Greenhouse gas emissions associated with suboptimal asthma care in the UK: the SABINA healthCARe-Based envirONmental cost of treatment (CARBON) study.

BACKGROUND: Poorly controlled asthma is associated with increased morbidity and healthcare resource utilisation (HCRU). Therefore, to quantify the environmental impact of asthma care, this retrospective, cohort, healthCARe-Based envirONmental cost of treatment (CARBON) study estimated greenhouse gas (GHG) emissions in the UK associated with the management of well-controlled versus poorly controlled asthma. METHODS: Patients with current asthma (aged ≥12 years) registered with the Clinical Practice Research Datalink (2008‒2019) were included. GHG emissions, measured as carbon dioxide equivalent (CO2e), were estimated for asthma-related medication use, HCRU and exacerbations during follow-up of patients with asthma classified at baseline as well-controlled (<3 short-acting ß2-agonist (SABA) canisters/year and no exacerbations) or poorly controlled (≥3 SABA canisters/year or ≥1 exacerbation). Excess GHG emissions due to suboptimal asthma control included ≥3 SABA canister prescriptions/year, exacerbations and any general practitioner and outpatient visits within 10 days of hospitalisation or an emergency department visit. RESULTS: Of the 236 506 patients analysed, 47.3% had poorly controlled asthma at baseline. Scaled to the national level, the overall carbon footprint of asthma care in the UK was 750 540 tonnes CO2e/year, with poorly controlled asthma contributing excess GHG emissions of 303 874 tonnes CO2e/year, which is equivalent to emissions from >124 000 houses in the UK. Poorly controlled versus well-controlled asthma generated 3.1-fold higher overall and 8.1-fold higher excess per capita carbon footprint, largely SABA-induced, with smaller contributions from HCRU. CONCLUSIONS: These findings suggest that addressing the high burden of poorly controlled asthma, including curbing high SABA use and its associated risk of exacerbations, may significantly alleviate asthma care-related carbon emissions.

Local variation in low carbon footprint inhalers in pre-COVID pandemic primary care prescribing guidelines for adult asthma in England and its potential impact.

AIMS: Pressurised metered-dose inhalers (MDIs) have a much higher carbon footprint than dry powder inhalers (DPIs). We aimed to describe variations of inhaler options in local adult asthma prescribing guidance. METHODS: We reviewed local clinical commissioning group (CCG) adult asthma prescribing guidance for primary care in England in 2019 and recorded DPI and MDI inclusion. The relationship to prescribing data from OpenPrescribing.net was examined. RESULTS: In total, 58 unique guidance documents were analysed covering 144 out of 191 CCGs in England. Only 3% of CCG guidelines expressed an overall preference for DPIs, while 12% explicitly preferred MDIs. The inclusion of DPIs first-line was 77% for short-acting ß-agonists, 78% for low-dose inhaled corticosteroid (ICS) inhalers and 90-96% for combination long-acting ß-agonist/ICS inhalers. MDIs were included first-line in 98-100% of these classes. In 26% of CCGs, there was no first-line DPI option for at least 1 asthma management step. Ten percent of CCGs had no DPI included first-line for any of the 5 classes examined. Many CCGs recommended higher carbon footprint options; Ventolin MDI (25.6%), inhalers containing HFA227ea (57.9%) and ICS regimes recommending 2 puffs of a lower dose over 1 puff of higher dose (94.2%). MDIs were prescribed more in CCGs that recommended them. CONCLUSION: Before the COVID pandemic, there was substantial variation between CCGs in adult asthma prescribing guidance regarding higher and lower carbon footprint options. There may still be scope to amend local guidance to improve clinical and environmental outcomes. This study provides a method and baseline for further investigation of this.

A retrospective analysis of smoking cessation measures: A single-center approach.

Smoking is a detrimental addiction contributing to many pathologies including cardiovascular disease and cancer. This retrospective study's aim was to assess the impact that conservative measures, like nicotine replacement therapy (NRT) and cessation clinic referral, have on smoking cessation on a respiratory ward. The baseline data obtained on admission to the hospital revealed that only 50% of patients were asked about their smoking status. Using a checklist, the health care professionals were encouraged to take a more proactive approach in promoting smoking cessation, resulting in 100% of the patients being asked about their smoking status. Of these, 81.8% agreed to try nicotine replacement therapy and 36.3% agreed to a Hertfordshire Stop Smoking Service referral. In the future, further studies are planned to assess the long-term effectiveness of this intervention in getting patients to stop smoking by following them up at a 3-month interval.

