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.

Q fever, a rare cause of secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome in which Coxiella burnetii is a very infrequent etiology. We present the case of a 62-year-old male with progressive pulmonary infiltrates, fever, hepatitis, and bicytopenia despite broad spectrum antibiotics. A thorough clinical evaluation led to a high suspicion of Coxiella burnetii infection, subsequently confirmed through a positive serum polymerase chain reaction (PCR) analysis. HLH diagnosis was established based on the fulfillment of 5/8 diagnostic criteria, obviating the need for a bone marrow biopsy. Targeted antibiotic treatment and dexamethasone led to full recovery within two weeks, eliminating the need for stronger immunosuppressive therapy.

Persistent Respiratory Failure and Re-Admission in Patients with Chronic Obstructive Pulmonary Disease Following Hospitalization for COVID-19.

Background: Chronic obstructive pulmonary disease (COPD) has been associated with worse clinical evolution/survival during a hospitalization for SARS-CoV2 (COVID-19). The objective of this study was to learn the situation of these patients at discharge as well as the risk of re-admission/mortality in the following 12 months. Methods: We carried out a subanalysis of the RECOVID registry. A multicenter, observational study that retrospectively collected data on severe acute COVID-19 episodes and follow-up visits for up to a year in survivors. The data collection protocol includes general demographic data, smoking, comorbidities, pharmacological treatment, infection severity, complications during hospitalization and required treatment. At discharge, resting oxygen saturation (SpO2), dyspnea according to the mMRC (modified Medical Research Council) scale and long-term oxygen therapy prescription were recorded. The follow-up database included the clinical management visits at 6 and 12 months, where re-admission and mortality were recorded. Results: A total of 2047 patients were included (5.6% had a COPD diagnosis). At discharge, patients with COPD had greater dyspnea and a greater need for prescription home oxygen. After adjusting for age, sex and Charlson comorbidity index, patients with COPD had a greater risk of hospital re-admission due to respiratory causes (HR 2.57 [1.35-4.89], p = 0.004), with no significant differences in survival. Conclusion: Patients with COPD who overcome a serious SARS-CoV2 infection show a worse clinical situation at discharge and a greater risk of re-admission for respiratory causes.

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.

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.

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.

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.

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.

Peripheral Neutrophil-to-Lymphocyte Ratio in Bronchiectasis: A Marker of Disease Severity.

Most patients with bronchiectasis have a predominantly neutrophilic inflammatory profile, although other cells such as lymphocytes (as controllers of bronchial inflammation) and eosinophils also play a significant pathophysiological role. Easy-to-interpret blood biomarkers with a discriminative capacity for severity or prognosis are needed. The objective of this study was to assess whether the peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with different outcomes of severity in bronchiectasis. A total of 1369 patients with bronchiectasis from the Spanish Registry of Bronchiectasis were included. To compare groups, the sample was divided into increasing quartiles of NLR ratio. Correlations between quantitative variables were established using Pearson's P test. A simple linear regression (with the value of exacerbations as a quantitative variable) was used to determine the independent relationship between the number and severity of exacerbations and the NLR ratio. The area under the curve (AUC)-ROC was used to determine the predictive capacity of the NLR for severe bronchiectasis, according to the different multidimensional scores. Mean age: 69 (15) years (66.3% of women). The mean NLR was 2.92 (2.03). A higher NLR was associated with more severe bronchiectasis (with an especially significant discriminative power for severe forms) according to the commonly used scores (FACED, E-FACED and BSI), as well as with poorer quality of life (SGRQ), more comorbidities (Charlson index), infection by pathogenic microorganisms, and greater application of treatment. Furthermore, the NLR correlated better with severity scores than other parameters of systemic inflammation. Finally, it was an independent predictor of the incident number and severity of exacerbations. In conclusion, the NLR is an inexpensive and easy-to-measure marker of systemic inflammation for determining severity and predicting exacerbations (especially the most severe) in patients with bronchiectasis.

Short and Long-Term Impact of COVID-19 Infection on Previous Respiratory Diseases.

