Evaluation of Different Doses in Inhaled Therapy: A Comprehensive Analysis.

BACKGROUND: Currently, there is a considerable degree of confusion over the dosage of inhaled medications. Here, we carried out a review of all the doses used for the devices used in inhalation therapy. METHODS: We first performed a systematic search of the different inhalation devices included on the July 2023 Spanish Ministry of Health Billing List. We then consulted the Spanish Agency for Medicines and Health Products to find the updated official label and to obtain the information on the exact composition. RESULTS: We identified 90 unique products, of which 22 were long-acting bronchodilators (and combinations thereof) and 68 were products containing inhaled corticosteroids (ICS). Overall, 10 products with bronchodilators and 40 with ICS were marketed with the metered dose, while 11 with bronchodilators and 28 with ICS were marketed with the delivered dose. In addition, in some bronchodilators, the drug was referred to as a type of salt, whereas in others the information referred to the drug itself. CONCLUSIONS: Our data show that for each inhaled drug there may be up to four different doses and that the marketed name may refer to any of these. Clinicians must be aware of these different dosages when prescribing inhaled medications.

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. METHODOLOGY: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. RESULTS: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. CONCLUSIONS: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug.

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine.

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein's dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.

Evaluation of bone metabolism in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) bone disease (CFBD) has attracted considerable recent interest from researchers, although several aspects of CFBD pathophysiology remain poorly understood. The objective of this research was to investigate CFBD in children with CF and its relation to clinical and bone metabolism markers. METHODS: In a prospective observational study of 68 patients with CF and 63 healthy controls, we studied bone turnover biomarkers and bone mineral density (BMD). The biomarkers included osteocalcin, total-alkaline phosphatase, bone-alkaline phosphatase, N-terminal propeptide of type-1-procollagen, osteoprotegerin (OPG), interleukine-6, tumor necrosis factor alpha (TNF-α), type-1-collagen cross-linked C-telopeptide (CTX), parathormone (PTH), 25-vitamin D, 1,25-vitamin D, calcium and phosphorus. BMD was examined in lumbar spine, comparing two healthy Spanish populations. Two regression analyses were applied to any significant associations to evaluate predictors of BMD and of CF, expressed as odds ratios (OR) with 95% confidence intervals. RESULTS: After adjusting for age, sex, and height Z-score, gains in BMD LS in children and adolescents (6-16 years) with CF were not less than in healthy reference population. Patients with CF showed significant associations with different bone turnover biomarkers. Age, gender, body mass index, PTH, CTX and OPG were significant predictors of BMD (R2 = 0.866, p < 0,001). Moreover, we found that PTH (OR = 1.070; 95% CI 1.019-1.123), and TNFα (OR = 2.173; 95% CI 1.514-3.118) were significantly linked to CF, and calcium (OR = 0.115; 95% CI 0.025-0.524), 1,25-vitamin D (OR = 0.979; 95% CI 0.962 0.996) and OPG (OR = 0.189; 95% CI 0.073-0.489) were significant reduced. CONCLUSION: A normal bone mineral density along with altered remodeling was found in CF patients with a normal nutritional status and without acute lung disease.

Impact of SARS-CoV-2 infection in patients with cystic fibrosis in Spain: Incidence and results of the national CF-COVID19-Spain survey.

BACKGROUND: Given the high incidence of confirmed infection by SARS-CoV-2 and mortality by COVID-19 in the Spanish population, its impact was analysed among persons with Cystic Fibrosis (CF) as a group at risk of a worse evolution. The possible causes of the incidence observed in them are explained and how CF Units have faced this health challenge is detailed. METHODS: Retrospective descriptive observational study, for which a Spanish CF Patients with Confirmed COVID-19 Registry is created, requesting information on number of people affected between 8 March-16 May 2020 and their clinical-demographic characteristics from the CF Units participating in the European Cystic Fibrosis Society Patient Registry (ECFSPR). The accumulated incidence is calculated, compared with that of the general population. Additionally, a survey (CF-COVID19-Spain) is carried out on prevention of SARS-CoV-2 infection, workings of CF Units and possible reasons for the incidence observed. RESULTS: COVID-19 was diagnosed in eight CF patients, one of whom had received a lung transplant. The accumulated incidence was 32/10000 in CF patients and 49/10000 in the general population. General death rate was 5.85/10000 while no CF patients included in the ECFSPR died. The characteristics of those affected and the results of the survey are described. CONCLUSIONS: Despite being considered a disease at high risk of severe COVID-19, the low incidence and mortality in CF patients in Spain contrasts with the figures for the general population. The possible factors that would explain such findings are discussed, with the help of the results of the CF-COVID19-Spain survey.

