Longitudinal Study of Therapeutic Adherence in a Cystic Fibrosis Unit: Identifying Potential Factors Associated with Medication Possession Ratio.

Cystic fibrosis (CF) is a genetic and multisystemic disease that requires a high therapeutic demand for its control. The aim of this study was to assess therapeutic adherence (TA) to different treatments to study possible clinical consequences and clinical factors influencing adherence. This is an ambispective observational study of 57 patients aged over 18 years with a diagnosis of CF. The assessment of TA was calculated using the Medication Possession Ratio (MPR) index. These data were related to exacerbations and the rate of decline in FEV1 percentage. Compliance was good for all CFTR modulators, azithromycin, aztreonam, and tobramycin in solution for inhalation. The patients with the best compliance were older; they had exacerbations and the greatest deterioration in lung function during this period. The three variables with the highest importance for the compliance of the generated Random Forest (RF) models were age, FEV1%, and use of Ivacaftor/Tezacaftor. This is one of the few studies to assess adherence to CFTR modulators and symptomatic treatment longitudinally. CF patient therapy is expensive, and the assessment of variables with the highest importance for a high MPR, helped by new Machine learning tools, can contribute to defining new efficient TA strategies with higher benefits.

Association Between Evolution of Mucus Plugging, Parenchymal Alterations and Air Trapping on Computed Tomography and Risk of Exacerbations in Adults With Cystic Fibrosis

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New evidence in severe pneumonia: imipenem/cilastatin/relebactam

Imipenem combined with beta-lactamase inhibitor relebactam (IMI/REL) has an extensive bactericidal activity againstGram-negative pathogens producing class A or class C beta-lactamases, not active against class B and class D. The phase3 clinical trial (RESTORE-IMI-2), double-blind, randomized,evaluated IMI/REL vs. piperacillin-tazobactam (PIP/TAZ) fortreatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), demonstrated non-inferiorityat all-cause mortality at 28 days (15.9% vs 21.3%), favorable clinical response at 7-14 days end of treatment (61% vs59.8%) and with minor serious adverse effects (26.7% vs 32%).IMI/REL is a therapeutic option in HAP and VAP at approveddosage imipenem 500 mg, cilastatin 500 mg and relebactam250 mg once every 6h, by an IV infusion over 30 min (AU)

Treatment of Pulmonary Disease of Cystic Fibrosis: A Comprehensive Review.

Cystic fibrosis (CF) is a genetic disease that causes absence or dysfunction of a protein named transmembrane conductance regulatory protein (CFTR) that works as an anion channel. As a result, the secretions of the organs where CFTR is expressed are very viscous, so their functionality is altered. The main cause of morbidity is due to the involvement of the respiratory system as a result of recurrent respiratory infections by different pathogens. In recent decades, survival has been increasing, rising by around age 50. This is due to the monitoring of patients in multidisciplinary units, early diagnosis with neonatal screening, and advances in treatments. In this chapter, we will approach the different therapies used in CF for the treatment of symptoms, obstruction, inflammation, and infection. Moreover, we will discuss specific and personalized treatments to correct the defective gene and repair the altered protein CFTR. The obstacle for personalized CF treatment is to predict the drug response of patients due to genetic complexity and heterogeneity of uncommon mutations.

Predictive value of the modified Bhalla score for assessment of pulmonary exacerbations in adults with cystic fibrosis.

OBJECTIVES: The objective of this study was to analyze the predictive value of the modified Bhalla score in high-resolution computed tomography (HRCT) for assessment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) patients. We also describe the relationship between this score and pulmonary function test results. METHODS: We performed a multicenter and prospective study where adult patients with CF were included consecutively over 18 months. All patients underwent HRCT with acquisition in inspiration and expiration. The results were analyzed by an expert radiologist who assigned a modified Bhalla score value. Lung function was also assessed, and clinical variables were collected. Follow-up lasted approximately 1 year, and PEx were registered. RESULTS: The study population comprised 160 subjects selected from 360 CF patients monitored in the participating CF units. The mean age was 28 years, 47.5% were women, and mean forced expiratory volume in 1 s (FEV1) was 67.5%. The mean global modified Bhalla score was 14.5 ± 0.31 points. Pulmonary function test (PFT) results and the modified Bhalla score correlated well, mainly forced vital capacity (FVC) and FEV1. We constructed a statistical model based on the overall Bhalla score to predict the number of PEx. CONCLUSIONS: The overall modified Bhalla score can predict future PEx in CF patients. This useful tool can help to prevent PEx in higher risk patients. KEY POINTS: • Pulmonary function test results and the modified Bhalla score correlated well with FVC and FEV1. • The total modified Bhalla score can predict the number of exacerbations in adult CF patients. • Our findings highlight the need to establish a unified protocol for chest HRCT during the follow-up of adult patients with CF in order to anticipate possible complications and determine their impact on pulmonary function.

