Long-Term Usage and Improved Clinical Outcomes with Adoption of a COPD Digital Support Service: Key Findings from the RECEIVER Trial.

Purpose: Digital tools may improve chronic obstructive pulmonary disease (COPD) management, but further evidence of significant, persisting benefits are required. The RECEIVER trial was devised to evaluate the Lenus COPD support service by determining if people with severe COPD would continue to utilize the co-designed patient web application throughout study follow-up and to explore the impact of this digital service on clinical outcomes with its adoption alongside routine care. Patients and Methods: The prospective observational cohort hybrid implementation-effectiveness study began in September 2019 and included 83 participants. Recruitment stopped in March 2020 due to COVID-19, but follow-up continued as planned. A contemporary matched control cohort was identified to compare participant clinical outcomes with and minimize biases associated with wider COVID-19 impacts. Utilization was determined by daily COPD assessment test (CAT) completion through the application. Survival metrics and post-index date changes in annual hospitalizations were compared between the RECEIVER and control cohorts. Longitudinal quality of life and symptom burden data and community-managed exacerbation events were also captured through the application. Results: High and sustained application utilization was noted across the RECEIVER cohort with a mean follow-up of 78 weeks (64/83 participants completed at least one CAT entry on ≥50% of possible follow-up weeks). Subgroup analysis of participants resident in more socioeconomically deprived postcode areas revealed equivalent utilization. Median time to death or a COPD or respiratory-related admission was higher in the RECEIVER cohort compared to control (335 days vs 155 days). Mean reduction in annual occupied bed days was 8.12 days vs 3.38 days in the control cohort. Quality of life and symptom burden remained stable despite the progressive nature of COPD. Conclusion: The sustained utilization of the co-designed patient application and improvements in participant outcomes observed in the RECEIVER trial support scale-up implementation with continued evaluation of this digital service.

Predicting mortality after hospitalisation for COPD using electronic health records.

BACKGROUND: Few prognostic models exist for patients hospitalised with chronic obstructive pulmonary disease (COPD); most are based on small cohorts enroled by specialists in academic centres. Electronic health records (EHRs) provide an opportunity to develop more representative models, although they may not record some variables used in existing models. MATERIALS AND METHODS: for this retrospective cohort study, using EHRs, we identified 17,973 patients with an unplanned hospitalisation for COPD (in any diagnostic position) in the Glasgow area between 2011 and 2017. Patients with known lung cancer were excluded. EHR were linked to prior admissions, community prescribing and laboratory data. A pragmatic, parsimonious multivariable model was developed to predict 90-day mortality. RESULTS: we identified 12 variables strongly related to prognosis, including age, sex, length of index hospitalisation stay, prior diagnosis of cancer (excluding lung cancer) or dementia, prescription of oxygen or digoxin, neutrophil/lymphocyte ratio and serum chloride, urea, creatinine and albumin. The model achieved excellent calibration with reasonable discrimination (area under the curve: 0.806; 95% CI: 0.792-0.820). A risk-score was developed and an electronic risk-calculator is provided. CONCLUSIONS: a small number of variables, including prescriptions and laboratory data obtained from routine EHRs predict 90-day mortality after a hospitalisation for COPD. The risk-calculator provided might prove useful for service-evaluation and audit, to guide clinical management and to risk-stratify and select patients to be invited to participate in clinical research.

Assistive technologies for home NIV in patients with COPD: feasibility and positive experience with remote-monitoring and volume-assured auto-EPAP NIV mode.