The clinical implications of triple therapy in fixed-dose combination in COPD: from the trial to the patient.

The emergence of a fixed-dose combination (FDC) of a long-acting ß2-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS) in a single inhalation device has changed the approach to inhaled therapy. Although clinical trials describe the efficacy and safety of these FDCs, their use in daily clinical practice can present challenges for the clinician in two specific scenarios. In patients who are already receiving triple therapy via different devices, switching to FDCs could confer benefits by reducing critical errors in the management of inhalers, improving therapeutic adherence, and lowering costs, while maintaining the same clinical efficacy. In patients who are not receiving triple therapy in different devices and who require a change in treatment, triple therapy FDC has shown benefits in clinical trials. Although methodological differences among the trials advise against direct comparison, clinical results show good efficacy, but also considerable variability, and a number of clinical outcomes have yet to be explored. In the future, trials must be developed to complete clinical efficacy data. Real-world efficacy trials are needed, and studies must be designed to determine the profile of patients who present a greater therapeutic response to each FDC in order to pave the way towards more personalized treatment.

Triple therapy for COPD: a crude analysis from a systematic review of the evidence.

We systematically reviewed the current knowledge on fixed-dose triple therapies for the treatment of chronic obstructive pulmonary disease (COPD), with a specific focus on its efficacy versus single bronchodilation, double fixed dose combinations, and open triple therapies. Articles were retrieved from PubMed, Embase, and Scopus up to 3 August 2018. We selected articles with randomized controlled or crossover design conducted in patients with COPD and published as full-length articles or scientific letters, evaluating triple therapy combinations in a single or different inhaler, and with efficacy data versus monocomponents, double combinations, or open triple therapies. Our systematic search reported 108 articles, of which 24 trials were finally selected for the analysis. A total of 7 studies with fixed dose triple therapy combinations, and 17 studies with open triple therapies combinations. Triple therapy showed improvements in lung function [trough forced expiratory volume (FEV1) ranging from not significant (NS) to 147 ml], health status using the St. George's Respiratory Questionnaire [(SGRQ) from NS to 8.8 points], and exacerbations [risk ratio (RR) from NS to 0.59 for all exacerbations] versus single or double therapies with a variability in the response, depending the specific combination, and the comparison group. The proportion of adverse effects was similar between study groups, the exception being the increase in pneumonia for some inhaled corticosteroid (ICS) containing groups. The reviews of this paper are available via the supplementary material section.

Ten Research Questions for Improving COPD Care in the Next Decade.

With the 60th anniversary of the CIBA symposium, it is worth evaluating research questions that should be prioritized in the future. Coming research initiatives can be summarized in 10 main areas. (1) From epidemiology the impact of new forms of electronic cigarettes on prevalence and mortality of COPD will be sought. (2) The study of the disease endotypes and its relationship phenotypes will have to be unraveled in the next decade. (3) Diagnosis of COPD faces several challenges opening the possibility of a change in the definition of the disease itself. (4) Patients' classification and risk stratification will need to be clarified and reassessed. (5) The asthma-COPD overlap dilemma will have to be clarified and define whether both conditions represent one only chronic airway disease again. (6) Integrating comorbidities in COPD care will be key in a progressively ageing population to improve clinical care in a chronic care model. (7) Nonpharmacological management have areas for research including pulmonary rehabilitation and vaccines. (8) Improving physical activity should focus research because of the clear prognostic impact. (9). Pharmacological therapies present several challenges including efficacy and safety issues with current medications and the development of biological therapy. (10) The definition, identification, categorization and specific therapy of exacerbations will also be an area of research development. During the next decade, we have a window of opportunity to address these research questions that will put us on the path for precision medicine.