Desaturations During 6-Minute Walk Test and Predicting Nocturnal Desaturations in Adult Subjects With Cystic Fibrosis.

BACKGROUND: Nocturnal desaturation in cystic fibrosis (CF) may have prognostic implications because a significant and maintained nocturnal desaturation can contribute to the development and progression of pulmonary hypertension with cor pulmonale. Its relation with the desaturation in exercise has not been sufficiently studied. We aimed to determine whether desaturation during 6MWT can be an indicator of nocturnal desaturation in adult subjects with CF. METHODS: 57 subjects were included: 50.9% male, 27.5 ± 7.7 y old, mean FEV1 = 2.37 ± 0.74 L, and %FEV1 67 ± 18.1%. Desaturation during 6MWT was defined as oxygen saturation (SpO2 ) ≤ 90% or a decline of > 4 points in SpO2 from baseline, and nocturnal desaturation as a desaturation index > 4 or > 5% of sleep time with SpO2 ≤ 90%. RESULTS: Desaturation observed during 6MWT in adult subjects with CF did not correlate with nocturnal desaturation (P = .27). Subjects with %FEV1 ≤ 55% and diffusion capacity of carbon monoxide (DLCO) ≤ 50 mmol/min/mm Hg were at higher risk of 6MWT desaturation. Nocturnal desaturation was more frequent in males, with PaO2 ≤ 71 mm Hg in blood gas analysis. CONCLUSIONS: Desaturation observed in 6MWT cannot predict desaturation at night in adults with CF. Other parameters were identified as predictors of desaturation.

A simple algorithm for the identification of clinical COPD phenotypes.

This study aimed to identify simple rules for allocating chronic obstructive pulmonary disease (COPD) patients to clinical phenotypes identified by cluster analyses.Data from 2409 COPD patients of French/Belgian COPD cohorts were analysed using cluster analysis resulting in the identification of subgroups, for which clinical relevance was determined by comparing 3-year all-cause mortality. Classification and regression trees (CARTs) were used to develop an algorithm for allocating patients to these subgroups. This algorithm was tested in 3651 patients from the COPD Cohorts Collaborative International Assessment (3CIA) initiative.Cluster analysis identified five subgroups of COPD patients with different clinical characteristics (especially regarding severity of respiratory disease and the presence of cardiovascular comorbidities and diabetes). The CART-based algorithm indicated that the variables relevant for patient grouping differed markedly between patients with isolated respiratory disease (FEV1, dyspnoea grade) and those with multi-morbidity (dyspnoea grade, age, FEV1 and body mass index). Application of this algorithm to the 3CIA cohorts confirmed that it identified subgroups of patients with different clinical characteristics, mortality rates (median, from 4% to 27%) and age at death (median, from 68 to 76 years).A simple algorithm, integrating respiratory characteristics and comorbidities, allowed the identification of clinically relevant COPD phenotypes.

Long-term safety and efficacy of tobramycin in the management of cystic fibrosis.

Cystic fibrosis (CF) is a fatal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene whose mortality is conditioned by a progressive decline in lung function. Bacterial infections play a key role in this decline. Chronic bacterial infection in CF patients varies over time and the presence of Pseudomonas aeruginosa in sputum is a marker of poor prognosis. P. aeruginosa is eradicated from the airways using inhaled antibiotics administered in various formulations and devices. Antipseudomonal antibiotics have extended the survival of CF patients to 40 years. Tobramycin is a bactericidal aminoglycoside antibiotic with demonstrated activity against gram-negative microorganisms. Initially, the drug was administered as an inhaled parenteral solution. Subsequently, a specific tobramycin inhalation solution was developed. PulmoSphere™ technology enables dry tobramycin powder to be formulated for inhalation (tobramycin inhalation powder) using a small and portable capsule-based breath-activated device (T-326). Chronic colonization by P. aeruginosa is the main indication for aerosol antibiotic therapy. The American Cystic Fibrosis Foundation, European guidelines, and Spanish consensus guidelines provide different recommendations for eradication.