COVID-19 and pneumothorax: a multicentre retrospective case series.

INTRODUCTION: Pneumothorax and pneumomediastinum have both been noted to complicate cases of coronavirus disease 2019 (COVID-19) requiring hospital admission. We report the largest case series yet described of patients with both these pathologies (including nonventilated patients). METHODS: Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival. RESULTS: 71 patients from 16 centres were included in the study, of whom 60 had pneumothoraces (six with pneumomediastinum in addition) and 11 had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication while intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1±6.5%) or isolated pneumomediastinum (53.0±18.7%; p=0.854). The incidence of pneumothorax was higher in males. 28-day survival was not different between the sexes (males 62.5±7.7% versus females 68.4±10.7%; p=0.619). Patients aged ≥70 years had a significantly lower 28-day survival than younger individuals (≥70 years 41.7±13.5% survival versus <70 years 70.9±6.8% survival; p=0.018 log-rank). CONCLUSION: These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage continuation of active treatment where clinically possible.

Sustainability in Inhaled Drug Delivery.

Asthma and chronic obstructive pulmonary disease (COPD) are amongst the most common chronic diseases worldwide, and are largely preventable by improving the quality of the air we breathe. The most commonly deployed treatment, the metered dose inhaler (MDI), uses hydrofluorocarbon propellants, which are powerful greenhouse gases that contribute disproportionately to the climate crisis. Alternative treatment strategies are required if we are to avoid contributing to the worst effects of climate change. These strategies include promoting non-pharmacological therapies like smoking cessation and pulmonary rehabilitation; empowering patients to gain better disease control through written management plans and encouraging preventer, rather than reliever therapies. Pharmacological strategies include: improving inhaler technique and spacer use; minimising propellant release by using smaller volume MDIs and simpler dosing regimes; dose counters to prevent waste; switching to low global warming potential inhalers; and inhaler recycling. There are also opportunities to improve disease control alongside reduced greenhouse gas emissions, including better matching of patients' devices to inhaler technique rather than defaulting to MDIs, stopping unnecessary inhaled steroids in COPD and maintenance and reliever therapy in asthma. New, lower global warming potential propellants are on the horizon, and their introduction could offer a golden opportunity to enhance MDIs usability and sustainability by making them refillable, integrating whistles to optimise inhalation technique, adding integrated caps, optimising materials for recycling and adding dose counters to all MDIs.

Carbon footprint impact of the choice of inhalers for asthma and COPD.

In the 1990s, metered dose inhalers (MDIs) containing chlorofluorocarbons were replaced with dry-powder inhalers (DPIs) and MDIs containing hydrofluorocarbons (HFCs). While HFCs are not ozone depleting, they are potent greenhouse gases. Annual carbon footprint (CO2e), per patient were 17 kg for Relvar-Ellipta/Ventolin-Accuhaler; and 439 kg for Seretide-Evohaler/Ventolin-Evohaler. In 2017, 70% of all inhalers sold in England were MDI, versus 13% in Sweden. Applying the Swedish DPI and MDI distribution to England would result in an annual reduction of 550 kt CO2e. The lower carbon footprint of DPIs should be considered alongside other factors when choosing inhalation devices.

Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England.

OBJECTIVES: Metered-dose inhalers (MDIs) contain propellants which are potent greenhouse gases. Many agencies propose a switch to alternative, low global warming potential (GWP) inhalers, such as dry powder inhalers (DPIs). We aimed to analyse the impact on greenhouse gas emissions and drug costs of making this switch. SETTING: We studied National Health Service prescription data from England in 2017 and collated carbon footprint data on inhalers commonly used in England. DESIGN: Inhalers were separated into different categories according to their mechanisms of action (eg, short-acting beta-agonist). Within each category we identified low and high GWP inhalers and calculated the cost and carbon impact of changing to low GWP inhalers. We modelled scenarios for swapping proportionally according to the current market share of each equivalent DPI (model 1) and switching to the lowest cost pharmaceutically equivalent DPI (model 2). We also reviewed available data on the carbon footprint of inhalers from scientific publications, independently certified reports and patents to provide more accurate carbon footprint information on different types of inhalers. RESULTS: If MDIs using HFA propellant are replaced with the cheapest equivalent DPI, then for every 10% of MDIs changed to DPIs, drug costs decrease by £8.2M annually. However if the brands of DPIs stay the same as 2017 prescribing patterns, for every 10% of MDIs changed to DPIs, drug costs increase by £12.7M annually. Most potential savings are due to less expensive long-acting beta-agonist (LABA)/inhaled corticosteroids (ICS) inhalers. Some reliever inhalers (eg, Ventolin) have a carbon footprint over 25 kg CO2e per inhaler, while others use far less 1,1,1,2-tetrafluoroethane (HFA134a) (eg, Salamol) with a carbon footprint of <10 kg CO2e per inhaler. 1,1,1,2,3,3,3-Heptafluoropropane (HFA227ea) LABA/ICS inhalers (eg, Flutiform) have a carbon footprint over 36 kg CO2e, compared with an equivalent HFA134a combination inhaler (eg, Fostair) at <20 kg CO2e. For every 10% of MDIs changed to DPIs, 58 kt CO2e could be saved annually in England. CONCLUSIONS: Switching to DPIs would result in large carbon savings and can be achieved alongside reduced drug costs by using less expensive brands. Substantial carbon savings can be made by using small volume HFA134a MDIs, in preference to large volume HFA134a MDIs, or those containing HFA227ea as a propellant.

