An Update on CFTR Modulators as New Therapies for Cystic Fibrosis.

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

COVID-19 and delivery of difficult asthma services.

The COVID-19 pandemic necessitated an urgent reconfiguration of our difficult asthma (DA) service. We rapidly switched to virtual clinics and rolled out home spirometry based on clinical need. From March to August 2020, 110 patients with DA (68% virtually) were seen in clinic, compared with March-August 2019 when 88 patients were seen face-to-face. There was DA clinic cancellation/non-attendance (16% vs 43%; p<0.0003). In patients with home spirometers, acute hospital admissions (6 vs 26; p<0.01) from March to August 2020 were significantly lower compared with the same period in 2019. There was no difference in the number of courses of oral corticosteroids or antibiotics prescribed (47 vs 53; p=0.81). From April to August 2020, 50 patients with DA performed 253 home spirometry measurements, of which 39 demonstrated >20% decrease in forced expiratory volume in 1 s, resulting in new action plans in 87% of these episodes. In our DA cohort, we demonstrate better attendance rates at virtual multidisciplinary team consultations and reduced hospital admission rates when augmented with home spirometry monitoring.

Very low rates of culture-confirmed invasive bacterial infections in a prospective 3-year population-based surveillance in Southwest London.

OBJECTIVES: To estimate the incidence, clinical characteristics and risk factors for culture-confirmed invasive bacterial infections in England. DESIGN: Prospective, observational, study of all children with positive blood and/or cerebrospinal fluid (CSF) culture over a 3-year period (2009-2011). SETTING: All five hospitals within a geographically defined region in southwest London providing care for around 600 000 paediatric residents. PATIENTS: Children aged 1 month to 15 years MAIN OUTCOME MEASURES: Rates of community-acquired and hospital-acquired invasive bacterial infections in healthy children and those with co-morbidities; pathogens by age group, risk group and clinical presentation. RESULTS: During 2009-2011, 44 118 children had 46 039 admissions, equivalent to 26 admissions per 1000 children. Blood/CSF cultures were obtained during 44.7% of admissions, 7.4% were positive but only 504 were clinically significant, equivalent to 32.9% of positive blood/CSF cultures, 2.4% of all blood/CSF cultures and 1.1% of hospital admissions. The population incidence of culture-confirmed invasive bacterial infection was 28/100 000. One-third of infections were hospital acquired and, of the community-acquired infections, two-thirds occurred in children with pre-existing co-morbidities. In previously healthy children, therefore, the incidence of community-acquired invasive bacterial infection was only 6.4/100 000. CONCLUSIONS: Although infection was suspected in almost half the children admitted to hospital, a significant pathogen was cultured from blood or CSF in only 2.4%, mainly among children with pre-existing co-morbidities, who may require a more broad-spectrum empiric antibiotic regime compared to previously healthy children. Invasive bacterial infection in previously healthy children is now very rare. Improved strategies to manage low-risk febrile children are required.