Immunoglobulin genes and severity of COVID-19.

There is tremendous interindividual and interracial variability in the outcome of SARS-CoV-2 infection, suggesting the involvement of host genetic factors. Here, we investigated whether IgG allotypes GM (γ marker) 3 and GM 17, genetic markers of IgG1, contributed to the severity of COVID-19. IgG1 plays a pivotal role in response against SARS-CoV-2 infection. We also investigated whether these GM alleles synergistically/epistatically with IGHG3 and FCGR2A alleles-which have been previously implicated in COVID-19-modulated the extent of COVID-19 severity. The study population consisted of 316 COVID-19 patients who needed treatment in the intensive care unit of Hospital Universitario Central de Asturias. All individuals were genotyped for GM 3/17, IGHG3 hinge length, and FCGR2A rs1801274 A/G polymorphisms. Among the 316 critical patients, there were 86 deaths. The risk of death among critical patients was significantly higher in subjects with GM 17 (IgG1) and short hinge length (IgG3). GM 17-carriers were at almost three-fold higher risk of death than non-carriers (p < 0.001; OR = 2.86, CI 1.58-5.16). Subjects with short hinge length of IgG3 had a two-fold higher risk of death than those with medium hinge length (p = 0.01; OR = 2.16, CI 1.19-3.90). GM 3/3 and IGHG3 (MM) genotypes were less frequent among death vs. survivors (9% vs 36%, p < 0.001) and associated with protective effect (OR = 0.18, 95% CI = 0.08-0.39). This is the first report implicating IgG1 allotypes in COVID-19-spurred death. It needs to be replicated in an independent study population.

Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19.

MDA5, encoded by the IFIH1gene, is a cytoplasmic sensor of viral RNAs that triggers interferon (IFN) antiviral responses. Common and rare IFIH1 variants have been associated with the risk of type 1 diabetes and other immune-mediated disorders, and with the outcome of viral diseases. Variants associated with reduced IFN expression would increase the risk for severe viral disease. The MDA5/IFN pathway would play a critical role in the response to SARS-CoV-2 infection mediating the extent and severity of COVID-19. Here, we genotyped a cohort of 477 patients with critical ICU COVID-19 (109 death) for three IFIH1 functional variants: rs1990760 (p.Ala946Thr), rs35337543 (splicing variant, intron 8 + 1G > C), and rs35744605 (p.Glu627Stop). The main finding of our study was a significant increased frequency of rs1990760 C-carriers in early-onset patients (< 65 years) (p = 0.01; OR = 1.64, 95%CI = 1.18-2.43). This variant was also increased in critical vs. no-ICU patients and in critical vs. asymptomatic controls. The rs35744605 C variant was associated with increased blood IL6 levels at ICU admission. The rare rs35337543 splicing variant showed a trend toward protection from early-onset critical COVID-19. In conclusion, IFIH1 variants associated with reduced gene expression and lower IFN response might contribute to develop critical COVID-19 with an age-dependent effect.

IGHG3 hinge length variation was associated with the risk of critical disease and death in a Spanish COVID-19 cohort.

IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.

The FCGR2A rs1801274 polymorphism was associated with the risk of death among COVID-19 patients.

Polymorphisms of Fcγ receptors have been associated with variable responses to infections. We determined the association of functional polymorphisms rs1801274 in the FCGR2A and rs396991 in the FCGR3A with COVID-19 severity. This study involved 453 patients with severe COVID-19, in which the FCGR2A rs1801274 G-allele (131-Arg) was significantly associated with death (p = 0.02, OR = 1.47). This effect was independent of age and increased IL6 and D-Dimer levels. This study suggests that the FCGR2A gene might be associated with the risk of death among COVID-19 patients. Our study has several limitations, mainly the limited number of patients and the inclusion of a single population. It is thus necessary to confirm this result in larger cohorts from different populations.

FURIN gene variants (rs6224/rs4702) as potential markers of death and cardiovascular traits in severe COVID-19.