On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic. Till now, it affected 452.4 million (Spain, 11.18 million) persons all over the world with a total of 6.04 million of deaths (Spain, 100,992). It is observed that 75% of hospitalized COVID-19 patients have at least one COVID-19 associated comorbidity. It was shown that people with underlying chronic illnesses are more likely to get it and grow seriously ill. Individuals with COVID-19 who have a past medical history of cardiovascular disorder, cancer, obesity, chronic lung disease, diabetes, or neurological disease had the worst prognosis and are more likely to develop acute respiratory distress syndrome or pneumonia. COVID-19 can affect the respiratory system in a variety of ways and across a spectrum of levels of disease severity, depending on a person's immune system, age and comorbidities. Symptoms can range from mild, such as cough, shortness of breath and fever, to critical disease, including respiratory failure, shock and multi-organ system failure. So, COVID-19 infection can cause overall worsening of these previous respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc. This review aims to provide information on the impact of the COVID-19 disease on pre-existing lung comorbidities.

The Human Mycobiome in Chronic Respiratory Diseases: Current Situation and Future Perspectives.

Microbes play an important role in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, cystic fibrosis, non-cystic fibrosis bronchiectasis, and asthma. While the role of bacterial pathogens has been extensively studied, the contribution of fungal species to the pathogenesis of chronic lung diseases is much less understood. The recent introduction of next-generation sequencing techniques has revealed the existence of complex microbial lung communities in healthy individuals and patients with chronic respiratory disorders, with fungi being an important part of these communities' structure (mycobiome). There is growing evidence that the components of the lung mycobiome influence the clinical course of chronic respiratory diseases, not only by direct pathogenesis but also by interacting with bacterial species and with the host's physiology. In this article, we review the current knowledge on the role of fungi in chronic respiratory diseases, which was obtained by conventional culture and next-generation sequencing, highlighting the limitations of both techniques and exploring future research areas.

Systemic Inflammatory Biomarkers Define Specific Clusters in Patients with Bronchiectasis: A Large-Cohort Study.

Differential phenotypic characteristics using data mining approaches were defined in a large cohort of patients from the Spanish Online Bronchiectasis Registry (RIBRON). Three differential phenotypic clusters (hierarchical clustering, scikit-learn library for Python, and agglomerative methods) according to systemic biomarkers: neutrophil, eosinophil, and lymphocyte counts, C reactive protein, and hemoglobin were obtained in a patient large-cohort (n = 1092). Clusters #1-3 were named as mild, moderate, and severe on the basis of disease severity scores. Patients in cluster #3 were significantly more severe (FEV1, age, colonization, extension, dyspnea (FACED), exacerbation (EFACED), and bronchiectasis severity index (BSI) scores) than patients in clusters #1 and #2. Exacerbation and hospitalization numbers, Charlson index, and blood inflammatory markers were significantly greater in cluster #3 than in clusters #1 and #2. Chronic colonization by Pseudomonas aeruginosa and COPD prevalence were higher in cluster # 3 than in cluster #1. Airflow limitation and diffusion capacity were reduced in cluster #3 compared to clusters #1 and #2. Multivariate ordinal logistic regression analysis further confirmed these results. Similar results were obtained after excluding COPD patients. Clustering analysis offers a powerful tool to better characterize patients with bronchiectasis. These results have clinical implications in the management of the complexity and heterogeneity of bronchiectasis patients.

Phenotypic Clustering in Non-Cystic Fibrosis Bronchiectasis Patients: The Role of Eosinophils in Disease Severity.