Role of C-reactive protein as a biomarker for prediction of the severity of pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: Pulmonary exacerbation is one of the main risk factors for death in patients with cystic fibrosis. Several biomarkers have proven useful in the diagnosis and treatment of pulmonary exacerbations, although none has been associated with severity. The objective of the present study was to investigate whether C-reactive protein (CRP) level was associated with the severity of pulmonary exacerbation requiring admission to hospital in patients with cystic fibrosis. METHODS: We designed a severity index for exacerbations based on 4 clinical parameters and determined whether there was an association between CRP levels and severity of the exacerbation. We also investigated the association between CRP and baseline functional and clinical variables. RESULTS: Twenty-seven patients with cystic fibrosis required 62 admissions to hospital. CRP levels were not significantly associated with the severity index, although they were associated with specific patient characteristics: colonization by Pseudomonas aeruginosa, allergic bronchopulmonary aspergillosis, treatment with oral corticosteroids, and number of severe exacerbations treated with intravenous antibiotics during the previous year. CONCLUSIONS: CRP level is not associated with the severity of pulmonary exacerbations, but it is associated with specific clinical characteristics. This simple scoring system (severity index) could prove very useful for evaluating the severity of exacerbations.

Trastornos psicológicos y calidad de vida en pacientes con bronquiectasias no relacionadas con fibrosis quística / Presence of Anxiety and Depression in Patients With Bronchiectasis Unrelated to Cystic Fibrosis

Introducción: Los pacientes con bronquiectasias (BQ), como enfermos crónicos, pueden verse afectados por trastornos psicológicos. El objetivo del trabajo fue valorar la presencia de síntomas de ansiedad y depresión, mediante cuestionarios validados, en pacientes con BQ controlados en una unidad monográfica. Pacientes y métodos: De forma consecutiva se incluyeron en el estudio pacientes diagnosticados de BQ, no relacionadas con fibrosis quística, mediante una tomografía axial computarizada de alta resolución. Los enfermos estaban en fase estable en las últimas 3 semanas y cumplimentaron los cuestionarios Inventario de Depresión de Beck, Escala de Ansiedad Estado-Rasgo y Cuestionario Respiratorio St. George, después de firmar el consentimiento informado. Los pacientes fueron clasificados según las puntuaciones obtenidas en los cuestionarios de cribado psicológico y sus resultados se compararon con las variables clínicas, radiológicas y funcionales y con las puntuaciones de calidad de vida. Resultados: Setenta enfermos, 48 de ellos mujeres y 22 hombres, con una edad media de 64,19 años, respondieron de forma voluntaria a los cuestionarios. El 34% de los pacientes mostraron síntomas de depresión, y alrededor del 55% puntuaciones por encima del percentil 50 en ansiedad (rasgo y estado). La cantidad de expectoración se relacionó con la ansiedad rasgo. La colonización bacteriana se relacionó con la ansiedad (rasgo y estado), especialmente la colonización por Pseudomonas aeruginosa. El sexo femenino mostró mayor riego de depresión. No existió relación entre las clasificaciones establecidas de ansiedad y depresión y las puntuaciones de calidad de vida. Conclusiones: Los pacientes con BQ muestran en un alto porcentaje presencia de síntomas de ansiedad, rasgo y estado, así como de depresión. Los más afectados por ansiedad son los más expectoradores y los colonizados por bacterias, y por depresión, las mujeres. Creemos que es necesario valorar la presencia de psicomorbilidad asociada, especialmente en este perfil de enfermos (AU)

Introduction: Patients with chronic bronchiectasis (BQ) may suffer from psychological disorders. The objective of this study was to assess the presence of anxiety and depression in patients from a specialised BQ Unit, using validated questionnaires. Patients and methods: We included patients consecutively diagnosed with BQ (unrelated to cystic fibrosis) by high resolution computed tomography in the study. Patients were clinically stable in the previous three weeks and voluntarily completed the Beck Depression Inventory, State-Trait Anxiety Inventory and St. George's Respiratory Questionnaire, after signing the informed consent. They were classified according to their scores on the psychological screening questionnaires, and their results were compared with the clinical, radiological and functional parameters and Quality of Life. Results: 70 patients were included, 48 women and 22 men, with a mean age of 64.19 years. Thirty-four percent (34%) of patients showed symptoms of depression, and around 55% had scores above the 50th percentile in trait and state anxiety. The amount of sputum was associated with trait anxiety. Bacterial colonisation was related to anxiety (trait and state), especially Pseudomonas aeruginosa colonisation. Female patients showed a higher risk of depression. There was no relationship between the Quality of Life scores and the established classifications of anxiety and depression. Conclusions: A high percentage of patients with BQ presented anxiety (trait and state) and depression. The daily sputum production and bacterial colonisation (especially with P. aeruginosa) were the variables most related to anxiety; depression was more common in women. We believe that the presence of psychological disorders should be evaluated, especially in patients with this profile (AU)

Presence of anxiety and depression in patients with bronchiectasis unrelated to cystic fibrosis.