Furin is a protease that plays a key role in the infection cycle of SARS-CoV-2 by cleaving the viral proteins during the virus particle assembly. In addition, Furin regulates several physiological processes related to cardio-metabolic traits. DNA variants in the FURIN gene are candidates to regulate the risk of developing these traits as well as the susceptibility to severe COVID-19. We genotyped two functional FURIN variants (rs6224/rs4702) in 428 COVID-19 patients in the intensive care unit. The association with death (N = 106) and hypertension, diabetes, and hyperlipidaemia was statistically evaluated. The risk of death was associated with age, hypertension, and hypercholesterolemia. The two FURIN alleles linked to higher expression (rs6224 T and rs4702 A) were significantly increased in the death cases (odds ratio= 1.40 and 1.43). Homozygosis for the two high expression genotypes (rs6224 TT and rs4702 AA) and for the T-A haplotype was associated with an increased risk of hypercholesterolemia. In the multiple logistic regression both, hypercholesterolemia and the TT + AA genotype were significantly associated with death. In conclusion, besides its association with hypercholesterolemia, FURIN variants might be independent risk factors for the risk of death among COVID-19 patients.

Results in clinical practice in the treatment of severe eosinophilic asthma with mepolizumab: a real-life study.

OBJECTIVE: Add-on therapy with monoclonal antibodies is the recommended therapy for severe asthmatic patients refractory to maintenance treatment. In randomized control trials, mepolizumab reduced the number of exacerbations, the need of oral corticosteroids (OCS), increased asthma control, and lung function in a population of uncontrolled severe eosinophilic asthmatic patients. In this piece of work, we aimed to assess mepolizumab efficacy and safety in a cohort of patients with severe eosinophilic asthma in real-life conditions. METHODS: A retrospective study was carried out at eight hospitals from Asturias (Spain). The sample included patients treated with mepolizumab from 1 January 2016 to 31 March 2019. Demographic and clinical variables were collected, including OCS use, asthma control, lung function, and exacerbation rate. RESULTS: Sixty-nine patients (72% women) with mean age 56 ± 13 years were included. Annual exacerbation rate decreased from 4.7 (SD 3.7) to 1.3 (SD 2.5) (p < 0.001). The number of patients requiring OCS treatment decreased from 25 patients (36%, mean prednisone dose = 18 mg/day) to 13 patients (19%, mean prednisone dose = 9 mg/day) (p < 0.001). Twelve patients (48%) stopped OCS treatment. Forced expired volume in one second (FEV1) as percentage increased from 68% (SD 20) to 76% (SD 21) (p < 0.001). Fifty-six patients (81%) were considered responders to mepolizumab. No serious adverse events were detected during the study period. CONCLUSIONS: Overall, this study demonstrates mepolizumab efficacy and safety in a cohort of patients with uncontrolled severe eosinophilic asthma in routine clinical practice.

The Interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19.

BACKGROUND AND AIMS: The interferon-induced transmembrane proteins play an important antiviral role by preventing viruses from traversing the cellular lipid bilayer. IFITM3 gene variants have been associated with the clinical response to influenza and other viruses. Our aim was to determine whether the IFITM3 rs12252 polymorphism was associated with the risk of developing severe symptoms of COVID-19 in our population. METHODS: A total of 288 COVID-19 patients who required hospitalization (81 in the intensive care unit) and 440 age matched controls were genotyped with a Taqman assay. Linear regression models were used to compare allele and genotype frequencies between the groups, correcting for age and sex. RESULTS: Carriers of the minor allele frequency (rs12252 C) were significantly more frequent in the patients compared to controls after correcting by age and sex (p = 0.01, OR = 2.02, 95%CI = 1.19-3.42). This genotype was non-significantly more common among patients who required ICU. CONCLUSIONS: The IFITM3 rs12252 C allele was a risk factor for COVID-19 hospitalization in our Caucasian population. The extent of the association was lower than the reported among Chinese, a population with a much higher frequency of the risk allele.