BACKGROUND: Outcomes for patients with chronic obstructive pulmonary disease (COPD) with persistent hypercapnic respiratory failure are improved by long-term home non-invasive ventilation (NIV). Provision of home-NIV presents clinical and service challenges. The aim of this study was to evaluate outcomes of home-NIV in hypercapnic patients with COPD who had been set-up at our centre using remote-monitoring and iVAPS-autoEPAP NIV mode (Lumis device, ResMed). METHODS: Retrospective analysis of a data set of 46 patients with COPD who commenced remote-monitored home-NIV (AirView, ResMed) between February 2017 and January 2018. Events including time to readmission or death at 12 months were compared with a retrospectively identified cohort of 27 patients with hypercapnic COPD who had not been referred for consideration of home-NIV. RESULTS: The median time to readmission or death was significantly prolonged in patients who commenced home-NIV (median 160 days, 95% CI 69.38 to 250.63) versus the comparison cohort (66 days, 95% CI 21.9 to 110.1; p<0.01). Average time to hospital readmission was 221 days (95% CI, 47.77 to 394.23) and 70 days (95% CI, 55.31 to 84.69; p<0.05), respectively. Median decrease in bicarbonate level of 4.9 mmol/L (p<0.0151) and daytime partial pressure of carbon dioxide 2.2 kPa (p<0.032) in home-NIV patients with no required increase in nurse home visits is compatible with effectiveness of this service model. Median reduction of 14 occupied bed days per annum was observed per patient who continued home-NIV throughout the study period (N=32). CONCLUSION: These findings demonstrate the feasibility and provide initial utility data for a technology-assisted service model for the provision of home-NIV therapy for patients with COPD.

Remote-Management of COPD: Evaluating the Implementation of Digital Innovation to Enable Routine Care (RECEIVER): the protocol for a feasibility and service adoption observational cohort study.

INTRODUCTION: Reductions in exacerbation and hospitalisations are the outcomes rated as most important by people with chronic obstructive pulmonary disease (COPD). Most COPD management is currently based on a reactive approach, and delays in recognising treatable opportunities underpin COPD care quality gaps. Innovations that empower COPD self-management, facilitate integrated clinical care and support delivery of evidence-based treatment interventions are urgently required. METHODS AND ANALYSIS: The Remote-Management of COPD: Evaluating the Implementation of Digital Innovation to Enable Routine Care trial is a prospective observational cohort hybrid implementation and effectiveness study that will explore the adoption of a digital service model for people with 'high-risk' COPD and evaluate the feasibility of this approach versus current standards of care. People with COPD, who have had recent severe exacerbation and/or COPD-obstructive sleep apnoea overlap or chronic hypercapnic respiratory failure requiring home non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP), with internet access will be recruited into the study and enrolled into the digital service.Study endpoints will examine participant utilisation, clinical service impact and clinical outcomes compared with historical and contemporary control patient data. The digital infrastructure will also provide a foundation to explore the feasibility of approaches to predict outcomes and exacerbation in people with COPD through machine learning analysis. ETHICS AND DISSEMINATION: Ethical approval for this clinical trial has been obtained from the West of Scotland Research Ethics Service. The trial will commence in September 2019 for a duration of 2 years. Results will be presented at local, national and international meetings, as well as submission for publication to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04240353.

The Activation State of CD4 T Cells Alters Cellular Peptidase Activities, HIV Antigen Processing, and MHC Class I Presentation in a Sequence-Dependent Manner.

CD4 T cell activation is critical to the initiation of adaptive immunity. CD4 T cells are also the main targets of HIV infection, and their activation status contributes to the maintenance and outcome of infection. Although the role of activation in the differentiation and proliferation of CD4 T cells is well studied, its impact on the processing and MHC class I (MHC-I) presentation of epitopes and immune recognition by CD8 T cells are not investigated. In this study, we show that the expression and hydrolytic activities of cellular peptidases are increased upon TCR-dependent and MHC-peptide activation of primary CD4 T cells from healthy or HIV-infected persons. Changes in peptidase activities altered the degradation patterns of HIV Ags analyzed by mass spectrometry, modifying the amount of MHC-I epitopes produced, the antigenicity of the degradation products, and the coverage of Ags by degradation peptides presentable by MHC-I. The computational analysis of 2237 degradation peptides generated during the degradation of various HIV-antigenic fragments in CD4 T cells identified cleavage sites that were predictably enhanced, reduced, or unchanged upon cellular activation. Epitope processing and presentation by CD4 T cells may be modulated by the activation state of cells in a sequence-dependent manner. Accordingly, cellular activation modified endogenous Ag processing and presentation and killing of HIV-infected CD4 T cells by CD8 T cells in a way that mirrored differences in in vitro epitope processing. The clearance of HIV-infected cells may rely on different immune responses according to activation state during HIV infection.