Lipid conjugation of TLR7 agonist Resiquimod ensures co-delivery with the liposomal Cationic Adjuvant Formulation 01 (CAF01) but does not enhance immunopotentiation compared to non-conjugated Resiquimod+CAF01.

Pattern recognition receptors, including the Toll-like receptors (TLRs), are important in the induction and activation of two critical arms of the host defence to pathogens and microorganisms: the rapid innate immune response (as characterised by the production of Th1 promoting cytokines and type 1 interferons) and the adaptive immune response. Through this activation, ligands and agonists of TLRs can enhance immunotherapeutic efficacy. Resiquimod is a small (water-soluble) agonist of the endosome-located Toll-like receptors 7 and 8 (TLR7/8). However due to its molecular attributes it rapidly distributes throughout the body after injection. To circumvent this, these TLR agonists can be incorporated within delivery systems, such as liposomes, to promote the co-delivery of both antigen and agonists to antigen presenting cells. In this present study, resiquimod has been chemically conjugated to a lipid to form a lipid-TLR7/8 agonist conjugate which can be incorporated within immunogenic cationic liposomes composed of dimethyldioctadecylammonium bromide (DDA) and the immunostimulatory glycolipid trehalose 6,6' - dibehenate (TDB). This DDA:TDB-TLR7/8 formulation offers similar vesicle characteristics to DDA:TDB (size and charge) and offers high retention of both resiquimod and the electrostatically adsorbed TB subunit antigen Ag85B-ESAT6-Rv2660c (H56). Following immunisation through the intramuscular (i.m.) route, these cationic DDA:TDB-TLR7/8 liposomes form a vaccine depot at the injection site. However, immunisation studies have shown that this biodistribution does not translate into notably increased antibody nor Th1 responses at the spleen and draining popliteal lymph node compared to DDA:TDB liposomes. This work demonstrates that the conjugation of TLR7/8 agonists to cationic liposomes can promote co-delivery but the immune responses stimulated do not merit the added complexity considerations of the formulation.

Sustainability in quality improvement: redefining value.

Sustainability can be considered a domain of quality in -healthcare, extending the responsibility of health services to patients not just of today but of the future. The longer term -perspective highlights the impacts of our healthcare system on our environment and communities and in turn back onto population health. A sustainable approach will therefore expand the healthcare definition of value to measure health outcomes against environmental and social impacts alongside financial costs. We set out a practical framework for including these new dimensions in an already well-defined model of quality improvement. This has the potential to harness the growing quality improvement movement to shape a more sustainable health service, while improving patient outcomes. Early experience suggests that the new model may also provide immediate -benefits, including additional motivation for clinicians to engage in quality improvement, directing their efforts towards high value interventions and enabling capture and communication of a wider range of impacts on patients, staff and communities.

High-throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization.

Microfluidics has recently emerged as a new method of manufacturing liposomes, which allows for reproducible mixing in miliseconds on the nanoliter scale. Here we investigate microfluidics-based manufacturing of liposomes. The aim of these studies was to assess the parameters in a microfluidic process by varying the total flow rate (TFR) and the flow rate ratio (FRR) of the solvent and aqueous phases. Design of experiment and multivariate data analysis were used for increased process understanding and development of predictive and correlative models. High FRR lead to the bottom-up synthesis of liposomes, with a strong correlation with vesicle size, demonstrating the ability to in-process control liposomes size; the resulting liposome size correlated with the FRR in the microfluidics process, with liposomes of 50 nm being reproducibly manufactured. Furthermore, we demonstrate the potential of a high throughput manufacturing of liposomes using microfluidics with a four-fold increase in the volumetric flow rate, maintaining liposome characteristics. The efficacy of these liposomes was demonstrated in transfection studies and was modelled using predictive modeling. Mathematical modelling identified FRR as the key variable in the microfluidic process, with the highest impact on liposome size, polydispersity and transfection efficiency. This study demonstrates microfluidics as a robust and high-throughput method for the scalable and highly reproducible manufacture of size-controlled liposomes. Furthermore, the application of statistically based process control increases understanding and allows for the generation of a design-space for controlled particle characteristics.