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.

Assessment of risk scores in Covid-19.

OBJECTIVE: To analyse the accuracy of commonly used risk scores (PSI and CURB-65) in predicting mortality and need for ICU admission in Covid-19. MATERIAL AND METHODS: Prospective study of patients diagnosed with Covid-19 pneumonia. Patients were followed until home discharge or death. PSI, CURB-65, SMART-COP and MuLBSTA severity scores were assessed on admission. Risk scores were related to mortality and ICU admission. RESULTS: About 249 patients, 143 males (57.4%) were included. The mean age was 65.6 + 16.1 years. Factors associates with mortality in the multivariate analysis were age > 80 years (OR: 13.9; 95% CI 3.8-51.1) (P = .000), lymphocytes < 800 (OR: 2.9; CI 95% 1.1-7-9) (P = .040), confusion (OR: 6.3; 95% CI 1.6-24.7) (P = .008) and NT-proBNP > 500 pg/mL (OR: 10.1; 95% CI 1.1-63.1) (P = .039). In predicting mortality, the PSI score: AUC 0.874 (95% CI 0.808-0.939) and the CURB-65 score: AUC 0.852 (95% CI 0.794-0.909) were the ones that obtained the best results. In the need for ICU admission, the SMART-COP score: AUC 0.749 (95% CI 0.695-0.820) and the MuLBSTA score: AUC 0.777 (95% CI 0.713-0.840) were the ones that obtained better results, with significant differences with PSI and CURB-65. The scores with the lowest value for ICU admission prediction were PSI with AUC of 0.620 (95% CI 0.549-0.690) and CURB-65 with AUC of 0.604 (95% CI 0.528-0.680). CONCLUSIONS: Prognosis scores routinely used for CAP (PSI and CURB-65) were good predictors for mortality in patients with Covid-19 CAP but not for need of hospitalisation or ICU admission. In the evaluation of Covid-19 pneumonia, we need scores that allow to decide the appropriate level of care.

Worldwide Effects of Coronavirus Disease Pandemic on Tuberculosis Services, January-April 2020.

Coronavirus disease has disrupted tuberculosis services globally. Data from 33 centers in 16 countries on 5 continents showed that attendance at tuberculosis centers was lower during the first 4 months of the pandemic in 2020 than for the same period in 2019. Resources are needed to ensure tuberculosis care continuity during the pandemic.

Severe asthma and bronchiectasis.

Objective: The aim of our study was to determine the tomographic findings and prevalence of bronchiectasis in our population of patients with severe asthma, and to identify factors associated with the presence of bronchiectasis in these patients. Materials and methods: We retrospectively collected data from the medical histories of patients referred to the asthma unit of our hospital, with a diagnosis of severe asthma between 2015 and 2017. Patients with ABPA, cystic fibrosis, immunodeficiency or systemic disease were excluded. High-resolution thorax-computed tomodensitography (HRCT) was performed in all patients. A standardized protocol was applied in data collection. Results: A total of 108 patients comprising 50 men (46%) and 58 women (54%) were included in the study. Of the 108 patients, 59 (55%) had at least one abnormality detected by HRCT, the most commonly reported abnormalities being bronchiectasis (35%), bronchial wall thickening (33%), emphysema (7%), atelectasis area (6%), mosaic attenuation due to air trapping (4%), and "tree in bud" image (2%). Subjects with bronchiectasis were older (p = 0.001), had a longer asthma history (p = 0.048), had poorer pulmonary function tests with lower FVC (p = 0.031), had more severe bronchial obstruction with lower FEV1 (p = 0.008) and had lower FEV1/FVC (p = 0.003). They also experienced more frequent hospitalizations in the previous year (p = 0.019) and received treatment with omalizumab more frequently (p = 0.049). Plasma eosinophil count and IgE levels were comparable in both groups. In the multivariate analysis, the presence of bronchiectasis was associated with ages older than 40 (OR: 8.3; 95% CI: 1.7-41.2) and chronic airflow obstruction (OR: 5.4; 95% CI: 1.9-15.3). Conclusions: We found that in patients with severe asthma, the prevalence of bronchiectasis is high and that bronchiectasis is associated with a longer asthma history, greater severity and, more importantly, chronic airflow obstruction. These findings are still insufficient evidence to considere features of asthma-bronchiectasis overlap syndrome, a distinct phenotype of severe asthma, but bronchiectasis is a frequent phenomenon leading to a more severe disease with frequent exacerbations. The performance of thorax HRCT on patients with severe asthma can help to evaluate management strategies for the disease in order to improve treatment and prognosis.

