinin were decreased (p=0·014) in non-colonised volunteers. Of the 13 volunteers who became colonised after initial inoculation and were re-inoculated, only one (8%) became colonised after re-inoculation. Transmission from volunteers to 14 enrolled individuals with whom they shared a bedroom was not detected. Our findings suggest that controlled human infection with B pertussis in an outpatient setting is safe. Higher humoral and CD4+ T-cell responses with specificity to acellular pertussis vaccine antigens are associated with protection against colonisation by B pertussis after experimental challenge. This technique could enable the testing of potential novel vaccines or formulations for sustained protection against infection and transmission. EU Horizon 2020 (Innovative Medicines Initiative) and the National Institute for Health and Care Research Southampton Biomedical Research Centre.

Patient autonomy through informed consent is a foundational ethical principle for health care practitioners. Online consent processes risk producing "consent in name only," using manipulative or confusing user interfaces to extract consent artificially. This presents a significant danger for safe and ethical remote consultations for primary care providers, which often extract significant amounts of sensitive personal data. This study aims to examine the quality of consent obtained through both currently used and novel consent acquisition interfaces for remote e-consultations between a patient and a primary care provider. A total of 55 adult participants in the United Kingdom completed an interaction with a mock-up e-consultation system's consent interface for data processing, with 54 completing the full study protocol. The participants were then asked questions regarding what they had provided consent for and the usability of the interface. These responses led to the calculation of an industry-standard System Usability Scale (SUS) score and a novel Quality of Informed Consent Collected Digitally (QuICCDig) score. Users perceiving interfaces to be more usable (with a greater SUS score) were statistically significantly (n=54; P=.004) correlated with an increase in the quality of consent collected from those users (with a higher QuICCDig score). Nonetheless, both existing and novel user interfaces for collecting e-consultation consent were rated poorly, achieving a maximum SUS letter grade of "F." In total, 45% (25/55) of all the participants reported not recalling making a privacy-related decision at all during their consultation, and 87% (48/55) did not recall being offered any alternatives to e-consultation. The findings demonstrate that current methods for collecting consent in telemedical applications may not be fit for purpose and potentially fail to collect valid informed consent. However, increased usability scores from users do appear to drive improvements in the quality of consent collected. Therefore, decision-makers should place importance on high-quality interface design when building or procuring these systems. We have also provided the QuICCDig score for further use.

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from infection globally, yet the contribution of non-classical T-cell pathways to human immunity remains poorly defined. CD1c-autoreactive T-cells, which recognise self-lipids presented by the antigen-presenting molecule CD1c, are frequent in human blood, but their role during infection is unclear. Here, we investigate how CD1c-expressing antigen-presenting cells (APCs) and Mtb infection shape CD1c-autoreactive T-cell responses using engineered human APC systems, complemented by single-cell transcriptomic profiling to define the ex vivo phenotypic landscape of these T-cells. CD1c is present within human TB granulomas, whereas Mtb down-modulates CD1c expression on infected APCs, consistent with an immune evasion strategy. CD1c-autoreactive T-cells respond more strongly to Mtb-infected CD1c+ APCs than to uninfected cells, exhibiting enhanced activation, cytotoxicity, and diverse cytokine secretion via CD1c-dependent recognition. Under in vitro conditions, these T-cells reduce relative Mtb burden in infected phagocytes. Single-cell RNA-sequencing reveals cytotoxic effector-memory programmes and expression of antimicrobial molecules, providing a mechanistic basis for these responses. Together, these findings define a human CD1c-restricted T-cell response to Mtb-infected APCs and identify autoreactive CD1c-restricted T-cells as a candidate cellular axis for lipid-directed immunity in TB.