INTRODUCTION: Patients with chronic bronchiectasis (BQ) may suffer from psychological disorders. The objective of this study was to assess the presence of anxiety and depression in patients from a specialised BQ Unit, using validated questionnaires. PATIENTS AND METHODS: We included patients consecutively diagnosed with BQ (unrelated to cystic fibrosis) by high resolution computed tomography in the study. Patients were clinically stable in the previous three weeks and voluntarily completed the Beck Depression Inventory, State-Trait Anxiety Inventory and St. George's Respiratory Questionnaire, after signing the informed consent. They were classified according to their scores on the psychological screening questionnaires, and their results were compared with the clinical, radiological and functional parameters and Quality of Life. RESULTS: Seventy patients were included, 48 women and 22 men, with a mean age of 64.19years. Thirty-four percent (34%) of patients showed symptoms of depression, and around 55% had scores above the 50th percentile in trait and state anxiety. The amount of sputum was associated with trait anxiety. Bacterial colonization was related to anxiety (trait and state), especially Pseudomonas aeruginosa colonization. Female patients showed a higher risk of depression. There was no relationship between the Quality of Life scores and the established classifications of anxiety and depression. CONCLUSIONS: A high percentage of patients with BQ presented anxiety (trait and state) and depression. The daily sputum production and bacterial colonization (especially with P. aeruginosa) were the variables most related to anxiety; depression was more common in women. We believe that the presence of psychological disorders should be evaluated, especially in patients with this profile.

Ventilación mecánica no invasiva en una población anciana que ingresa en una unidad de monitorización respiratoria: causas, complicaciones y evolución al año de seguimiento / Non-invasive Ventilation in an Elderly Population Admitted to a Respiratory Monitoring Unit: Causes, Complications and One-year Evolution

Objetivo: Determinar la utilidad de la ventilación mecánica no invasiva (VMNI) en pacientes ancianos (≥75 años) que ingresan en una unidad de monitorización respiratoria (UMR) durante el ingreso y al año del alta. Comparamos los resultados con el grupo de pacientes de menor edad (<75 años). Material y métodos: Estudio prospectivo observacional realizado en el Hospital La Princesa (Madrid, España). Se reclutaron todos los pacientes ≥75 años que ingresaron en nuestra UMR en acidosis respiratoria (pH <7,35 y PaCO2 >45mmHg) y que recibieron tratamiento con VMNI. Se recogieron variables relativas a características sociodemográficas y de la vida basal, antecedentes patológicos previos, motivos de ingreso y gravedad, datos analíticos al ingreso y evolución gasométrica al inicio de la VMNI, en la primera hora y tras 24h, complicaciones y evolución al año de seguimiento. Resultados: La edad media fue de 80,6 años. El índice de Charlson fue de 3,27. Aproximadamente la mitad de los pacientes presentaban alguna limitación para las actividades de la vida diaria. Los principales motivos de ingreso fueron la agudización de la EPOC y la insuficiencia cardíaca. En 36 casos se registraron complicaciones (11 insuficiencia renal, 6 fibrilación auricular). La supervivencia al año del seguimiento fue del 63,21%. Conclusiones: La VMNI es una buena alternativa en pacientes ancianos que ingresan en acidosis respiratoria. No detectamos diferencias en la mortalidad durante el ingreso con el grupo <75 años. Los pacientes ancianos ingresan más entre los 6-12 meses posteriores al alta, y esto podría deberse a una peor situación funcional tras un ingreso que requiere VMNI(AU)

Objective: To determine the usefulness of non-invasive ventilation (NIV) in elderly patients (≥75) admitted to a respiratory monitoring unit (RMU) during hospitalization and one year later in comparison with the results from the younger age group (<75). Material and methods: Ours is a prospective observational study carried out at the Hospital Universitario La Princesa (Madrid, Spain). We recruited all patients who were ≥75 years old and were admitted to our RMU during the period 2008-2009 with respiratory acidosis (pH <7.35 and PaCO2 >45mmHg) requiring NIV. We gathered data for basic variables as well as sociodemographics, history of previous pathologies, reason for hospitalization and severity, analysis upon admission and the evolution of blood gases at the start of NIV (within the first hour and after 24hours), complications and evolution at the one-year follow-up. Results: Mean age of the sample was 80.6 years. The Charlson index was 3.27. About half of the patients had some limitation for performing daily activities. The main reasons for admission were COPD exacerbation and heart failure. There were complications in 36% of the cases (11 renal failure and 6 atrial fibrillation). The survival rate at the one-year follow-up was 63.21%. Conclusions: NIV is a good alternative in elderly patients admitted to the hospital with respiratory acidosis. We did not detect differences in mortality during admission between the two groups. The elderly patients were more frequently re-admitted than the younger group in the 6-12 months after hospital discharge. This could be due to their poorer functional state after hospitalization requiring NIV(AU)

Non-invasive ventilation in an elderly population admitted to a respiratory monitoring unit: causes, complications and one-year evolution.