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.

Objective and Subjective Sleep Efficiency in Adult Patients with Cystic Fibrosis and Impact on Quality of Life.

INTRODUCTION: Poor sleep quality and excessive daytime sleepiness are common in patients with cystic fibrosis (CF), and both are negatively correlated with health-related quality of life (HRQoL). The objective of our study was to evaluate subjective and objective sleep quality in adult CF patients and its effect on HRQoL. MATERIALS AND METHODS: This was a descriptive, prospective, cross-sectional study of CF patients > 18 years of age. Patients underwent nocturnal polysomnography (PSG) and were administered the Pittsburgh Sleep Quality Index questionnaire (PSQI) and the Cystic Fibrosis Quality of Life Questionnaire (CFQR 14 + Spain). RESULTS: The study included 23 patients, 14 women (61%). The mean age of the participants was 32 + 18 years. The mean PSQI score was 5.57 + 3.55; 13 (56.5%) of the patients were poor sleepers, and 13% reported poor sleep quality; seven (30%) had sleep latency > 30 min, 10 (43.5%) had sleep efficiency < 85%. Nineteen underwent polysomnography. According to PSG measurements, sleep efficiency was less than 90% in 61% of the patients. Pathological values were found for the following parameters: intra-sleep wakefulness in 12 patients (63%); microarousal index in 12 patients (63%); and apnea-hypopnea index (AHI) in 2 patients. The desaturation time with SpO2 < 90% (T90) was > 30% in 3 patients. We observed a significant correlation between PSQI and all dimensions of CFQR 14. CONCLUSIONS: Subjective and objective sleep efficiency decreases in adult CF patients. Sleep quality has an impact on HRQoL. The PSQI questionnaire was able to discriminate sleep quality.

Factors associated with unreported tuberculosis cases in Spanish hospitals.

BACKGROUND: Under-reporting of tuberculosis (TB) cases complicates disease control, hinders contact tracing and alters the accuracy of epidemiological data, including disease burden. The objective of the present study is to evaluate the proportion of unreported TB cases in Spanish healthcare facilities and to identify the associated factors. METHODS: A multi-center retrospective study design was employed. The study included TB cases diagnosed in 16 facilities during 2011-2012. These cases were compared to those reported to the corresponding public health departments. Demographic, microbiological and clinical data were analyzed to determine the factors associated with unreported cases. Associated factors were analyzed on a bivariate level using the x(2) test and on a multivariate level using a logistic regression. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated. RESULTS: Of the 592 TB cases included in the study, 85 (14.4 %) were not reported. The percentage of unreported cases per healthcare center ranged from 0-45.2 %. The following variables were associated to under-reporting at a multivariate level: smear-negative TB (OR = 1.87; CI:1.07-3.28), extrapulmonary disease (OR = 2.07; CI:1.05-4.09) and retired patients (OR = 3.04; CI:1.29-7.18). A nurse case manager was present in all of the centers with 100 % reporting. The percentage of reported cases among the smear-positive cases was 9.4 % and 19.4 % (p = 0.001) among the rest of the study population. Smear-positive TB was no associated to under-reporting. CONCLUSIONS: It is important that TB Control Programs encourage thorough case reporting to improve disease control, contact tracing and accuracy of epidemiological data. The help from a TB nurse case manager could improve the rate of under-reporting.