Desired Improvement Tool (DIT): A tool to assess desire for improvement in psoriasis patients.

No validated instrument exists to measure desire for improvement in psoriasis patients. To address this void, we conducted a single-center longitudinal study of 268 moderate-to-severe psoriasis patients to psychometrically validate the Desired Improvement Tool (DIT). The DIT is a single-item instrument scored 0-5 by the patient. A 0 indicates the patient is satisfied with disease level and does not desire further treatment. A 5 indicates a large amount of improvement is desired. The DIT demonstrated high test-retest reliability (Spearman, r = 0.97). Predictive and construct validity were moderate-to-high: r = 0.70 for BSA, 0.67 for PASI, and 0.56 for PGA and r = 0.67 for Life Quality Assessment (LQA), respectively. A sensitivity analysis revealed the DIT responded to changes in BSA. As a psychometrically valid tool, the DIT may guide clinical management of psoriasis patients by capturing an important clinical construct in an expedient and quantifiable manner.

Predicting sleep disordered breathing in outpatients with suspected OSA.

OBJECTIVE: To validate the utilities of Berlin, STOP and STOP-BANG Questionnaires, other patient characteristics, comorbidities, Epworth Sleepiness Scale (ESS), fractional exhaled nitric oxide (FENO) and blood markers for the prediction of sleep disordered breathing (SDB) on limited polygraphy. SETTING: North Glasgow Sleep Service (a tertiary referral centre). PARTICIPANTS: 129 consecutive patients, aged ≥16 years, referred to the sleep clinic for assessment of possible obstructive sleep apnoea. INTERVENTIONS: We selected cut-points of apnoea hypopnoea index (AHI) of ≥5 and ≥15/h from their home polygraphy and determined associations of these with individual symptoms, questionnaire scores and other results. Receiver operating characteristic analysis and univariate and multivariate logistic regression were used to explore these. PRIMARY AND SECONDARY OUTCOMES MEASURES: Primary: The utility of STOP, STOP-BANG and Berlin Questionnaires for prediction of SDB. Secondary: The utility of other measures for prediction of SDB. RESULTS: AHI was ≥5 in 97 patients and ≥15 in 56 patients. STOP and STOP-BANG scores were associated with both AHI cut-points but results with ESS and Berlin Questionnaire scores were negative. STOP-BANG had a negative predictive value 1.00 (0.77-1.00) for an AHI ≥15 with a score ≥3 predicting AHI ≥5 with sensitivity 0.93 (95% CI 0.84 to 0.98) and accuracy 79%, while a score ≥6 predicted AHI ≥15 with specificity 0.78 (0.65 to 0.88) and accuracy 72%. Neck circumference ≥17 inch and presence of witnessed apnoeas were independent predictors of SDB. CONCLUSIONS: STOP and STOP-BANG Questionnaires have utility for the prediction of SDB in the sleep clinic population. Modification of the STOP-BANG Questionnaire merits further study in this and other patient groups.

Low-dose fluvastatin reverses the hypoxic pulmonary adventitial fibroblast phenotype in experimental pulmonary hypertension.

Hypoxic pulmonary hypertension is a worldwide public health problem. Statins attenuate hypoxic pulmonary hypertension in animal models, but the mechanism of action and applicability of these results to human treatment are not established. In hypoxic models, pulmonary artery fibroblast proliferation contributes substantially to pulmonary vascular remodeling. We previously showed that acute hypoxic pulmonary adventitial fibroblast proliferation can be selectively inhibited by statins and p38 mitogen-activated protein (MAP) kinase inhibitors. Here we used complementary chronic hypoxic and acute hypoxic coculture models to obtain necessary preclinical information regarding the utility of fluvastatin in the treatment of chronic hypoxic pulmonary hypertension. The effects of fluvastatin, cholesterol pathway intermediates, and related inhibitors on hypoxic adventitial fibroblast proliferation, p38 MAP kinase phosphorylation, and pulmonary artery smooth muscle cell proliferation were determined, using complementary chronic hypoxic rat and acute hypoxic bovine cell models. Fluvastatin reversed the proliferative phenotypic switch in adventitial fibroblasts from chronic hypoxic animals. This effect was circulation-specific, and implicated a Rac1-p38 MAP kinase signaling pathway. Coculture and conditioned media experiments also implicated this statin-sensitive signaling pathway in the release of pulmonary artery smooth muscle cell mitogens by hypoxic pulmonary adventitial fibroblasts. Treprostinil, sildenafil, and bosentan exerted no effect on the hypoxic fibroblast phenotype. Phenotypic changes (increased proliferation and mitogen release) in pulmonary artery fibroblasts during chronic hypoxia are dependent on a Rac1-p38 MAP kinase signaling pathway. The inhibition of these phenotypic changes with fluvastatin may be therapeutically relevant in high-altitude residents and in patients with hypoxic lung disease.

Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension.

RATIONALE: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies. OBJECTIVES: To investigate the prognosis of CTEPH in a national setting during recent years. METHODS: All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records. MEASUREMENTS AND MAIN RESULTS: A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%. CONCLUSIONS: The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition.

Fluvastatin inhibits hypoxic proliferation and p38 MAPK activity in pulmonary artery fibroblasts.

The earliest structural change in hypoxia-induced pulmonary hypertension is increased proliferation of adventitial fibroblasts. This fibroproliferative response occurs in acute and chronic hypoxic models, is dependent on p38 mitogen-activated protein (MAP) kinase activation, is selective for the pulmonary circulation, and would seem an important therapeutic target. Simvastatin attenuates pulmonary vascular remodeling in animal models, but additional information regarding mechanisms of action, differential antiproliferative effects and dose responses of available statins is required for appropriate clinical trial design. Our objectives were to determine the effects of statins on acute hypoxia-induced proliferation and p38 MAP kinase activation in pulmonary and systemic artery fibroblasts, to assess the effects of cholesterol intermediates, prenyltransferase and related inhibitors, and to determine the statin's mechanism of action. Atorvastatin, fluvastatin, and simvastatin inhibited adventitial fibroblast proliferation. At low doses (1 microM), this effect was selective for hypoxic (versus serum-induced) proliferation and was also selective for pulmonary (versus systemic) fibroblasts. Complete inhibition of hypoxia-induced p38 MAP kinase activity was achieved at this 1-microM dose. The lipophilic statins exhibited similar potency. The statin effect was reversed by geranylgeranyl pyrophosphate and mimicked by geranylgeranyl transferase and Rac1 inhibitors. Hypoxia-induced p38 MAP kinase activation and proliferation in pulmonary adventitial fibroblasts is dependent on a geranylgeranylated signaling protein, probably Rac1. One micromolar of fluvastatin exhibits a circulation- and stimulus-selective antiproliferative effect on pulmonary artery fibroblasts. The pharmacokinetics of fluvastatin would suggest that its antiproliferative effects may be useful in pulmonary hypertension associated with hypoxia.

Pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adult and pediatric patients with moderate to severe atopic dermatitis.

OBJECTIVE: To characterize the pharmacokinetics of tacrolimus after topical application in adult and pediatric patients with moderate to severe atopic dermatitis from all clinical trials in which tacrolimus blood levels were obtained. METHODS: Tacrolimus ointment 0.03% or 0.1% was applied twice daily. In the adult and pediatric pharmacokinetic studies, serial blood samples were obtained after single and repeated topical application. During the 12 clinical efficacy trials of tacrolimus ointment, single blood samples were obtained at various times relative to tacrolimus ointment application. RESULTS: In the pharmacokinetic studies, 89% to 95% of tacrolimus whole blood concentration samples were less than 1 ng/mL; mean maximum concentrations ranged from 0.2 to 1.6 ng/mL and mean area under the blood concentration-time curves (0-12 hours) ranged from 1.4 to 13.1 ng x hr/mL. Likewise, in the clinical efficacy trials, the majority (85%-99%) of tacrolimus concentration samples were less than 1 ng/mL. CONCLUSIONS: Tacrolimus ointment is associated with minimal systemic absorption and no evidence of systemic accumulation in patients with moderate to severe atopic dermatitis and extensive disease.