Status of and strategies for improving adherence to COPD treatment.

Despite the wide application of adherence as a concept, the definition, evaluation and improvement of the adherence to treatment by patients with chronic obstructive pulmonary disease (COPD) still present some challenges. First, it is necessary to clearly define the concepts of treatment adherence, compliance and persistence. Second, it is critical to consider the various methods of evaluating and quantifying adherence when interpreting adherence studies. In addition, the advantages and disadvantages of the different ways of measuring treatment adherence should be taken into account. Another subject of some debate is the number of variables associated with COPD treatment adherence. Adherence is a complex concept that goes beyond the dosage or the use of inhalation devices, and a number of variables are involved in determining adherence, from the clinical aspects of the disease to the patient's confidence in the doctor's expertise and the level of social support experienced by the patient. Notably, despite these challenges, the importance of adherence has been well established by clinical trials and routine clinical practice. The available evidence consistently shows the substantial impact that a lack of adherence has on the control of the disease and its long-term prognosis. For these reasons, the correct evaluation of therapeutic adherence should be a key objective in clinical interviews of patients. In recent years, various initiatives for improving adherence have been explored. All these initiatives have been based on patient education. Therefore, health care professionals should be aware of the issues pertaining to adherence and take the opportunity to educate patients each time they contact the health care system.

Outpatient Parenteral Antimicrobial Treatment for Non-Cystic Fibrosis Bronchiectasis Exacerbations: A Prospective Multicentre Observational Cohort Study.

BACKGROUND: The recently published guidelines of the Spanish Society of Pulmonology and Thoracic Surgery encourage physicians to use outpatient antimicrobial therapy to treat exacerbations in patients with non-cystic fibrosis bronchiectasis (NCFB). The published literature on this topic, however, is scarce. METHODS: We report a prospective observational cohort study of patients with NCFB who received treatment at home for at least one exacerbation episode between September 2012 and September 2017 as part of an outpatient parenteral antimicrobial therapy (OPAT) program. Patients were included in the analysis if they fulfilled all of the following criteria: established diagnosis of bronchiectasis according to current guidelines criteria, clinical exacerbation, requiring intravenous antibiotics because of failure to respond to oral antibiotics, or isolation of a microorganism resistant to oral options. OBJECTIVES: To evaluate the effectiveness and safety of the treatment of patients with NCFB exacerbations in an OPAT program under "real-world" conditions. RESULTS: Sixty-seven patients were treated in the OPAT program due to bacterial exacerbations of NCFB. Forty-five (67.2%) patients were admitted to hospital for a median of 7 days before starting OPAT. Sixty-three (94%) patients achieved resolution of the exacerbation at the end of therapy. Four patients needed hospital readmission, and one died. The OPAT program saved 11,586 days of hospital admission, equivalent to EUR 7,866,904. CONCLUSIONS: OPAT appears to be a safe, effective, and efficient strategy for treating patients with exacerbations of NCFB.

Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience.

BACKGROUND: The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs. METHODS: We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real-life in Spain. 20 CF patients were included, all aged 6 and upwards and presented with ppFEV1<40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months. RESULTS: The mean age was 26.65 (range of 10-45), while the mean ppFEV1 before the treatment was 32.4% and mean BMI was 19.9kg/m2. We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor/ivacaftor, but no differences were found. However, a moderate association between days of intravenous antibiotic needed and the use of lumacaftor/ivacaftor (p=0.001) was established. Indeed, under the lumacaftor/ivacaftor, patients required 5.8 days of intravenous antibiotic treatment compared to 14.9 days prior to study. Also, severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor/ivacaftor treatment (p=0.003). Finally, 75% of the sample presented with AEs, which led 35% of the subjects to discontinue the treatment. CONCLUSIONS: While treatment with lumacaftor/ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations, no improvement in ppFEV1 or BMI was found.

Cost of Hospitalizations due to Exacerbation in Patients with Non-Cystic Fibrosis Bronchiectasis.