Is Obesity a Problem in New Cystic Fibrosis Treatments?

INTRODUCTION: Malnutrition has always been a problem in CF (cystic fibrosis) patients; however, new treatments with CFTR (cystic fibrosis transmembrane conductance regulator protein) modulators have led to weight gain, with some patients at risk of overweight and obesity. OBJECTIVE: Our study aimed to analyze the evolution of BMI (body mass index) after one year of treatment with triple therapy and the factors associated with weight gain in CF patients undergoing treatment with triple therapy with CFTR protein modulators (ETI) (elexacaftor/tezacaftor/ivacaftor). METHODS: We conducted a prospective, observational, longitudinal, multicenter study in patients diagnosed with cystic fibrosis, aged 18 years or older, with at least one F508del allele and who underwent ETI therapy for at least one year, from 2020 to 2023. One hundred and eight patients from two cystic fibrosis units in Spain, Princess University Hospital of Madrid (74 patients) and Central University Hospital of Asturias (HUCA) (34 patients), were included. Demographic data, anthropometric data, lung function, and exacerbations were collected, comparing the data in the previous year to the start of therapy with the results after one year of treatment. Multivariant models were developed to account for repeated weight and BMI measurements, using a mixed effects model approach and accounting for possible modifying factors Results: One hundred and eight patients were included in the study, 58 men (53.7%) and 50 women (46.3%) with a mean age of 29.5 ± 9.4 years (18-59). Patient weight and BMI were recorded at baseline and at 3-month intervals during the study period. The weight increased from 59.6 kg to 62.6 kg and BMI increased from 21.9 kg/m2 to 23.0 kg/m2 after one year of treatment (p < 0.0001 for both). The proportion of underweight individuals decreased after one year of ETI therapy, from 9.3% to 1.9%, while the proportion of overweight or obese individuals increased from 8.3% to 22.9 % at the same time (p < 0.001). In relation to exacerbations, there is a significant increase in the number of patients who did not have any exacerbations after one year of treatment, which increased from 10.2% to 46.2% (p < 0.001), while the number of patients who had >4 exacerbations decreased significantly, from 40.7% to 1.9% (p < 0.001). FEV1% (forced expiratory volume) increased from 63.9 ± 20.9 to 76.8 ± 21.4 (p < 0.001) and the VR/TLC (residual volume/total lung capacity) value decreased from 45.1 ± 10.9 to 34.9 ± 6.2 (p < 0.001). The proportion with FEV1% > 80% increased from 23.1% before ETI therapy to 49.1% one year after ETI therapy. We performed multivariate mixed models to evaluate the evolution of BMI changes with time, accounting for repeated measures and for possible modifying factors. After the introduction of the triple therapy, patients included in the study had significant weight gain during the 12 months, and when including different covariates in the multivariate mixed model, we found that lower baseline BMI, lower baseline FEV1 and FVC (forced vital capacity), and higher VR/TLC value and higher number of exacerbations were associated with higher BMI changes over the study period. CONCLUSIONS: CF patients treated with triple therapy experience significant weight gain, increasing the proportion of overweight patients. CF patients who experienced greater weight gain were those with worse BMI at the start of treatment, as well as patients with worse lung function and a greater number of exacerbations in the year before starting ETI therapy.

Proposal for a standardized methodology for performing endobronchial ultrasound-guided mediastinal cryobiopsy: a four-step approach.

