Jonathan Ayling-Smith

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

Exophiala dermatitidis is increasingly isolated from cystic fibrosis (CF) respiratory samples. The decision to treat is hampered by limited evidence demonstrating the clinical significance of isolating E. dermatitidis. The objective was to assess the impact of E. dermatitidis isolation on the lung function of CF patients. The rate of lung function decline in the local CF population was calculated using historic lung function data. A control population who had never had E. dermatitidis cultured from the respiratory tract was compared with the E. dermatitidis group, calculating their rate of lung function decline before and after the first isolation of the organism. A total of 1840 lung function measurements were reviewed between the 31 E. dermatitidis group patients and 62 control patients. Their demographics were similar. The control group declined at a rate of −0.824 FEV1%/year. The rate of decline in the E. dermatitidis group prior to infection was −0.337 FEV1%/year (p = 0.2). However, post infection with E. dermatitidis, there was a significant increase in the rate of decline in lung function (−1.824 FEV1%/year, p < 0.01). The results suggest E. dermatitidis has a temporal relationship with accelerated rate of lung function decline. It is not clear if this is a cause or effect, but this accelerated rate of decline indicates a need for further investigation.

Pneumocystis pneumonia (PcP) is a serious complication of many significant immunocompromising conditions. Prior incidence estimates in Wales are based on PcP’s presentation in the HIV and transplant populations. The objectives were to describe the incidence of PcP in Wales using laboratory reporting measures and assess the impact of underlying immunosuppression cause on mortality. All positive PCR results for PcP between 2015 and 2018 were identified. The total number of unique positives with clinical and radiological correlation was 159 patients, a mean of 39.75 annually. The healthcare records of these patients were reviewed. The mortality at one month was 35.2% and 49.1% at one year. HIV remains the commonest cause of immunosuppression but has lower mortality than non-HIV conditions (12% vs. 59% at one year, p &lt; 0.00001). Non-HIV conditions were categorised as life-threatening and non-life threatening but had a non-significant mortality (66% vs. 54%; p = 0.149), highlighting the negative impact of PcP. An incidence of PcP in Wales of 1.23–1.26 cases per 100,000 has been identified, 32–35% greater than the upper limit previously estimated. There is high mortality in non-HIV patients regardless of immunosuppression cause. A heightened awareness of PcP in these groups will hasten diagnosis and potentially improve mortality.

<h3>Introduction</h3> Combining BTS/SIGN/NICE Asthma guidance with the recent BTS guidance on pulmonary aspergillosis (2025) a clear diagnostic pathway for clinical phenotyping of ABPA and Asthma within Bronchiectasis cohorts is now possible. We utlised this guidance to clinically phenotype those with asthma or ABPA within a specialist bronchiectasis service to optimise management and identify those in need of escalation or de-escalation of therapy. <h3>Methods</h3> The database of a specialist bronchiectasis service was interrogated. Patients with radiological evidence of bronchiectasis and a co-diagnosis of asthma were identified. The 2024 joint BTS/NICE/SIGN asthma criteria was retrospectively applied. In those identified as having asthma, the new diagnostic criteria for ABPA were evaluated. From primary and secondary care electronic records, healthcare utilization burden, inhaled therapy and oral corticosteroids usage was compared between ABPA and non-ABPA cohorts. <h3>Results</h3> Of the 113 patients with bronchiectasis and historical asthma diagnosis, 86 patients met current diagnostic criteria for asthma. Of these, 24 also met the diagnostic criteria for ABPA. In the 27 bronchiectasis patients with no current evidence of asthma, 25 were prescribed inhaled corticosteroids with an annual cost of £10,144 and 2,736 kg of CO2. Respiratory clinic attendance was more frequent in the preceding 12 months for patients with ABPA (median 3.5) than with ‘asthma-ectasis’ (2, p = 0.0114) (figure 1). Of the Asthma-ABPA cohort,16 patients have been highlighted for consideration of escalation of asthma therapy, including biologics, based on corticosteroid use or exacerbation frequency. <h3>Conclusion</h3> Historical asthma diagnoses are common in bronchiectasis patients, but updated guidance suggests many may be suitable for de-labelling and de-escalation of therapy.¹ Inappropriate corticosteroid treatment carries significant morbidity risk, with financial and environmental cost. Concurrently others with ‘asthma-ectasis’ may require escalation of asthma therapy including biologics but this need may be masked by concurrent bronchiectasis. New guidance allows effective clinical phenotyping to formally identify specific cohorts with overlap between Asthma, Bronchiectasis and ABPA to improve access to expertise and treatment options to reduce healthcare burden and morbidity. <h3>Reference</h3> Pollock, Jennifer <i>et al. Thorax</i> 2025;<b>80</b>(6):358–368.