BACKGROUND: Knowing the cost of hospitalizations for exacerbation in bronchiectasis patients is essential to perform cost-effectiveness studies of treatments that aim to reduce exacerbations in these patients. OBJECTIVES: To find out the mean cost of hospitalizations due to exacerbations in bronchiectasis patients, and to identify factors associated with higher costs. METHODS: Prospective, observational, multicenter study in adult bronchiectasis patients hospitalized due to exacerbation. All expenses from the patients' arrival at hospital to their discharge were calculated: diagnostic tests, treatments, transferals, home hospitalization, admission to convalescence centers, and hospitals' structural costs for each patient (each hospital's tariff for emergencies and 70% of the price of a bed for each day in a hospital ward). RESULTS: A total of 222 patients (52.7% men, mean age 71.8 years) admitted to 29 hospitals were included. Adding together all the expenses, the mean cost of the hospitalization was EUR 5,284.7, most of which correspond to the hospital ward (86.9%), and particularly to the hospitals' structural costs. The adjusted multivariate analysis showed that chronic bronchial infection by Pseudomonas aeruginosa, days spent in the hospital, and completing the treatment with home hospitalization were factors independently associated with a higher overall cost of the hospitalization. CONCLUSIONS: The mean cost of a hospitalization due to bronchiectasis exacerbation obtained from the individual data of each episode is higher than the cost per process calculated by the health authorities. The most determining factor of a higher cost is chronic bronchial infection due to P. aeruginosa, which leads to a longer hospital stay and the use of home hospitalization.

Double bronchodilation in chronic obstructive pulmonary disease: a crude analysis from a systematic review.

OBJECTIVE: The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting ß2-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation. METHODS: A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations. RESULTS: We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies. CONCLUSION: Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes.

Mortality from cystic fibrosis in Europe: 1994-2010.

OBJECTIVE: To date, available mortality trends due to cystic fibrosis (CF) have been limited to the analysis of certain countries in different parts of the world showing that mortality trends have been constantly decreasing. However, no studies have examined Europe as a whole. The present study aims to analyze CF mortality trends by gender within the European Union (EU) and to quantify potential years of life lost (PYLL). DESIGN: Deaths from the 27 EU countries were obtained from the statistical office of the EU from the years 1994-2010. Crude and age-standardized mortality rates (ASR) were estimated for women and men using the standard European population, expressed in deaths per 1,000,000 persons. The PYLL from ages 0 up to 30 years were estimated. Trends were studied by a joinpoint regression analysis. RESULTS: During the study period, 5,130 deaths (2,443 in males and 2,687 in females) were identified. Females had a slightly higher mortality rate than males, with a downward trend observed for both genders. In males, the ASR changed from 1.34 in 1994 to 1.03 in 2010. In females, the ASR changed from 1.42 in 1994 to 0.92 in 2010. The mean age at death and PYLL increased for both genders. The joinpoint analysis did not identify any significant joinpoint for either gender for ASR or PYLL. CONCLUSIONS: Our data suggest a continued downward trend of CF mortality throughout the EU, with differences by country and gender.

Bronchopulmonary infection-colonization patterns in Spanish cystic fibrosis patients: Results from a national multicenter study.

BACKGROUND: Clinical and demographical knowledge on Spanish cystic fibrosis (CF) patients is incomplete as no national registry exists. CF-microbiology has not been studied at national level. The results of the first Spanish multicenter study on CF microbiology are presented. METHODS: 24 CF-Units for adult (n=12) and pediatric (n=12) patients from 17 hospitals provided sputa and clinical data from 15 consecutive patients. Cultures and susceptibility testing were performed. Colonization impact on pulmonary function was assessed. RESULTS: 341 patients [mean (SD) age 21 (11) years, 180≥18years, mean (SD) FEV1=68 (25)%] were included. Pseudomonas aeruginosa was reported as chronic, intermittent or absent in 46%, 22% and 32% of patients, respectively. The annual prevalence was 62%. Positive P. aeruginosa and methicillin-resistant Staphylococcus aureus cultures were significantly associated with lower FEV1 (p<0.001 and p=0.003, respectively). CONCLUSIONS: The representative subset of the Spanish CF-population which has been clinically, demographically and microbiologically characterized will serve as a reference for future CF studies in Spain.