Endobronchial ultrasound (EBUS)-guided mediastinal cryobiopsy is a novel technique that increases the accuracy of diagnosing most pathologies that affect the mediastinum. Although EBUS-guided transbronchial needle aspiration (EBUS-TBNA) is the first choice in the diagnosis of mediastinal pathology, mediastinal cryobiopsy offers a larger and higher quality biopsy with minimal artifacts and no crushing when compared to conventional cytological samples obtained through EBUS-TBNA. It is particularly valuable in pathologies where EBUS-TBNA has diagnostic limitations, such as lymphoproliferative diseases, benign granulomatous conditions like sarcoidosis and silicosis, some rare infectious processes, metastases from rare non-pulmonary tumors, and in advanced stages of non-small cell lung cancer (NSCLC) where immunohistochemistry and molecular analysis are essential for personalized treatment. Therefore, mediastinal cryobiopsy seems to play a crucial role in these challenging scenarios. However, there is ongoing debate in the field of interventional pulmonology regarding the best approach for obtaining a mediastinal cryobiopsy. Some interventional pulmonologists use a high-frequency needle knife to create an incision in the tracheobronchial wall adjacent to the mediastinal lesion before inserting the cryoprobe, while others use a needle to create a pathway to the target area. There are also variations in the use of endoscopic or ultrasound imaging for guidance. In this article, we aim to review the current literature on different methods of performing mediastinal cryobiopsy and share our own clinical experience and methodology in a systematic way for its implementation in a safe, fast, and effective way.

Endobronchial ultrasound-guided transbronchial mediastinal cryobiopsy in the diagnosis of mediastinal lesions: safety, feasibility and diagnostic yield - experience in 50 cases.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the technique of choice in the study of mediastinal and hilar lesions; however, it can be affected by the insufficiency of intact biopsy samples, which might decrease its diagnostic yield for certain conditions, thus requiring re-biopsies or additional diagnostic procedures such as mediastinoscopy when the probability of malignancy remains high. Our objectives were to 1) attempt to reproduce this technique in the same conditions that we performed EBUS-TBNA, i.e. in the bronchoscopy suite and under moderate sedation; 2) describe the method used for its execution; 3) determine its feasibility by accessing different lymph node stations applying our method; and 4) analyse the diagnostic yield and its complications. Methods: This was a prospective study of 50 patients who underwent EBUS-TBNA and EBUS-guided transbronchial mediastinal cryobiopsy (TMC) in a single procedure using a 22-G TBNA needle and a 1.1-mm cryoprobe subsequently between January and August 2022. Patients with mediastinal lesions >1 cm were recruited, and EBUS-TBNA and TMC were performed in the same lymph node station. Results: The diagnostic yield was 82% and 96% for TBNA and TMC, respectively. Diagnostic yields were similar for sarcoidosis, while cryobiopsy was more sensitive than TBNA in lymphomas and metastatic lymph nodes. As for complications, there was no pneumothorax and in no case was there significant bleeding. There were no complications during the procedure or in the follow-up of these patients. Conclusions: TMC following our method is a minimally invasive, rapid and safe technique that can be performed in a bronchoscopy suite under moderate sedation, with a higher diagnostic yield than EBUS-TBNA, especially in cases of lymphoproliferative disorders and metastatic lymph nodes or when more biopsy sample is needed for molecular determinations.

The U-Shaped Relationship Between Eosinophil Count and Bronchiectasis Severity: The Effect of Inhaled Corticosteroids.

BACKGROUND: Although a proven relationship exists between the blood eosinophil count (BEC) and the severity of both asthma and COPD, its relationship with bronchiectasis has not been well established. The objective of this study was to analyze the relationship between BEC and the number and severity of exacerbations, and patients' responses to inhaled corticosteroid (IC) treatment in bronchiectasis RESEARCH QUESTION: Does an association exist among BEC, the number of exacerbations and severity of bronchiectasis, and IC treatment? STUDY DESIGN AND METHODS: This was a multicenter (43 centers) prospective observational study derived from the Spanish Bronchiectasis Registry. Patients with proven bronchiectasis and a known BEC were included, whereas those with asthma or antieosinophilic treatments were excluded. Patients were divided into four groups according to the BEC at the time of inclusion in the study in a steady-state situation: (1) eosinopenic bronchiectasis (< 50 eosinophils/µL), (2) low number of eosinophils (51-100/µL), (3) normal number of eosinophils (101-300/µL), and (4) eosinophilic bronchiectasis (> 300 eosinophils/µL). RESULTS: Nine hundred twenty-eight patients finally were included: 123 patients (13.3%) with < 50 eosinophils/µL (eosinopenic group), 164 patients (17.7%) with 50-100 eosinophils/µL, 488 patients (52.6%) with 101-300 eosinophils/µL, and 153 patients (16.5%) with > 300 eosinophils/µL (eosinophilic group). BEC showed a significant U-shaped relationship with severity, exacerbations, lung function, microbiologic profile, and IC treatment (these being higher in the eosinopenic group compared with the eosinophilic group). IC treatment significantly decreased the number and severity of exacerbations only in the group of bronchiectasis patients with > 300 eosinophils/µL. INTERPRETATION: A significant U-shaped relationship was found between BEC and severity and exacerbations in bronchiectasis that was more pronounced in the eosinopenic group. IC treatment decreased the number and severity of exacerbations only in the eosinophilic group.