Whether high blood eosinophil counts may define a better phenotype in bronchiectasis patients, as shown in chronic obstructive pulmonary disease (COPD), remains to be investigated. Differential phenotypic characteristics according to eosinophil counts were assessed using a biostatistical approach in a large cohort study from the Spanish Online Bronchiectasis Registry (RIBRON). The 906 patients who met the inclusion criteria were clustered into two groups on the basis of their eosinophil levels. The potential differences according to the bronchiectasis severity index (BSI) score between two groups (Mann-Whitney U test and eosinophil count threshold: 100 cells/µL) showed the most balanced cluster sizes: above-threshold and below-threshold groups. Patients above the threshold exhibited significantly better clinical outcomes, lung function, and nutritional status, while showing lower systemic inflammation levels. The proportion of patients with mild disease was higher in the above-threshold group, while the below-threshold patients were more severe. Two distinct clinical phenotypes of stable patients with non-cystic fibrosis (CF) bronchiectasis of a wide range of disease severity were established on the basis of blood eosinophil counts using a biostatistical approach. Patients classified within the above-threshold cluster were those exhibiting a mild disease, significantly better clinical outcomes, lung function, and nutritional status while showing lower systemic inflammatory levels. These results will contribute to better characterizing bronchiectasis patients into phenotypic profiles with their clinical implications.

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.

Effect of Sex Differences on Computed Tomography Findings in Adults With Cystic Fibrosis: A Multicenter Study.

BACKGROUND: The survival of women with cystic fibrosis (CF) is lower than that of men by approximately 5 years. While various factors have been put forward to account for this discrepancy, no specific reasons have been established. Our hypothesis was that anatomical-structural involvement is more pronounced in women with CF than in men and that this is reflected in thoracic HRCT findings. MATERIAL AND METHODS: We performed a prospective multicentre study, in which adult patients were consecutively included over 18 months. Chest HRCT was performed, and findings were scored by 2 thoracic radiologists using the modified Bhalla system. We also studied respiratory function, applied the CFQR 14+ questionnaire, and collected clinical variables. RESULTS: Of the 360 patients followed up in the participating units, 160 were eventually included. Mean age was 28 years, and 47.5% were women. The mean±SD global score on the modified Bhalla score was 13.7±3.8 in women and 15.2±3.8 in men (p=0.024). The highest scores were observed for sacculations, bronchial generations, and air trapping in women. Women had lower BMI, %FEV1, %FVC, and %DLCO. Similarly, the results for the respiratory domain in CFQR 14+ were worse in women, who also had more annual exacerbations. CONCLUSIONS: This is the first study to provide evidence of the implication of sex differences in HRCT findings in patients with CF. Women with CF present a more severe form of the disease that results in more frequent exacerbations, poorer functional and nutritional outcomes, deterioration of quality of life, and greater structural damage.

C-Reactive Protein Concentration in Steady-State Bronchiectasis: Prognostic Value of Future Severe Exacerbations. Data From the Spanish Registry of Bronchiectasis (RIBRON).

BACKGROUND: Both systemic inflammation and exacerbations have been associated with greater severity of bronchiectasis. Our objective was to analyze the prognostic value of the peripheral concentration of C-reactive protein (CRP) for the number and severity of exacerbations in patients with bronchiectasis. METHODS: Patients from the Spanish Bronchiectasis Registry (RIBRON) with valid data on their CRP value (in a clinically stable phase) and valid data on exacerbations during the first year of follow-up were included. A logistic regression analysis was used to evaluate the prognostic value of the CRP concentration (divided into tertiles) with the presence of at least one severe exacerbation or at least two mild-moderate exacerbations during the first year of follow-up. RESULTS: 802 patients (mean age: 68.1 [11.1 years], 65% female) were included. Of these, 33.8% and 13%, respectively, presented ≥2 mild-moderate exacerbations or at least one severe exacerbation during the first year of follow-up. The mean value of the CRP was 6.5 (17.6mg/L). Patients with a CRP value between 0.4 and 2.7mg/L (second tertile) and ≥2.7mg/L (third tertile) presented a 2.9 (95%CI: 1.4-5.9) and 4.2 (95%CI: 2.2-8.2) times greater probability, respectively, of experiencing a severe exacerbation than those with <0.4mg/L (control group), regardless of bronchiectasis severity or a history of previous exacerbations. However, the CRP value did not present any prognostic value for the number of mild-moderate exacerbations. CONCLUSIONS: The CRP value was associated with a greater risk of future severe exacerbations but not with mild or moderate exacerbations in patients with steady-state bronchiectasis.