A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis.

A 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI 75) is the current benchmark of primary endpoints for most clinical trials of psoriasis. Many consider this endpoint to be too stringent as it places potentially useful therapies at risk of failing to demonstrate efficacy. We hypothesized that a 50% reduction in the PASI score (PASI 50) represents a meaningful change in a person's life and thus is a better primary endpoint. To test this hypothesis, we analyzed PASI scores, quality of life (QoL) data, and desired re-treatment scores from a number of clinical trials in addition to studying individual elements that make up the PASI. This analysis shows (1). the PASI score is not linearly reflective of psoriasis severity (eg, a reduction in area of 95% without a change in redness, scaliness, and induration translates to only a 66% reduction in PASI); conversely, a drop in erythema, scale, and induration from an average of 3 to 1 would not lead to a 75% reduction in PASI; (2). treatment with methotrexate, an effective psoriasis therapy, more frequently reaches PASI 50 than PASI 75 as evidenced by a recent open trial in which 63% of patients achieved PASI 50 versus 26% achieving PASI 75; (3). improvement in QoL exists at PASI 50, using the Dermatology Quality of Life Index, as documented in several recently completed large clinical trials; (4). patients achieving PASI 75 frequently defer therapy until they are well below PASI 50; a clinical trial where retreatment was patient initiated showed patients did not re-treat until their PASI dropped to an average of 20% improvement from baseline; and (5). effective, meaningful therapies are consistently differentiated from placebo at PASI 50 as evidenced by histologic and photographic parameters of clinical trials of alefacept, efalizumab, and etanercept. We conclude that PASI 50 equates to a clinically meaningful improvement in psoriasis and represents a discerning primary endpoint.

Efficacy of acitretin and commercial tanning bed therapy for psoriasis.

OBJECTIVE: To assess the efficacy of acitretin and commercial tanning bed therapy for the treatment of moderate to severe chronic plaque-type psoriasis. DESIGN: Retrospective medical record review and telephone survey of subjects and prospective open-label trial. SETTING: University dermatology clinic. PATIENTS: The study population comprised 26 subjects in the retrospective study and 17 subjects in the prospective study, all with moderate to severe plaque-type psoriasis. INTERVENTION: Twelve weeks of daily oral acitretin (25 mg) therapy and commercial tanning bed UV exposure (mean UV-B output of 4.7%) for 4 to 5 days per week. RESULTS: In the retrospective review, 19 (83%) of 23 subjects had clearance or near clearance, 2 (9%) of 23 had moderate improvement, and 2 (9%) of 23 had no improvement. Patients reported a high degree of satisfaction with the treatment. In the prospective trial, the Psoriasis Area and Severity Index (PASI) and National Psoriasis Foundation scores decreased an average of 78.6% and 79.0% from baseline, respectively. A reduction from baseline in the PASI score of 50% and 75% (PASI 50 and PASI 75) was achieved by 13 (76%) and 10 (59%) patients, respectively. Adverse events were generally mild to moderate. CONCLUSIONS: Acitretin use in combination with commercial tanning bed therapy appears to be effective and useful for psoriasis in areas without access to physician-directed phototherapy. The variability of tanning salon light and quality mandates caution when using this therapy.

Induction of dramatic hyperpigmentation in a patient with generalized lichen planus treated with re-PUVA.

BACKGROUND: Retinoids plus PUVA (re-PUVA) may be used in the treatment of lichen planus in cases that do not respond to monotherapy. Hyperpigmentation is a potential side effect of re-PUVA therapy. OBJECTIVE: A case of remarkably intense transient hyperpigmentation secondary to re-PUVA therapy is presented. METHODS AND RESULTS: An 18-year-old male with lichen planus who had been taking isotretinoin 80 mg per day for seven days developed an exaggerated hyperpigmentation following the third dose of PUVA. CONCLUSION: As the hyperpigmentary reaction did not occur until the third PUVA dose, which was near the steady state of isotretinoin, this case may illustrate a case of photosensitization secondary to isotretinoin alone or isotretinoin in combination.