Th1 immune responses can be modulated by varying dimethyldioctadecylammonium and distearoyl-sn-glycero-3-phosphocholine content in liposomal adjuvants.

OBJECTIVES: Cationic liposomes of dimethyldioctadecylammonium bromide (DDA) combined with trehalose 6,6'-dibehenate (TDB) elicit strong cell-mediated and antibody immune responses; DDA facilitates antigen adsorption and presentation while TDB potentiates the immune response. To further investigate the role of DDA, DDA was replaced with the neutral lipid of distearoyl-sn-glycero-3-phosphocholine (DSPC) over a series of concentrations and these systems investigated as adjuvants for the delivery of Ag85B-ESAT-6-Rv2660c, a multistage tuberculosis vaccine. METHODS: Liposomal were prepared at a 5 : 1 DDA-TDB weight ratio and DDA content incrementally replaced with DSPC. The physicochemical characteristics were assessed (vesicle size, zeta potential and antigen loading), and the ability of these systems to act as adjuvants was considered. KEY FINDINGS: As DDA was replaced with DSPC within the liposomal formulation, the cationic nature of the vesicles decreases as does electrostatically binding of the anionic H56 antigen (Hybrid56; Ag85B-ESAT6-Rv2660c); however, only when DDA was completed replaced with DSPC did vesicle size increase significantly. T-helper 1 (Th1)-type cell-mediated immune responses reduced. This reduction in responses was attributed to the replacement of DDA with DSPC rather than the reduction in DDA dose concentration within the formulation. CONCLUSION: These results suggest Th1 responses can be controlled by tailoring the DDA/DSPC ratio within the liposomal adjuvant system.

Bilateral miliary shadowing on chest X-ray.

A patient presented with recent onset of increasing shortness of breath, weight loss and low-grade fever. His chest X-ray revealed bilateral miliary shadowing. He was investigated with CT-scanning of thorax. Later, a biopsy from supra-clavicular node and its immunocytochemistry studies confirmed metastasis from primary lung cancer. Primary lung cancer with miliary pulmonary metastases is a rare happening and is mostly associated with lung adenocarcinoma.

A case-study investigating the physicochemical characteristics that dictate the function of a liposomal adjuvant.

A range of particulate delivery systems have been considered as vaccine adjuvants. Of these systems, liposomes offer a range of advantages including versatility and flexibility in design format and their ability to incorporate a range of immunomodulators and antigens. Here we briefly outline research, from within our laboratories, which focused on the systematic evaluation of cationic liposomes as vaccines adjuvants. Our aim was to identify physicochemical characteristics that correlate with vaccine efficacy, with particular consideration of the interlink between depot-forming action and immune responses. A variety of parameters were investigated and over a range of studies we have confirmed that cationic liposomes, based on dimethyldioctadecylammonium bromide and trehalose 6,6'-dibehenate formed a depot at the injection site, which stimulates recruitment of antigen presenting cells to the injection site and promotes strong humoral and cell-mediated immune responses. Physicochemical factors which promote a strong vaccine depot include the combination of a high cationic charge and electrostatic binding of the antigen to the liposome system and the use of lipids with high transition temperatures, which form rigid bilayer vesicles. Reduction in vesicle size of cationic vesicles did not promote enhanced drainage from the injection site. However, reducing the cationic nature through substitution of the cationic lipid for a neutral lipid, or by masking of the charge using PEGylation, resulted in a reduced depot formation and reduced Th1-type immune responses, while Th2-type responses were less influenced. These studies confirm that the physicochemical characteristics of particulate-based adjuvants play a key role in the modulation of immune responses.

A rare presentation of a common disease: orificial tuberculosis.

Tuberculosis is a common condition with increasing incidence worldwide. Clinicians should be aware of cutaneous manifestations, even though these are uncommon, as recognition can lead to early diagnosis. Here, we present a case of orificial tuberculosis in a young HIV-negative man.