<h3>Introduction</h3> Nintedanib is an antifibrotic medication indicated for progressive fibrotic lung disease. Patients are usually started on full dose Nintedanib irrespective of their age, gender, body mass index (BMI) or ethnicity. Many patients are intolerant of full dose and medication is either reduced or discontinued. Our aim was to demonstrate clinically available predictive factors of full dose intolerance in a real-world cohort. <h3>Method</h3> We reviewed 127 patients initiated on Nintedanib at a single prescribing centre between December 2021 and October 2023. Patient data was obtained from electronic clinical records. Data was collected until there was dose reduction, discontinuation, or the last clinical entry prior to completion of the review in March 2025. The interval from Nintedanib initiation to the point of data collection was between 20–39 months. <h3>Results</h3> 51 patients (39.8%) tolerated 150 mg BD Nintedanib throughout, 71 (55.4%) required dose reduction and 5 (3.9%) were initiated at 100 mg. Female gender and an IPF diagnosis were significant predictive factors of intolerance of nintedanib at full dose (p&lt;0.001 and p=0.042); older age was a near significant predictive factor (p=0.051). Treatment was given for a mean of 26.52 months (SD=5.38) with dose reduction occurring after 8.14 months (SD=6.72). Discontinuation occurred after 19.59 months (SD=6.82). Nintedanib was paused or reduced due to diarrhoea (39.4%), deranged liver function (9.2%) and weight loss (5.7%). Nintedanib was discontinued in 27 patients and was due to diarrhoea 38.4%, death 34.6%, weight loss 15.3%, patient choice 7.7% and nausea in 3.8%. 20 patients passed away by the time of review with 10 in each group. <h3>Conclusion</h3> This single centre, retrospective real-world study has demonstrated significant rates of side effects and intolerance to Nintedanib 150 mg BD. It suggests that female gender and older age are predictive factors of intolerance of full dose Nintedanib. These findings warrant further investigation in a UK wide cohort which is planned for 2026, to further explore and consolidate these findings and potentially highlight others including ethnicity which wil be vital to guide clinicians to enable prescription of a dose that will be better tolerated from the outset and improve patient experience.

<h3>Introduction</h3> Bronchoalveolar lavage (BAL) differential cellular analysis may be a valuable tool in the diagnostic evaluation of patients with Interstitial Lung Disease (ILD), with international consensus guidelines typically recommending consideration in those without a definite Usual Interstitial Pneumonia pattern on HRCT, however the practical utility continues to be debated.¹ <h3>Method</h3> A single centre retrospective casenote review of patients undergoing BAL as part of ILD diagnostic workup. <h3>Results</h3> 36 patients underwent BAL between January 2022 and June 2025. 22 (61.1%) were female and median age was 66 years. 19 (52.7%) were ex-smokers with 13 (36.1%) non-smokers and 2 (5.5%) current smokers. The mean smoking pack year history was 21.3 years. BAL was generally well tolerated with no significant complications; 2 patients (5.5%) experienced minor complications with one experiencing hypoxia and subsequent early termination of the procedure; and one experiencing excessive coughing and discomfort. The most frequent diagnoses included acute hypersensitivity pneumonitis (25%), fibrotic hypersensitivity pneumonitis (19.4%) and connective tissue disease related ILD (8.3%). 3 patients (8.3%) had a diagnosis of unclassifiable ILD following BAL and subsequent discussion in an ILD MDT. 31 (86.1%) of patients had their management influenced through BAL analysis. 11 patients (30.5%) were commenced on immunosuppression and 6 patients (16.6%) on anti-fibrotic medications. <h3>Conclusion</h3> Bronchoalveolar lavage was safe and influenced MDT discussion and management in the majority of patients in this selected cohort. Systems standardising the integration of BAL into cytopathology departments and ILD MDTs might further increase utility and therefore aid in the diagnostic pathway of interstitial lung diseases. <h3>Reference</h3> Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, Drent M, Haslam PL, Kim DS, Nagai S, Rottoli P, Saltini C, Selman M, Strange C, Wood B; American Thoracic Society Committee on BAL in Interstitial Lung Disease. An official American thoracic society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. <i>Am J Respir Crit Care Med</i>. 2012;<b>185</b>(9):1004–14. doi: 10.1164/rccm.201202–0320ST. PMID: 22550210

Metabolic dysfunction-associated steatohepatitis (MASH) is an increasingly important contributor to morbidity and mortality. Little emphasis has been placed on its timely diagnosis and interventions to prevent adverse disease outcomes. The principal determinant of MASH outcomes is the liver fibrosis stage. The prevalence of MASH is higher among people living with obesity and/or type 2 diabetes, with MASH with moderate to advanced fibrosis affecting one in six adults. Delivering a paradigm shift in MASH diagnosis in the four countries studied will require an expansion of community-based diagnostic capability that will also foster prevention efforts and provide opportunities for treatment and care.