Respiratory Center Function and Its Impact in Obesity Hypoventilation Syndrome Treatment.

INTRODUCTION: Patients with obesity hypoventilation syndrome (OHS) need treatment with positive pressure either with continuous (CPAP) or double pressure (NIV). The apnea-hypopnea index (AHI) is considered a key data for making therapeutic decisions. We hypothesized that HR may be an useful tool to establish different phenotypes and individualize treatment in patients with OHS. Our objective was to analyze the role of the respiratory center response to hypercapnia (HR) in the adequacy of positive airway pressure therapy. METHOD: We included subjects with OHS treated with CPAP or NIV according to AHI and baseline pCO2. We analyzed therapeutic effectiveness and treatment changes prioritizing CPAP if AHI>30/h. Therapy was considered adequate if it was effective after two years. HR was measured with the p0.1/pEtCO2 ratio and its capability to select therapy was analyzed. The statistical study was performed by means comparison (Student's t) and multivariate analysis (logistic regression). RESULTS: 67 subjects were included of 68(11) years old, 37 (55%) males, initially 45 (67%) treated with NIV and 22 (33%) with CPAP, one case was excluded and in 25 (38%) the treatment was changed. Finally, CPAP was adequate for 29 subjects (44%) and NIV for 37 (56%). The CPAP group showed AHI 57/h (24) and p0.1/pEtCO2 0.37cmH2O/mmHg (0.23), NIV group AHI 43/h (35) and p0.1/pEtCO2 0.24 (0.15) with p=0.049 and 0.006. In multivariate analysis, p0.1/pEtCO2 (p=0.033) and AHI>30 (p=0.001) were predictors of adequate therapy. CONCLUSION: Measuring the RH of the respiratory center helps to select the most appropriate treatment for patients with OHS.

The role of precision medicine in bronchiectasis: emerging data and clinical implications.

INTRODUCTION: Bronchiectasis is a very heterogeneous disease. This heterogeneity has several consequences: severity cannot be measured by a single variable, so multidimensional scores have been developed to capture it more broadly. Some groups of patients with similar clinical characteristics or prognoses (clinical phenotypes), and even similar inflammatory profiles (endotypes), have been identified, and these have been shown to require a more specific treatment. AREAS COVERED: We comment on this 'stratified' model of medicine as an intermediate step toward the application of the usual concepts on which precision medicine is based (such as cellular, molecular or genetic biomarkers, treatable traits and individual clinical fingerprinting), whereby each subject presents certain specific characteristics and receives individualized treatment. EXPERT OPINION: True precision or personalized medicine is based on concepts that have not yet been fully achieved in bronchiectasis, although some authors are already beginning to adapt them to this disease in terms of pulmonary and extrapulmonary etiologies, clinical fingerprinting (specific to each individual), cellular biomarkers such as neutrophils and eosinophils (in peripheral blood) and molecular biomarkers such as neutrophil elastase. In therapeutic terms, the future is promising, and some molecules with significant antibiotic and anti-inflammatory properties are being developed.