OBJECTIVE: To determine the usefulness of non-invasive ventilation (NIV) in elderly patients (≥75) admitted to a respiratory monitoring unit (RMU) during hospitalization and 1 year later in comparison with the results from the younger age group (<75). MATERIAL AND METHODS: Ours is a prospective observational study carried out at the Hospital Universitario La Princesa (Madrid, Spain). We recruited all patients who were ≥75 years old and were admitted to our RMU during the period 2008-2009 with respiratory acidosis (pH<7.35 and PaCO(2)>45 mmHg) requiring NIV. We gathered data for basic variables as well as sociodemographics, history of previous pathologies, reason for hospitalization and severity, analysis upon admission and the evolution of blood gases at the start of NIV (within the first hour and after 24 h), complications and evolution at the 1-year follow-up. RESULTS: Mean age of the sample was 80.6. The Charlson index was 3.27. About half of the patients had some limitation for performing daily activities. The main reasons for admission were COPD exacerbation and heart failure. There were complications in 36% of the cases (11 renal failure and 6 atrial fibrillation). The survival rate at the 1-year follow-up was 63.21%. CONCLUSIONS: NIV is a good alternative in elderly patients admitted to the hospital with respiratory acidosis. We did not detect differences in mortality during admission between the two groups. The elderly patients were more frequently re-admitted than the younger group in the 6-12 months after hospital discharge. This could be due to their poorer functional state after hospitalization requiring NIV.

Antibioterapia inhalada en la fibrosis quística / Inhaled antibiotic therapy in cystic fibrosis

La fibrosis quística es la enfermedad genética letal más frecuente en la población caucasiana. La infecciónbronquial crónica, especialmente por Pseudomonas aeruginosa, es la principal causa de morbimortalidad deesta patología. El tratamiento antibiótico por aerosol alcanza altas concentraciones en la vía aérea con bajatoxicidad, por lo que permite el empleo crónico. En la actualidad hay 2 antibióticos aprobados para su usoinhalatorio, la tobramicina en solución para inhalación y el colistimetato de sodio, existiendo con este últimomenos evidencias en estudios clínicos. La indicación fundamental es la colonización bronquial crónica por P.aeruginosa, aunque cada vez se demuestra más relevancia en la primoinfección por esta bacteria, acompañadao no de antibióticos por vía oral o intravenosos. Más controvertido es el uso de la aerosolterapia antibiótica enla profilaxis bacteriana o en la exacerbación respiratoria. Durante muchos años se han estado empleandoformulaciones intravenosas de distintos antibióticos en aerosol, las cuales están en distintas fases de investigaciónpara su lanzamiento como presentación por vía nebulizada. Además de su indicación en el tratamientode la infección por P. aeruginosa se han empleado otros antibióticos en aerosol para otros patógenos comoStaphylococus aureus resistentes a meticilina, Mycobacterium abscessus o Aspergillus fumigatus(AU)

Cystic fibrosis is the most frequent fatal genetically-transmitted disease among Caucasians. Chronic bronchialinfection, especially by Pseudomonas aeruginosa, is the main cause of morbidity and mortality in this disease.Aerosolized antibiotic therapy achieves high drug concentrations in the airway with low toxicity, allowingchronic use. Currently, two antibiotics have been approved for inhalation therapy, tobramycin inhalationsolution and colistimethate sodium aerosol. There is less evidence from clinical trials for the latter. The mainindication for these drugs is chronic bronchial colonization by P. aeruginosa, although there is increasingevidence of the importance of the primary infection by this bacterium, whether treated by oral or intravenousantibiotics or not. More controversial is the use of aerosolized antibiotic therapy in bacterial prophylaxis orrespiratory exacerbations. For many years, intravenous formulations of distinct antibiotics for aerosolized usehave been employed, which are in distinct phases of research for use in nebulizer therapy. In addition to beingused to treat P. aeruginosa infection, aerosolized antibiotics have been used to treat other pathogens such asmethicillin-resistant Staphylococus aureus, Mycobacterium abscessus and Aspergillus fumigatus(AU)