Structural Lung Disease and Clinical Phenotype in Bronchiectasis Patients: The EMBARC CT Study.

Rationale: Chest computed tomography (CT) scans are essential to diagnose and monitor bronchiectasis (BE). To date, few quantitative data are available about the nature and extent of structural lung abnormalities (SLAs) on CT scans of patients with BE. Objectives: To investigate SLAs on CT scans of patients with BE and the relationship of SLAs to clinical features using the EMBARC (European Multicenter Bronchiectasis Audit and Research Collaboration) registry. Methods: CT scans from patients with BE included in the EMBARC registry were analyzed using the validated Bronchiectasis Scoring Technique for CT (BEST-CT). The subscores of this instrument are expressed as percentages of total lung volume. The items scored are atelectasis/consolidation, BE with and without mucus plugging (MP), airway wall thickening, MP, ground-glass opacities, bullae, airways, and parenchyma. Four composite scores were calculated: total BE (i.e., BE with and without MP), total MP (i.e., BE with MP plus MP alone), total inflammatory changes (i.e., atelectasis/consolidation plus total MP plus ground-glass opacities), and total disease (i.e., all items but airways and parenchyma). Measurements and Main Results: CT scans of 524 patients with BE were analyzed. Mean subscores were 4.6 (range, 2.3-7.7) for total BE, 4.2 (1.2-8.1) for total MP, 8.3 (3.5-16.7) for total inflammatory changes, and 14.9 (9.1-25.9) for total disease. BE associated with primary ciliary dyskinesia was associated with more SLAs, whereas chronic obstructive pulmonary disease was associated with fewer SLAs. Lower FEV1, longer disease duration, Pseudomonas aeruginosa and nontuberculous mycobacterial infections, and severe exacerbations were all independently associated with worse SLAs. Conclusions: The type and extent of SLAs in patients with BE are highly heterogeneous. Strong relationships between radiological disease and clinical features suggest that CT analysis may be a useful tool for clinical phenotyping.

Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression.

RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC). METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV1pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC. RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95% CI 0.11-0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07-0.46; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06-0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12-0.97; p=0.044). These associations were absent for SCC. CONCLUSION: This study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Validating a clinical prediction score for Legionella-related community acquired pneumonia.

BACKGROUND: Legionella-related community acquired pneumonia (CAP) is a disease with an increasing incidence and a high mortality rate, especially if empirical antibiotic therapy is inadequate. Antibiotic treatment highly relies on clinical symptoms, although proven non-specific, because currently available diagnostic techniques provide insufficient accuracy for detecting Legionella CAP on admission. This study validates a diagnostic scoring system for detection of Legionella-related CAP, based on six items on admission (Legionella prediction score). METHODS: We included patients with Legionella-related CAP admitted to five large Dutch hospitals between 2006 and 2016. Controls were non-Legionella-related CAP patients. The following six conditions were rewarded one point if present: fever > 39.4 °C; dry cough; hyponatremia (sodium) < 133 mmol/L; lactate dehydrogenase (LDH) > 225 mmol/L; C-reactive protein (CRP) > 187 mg/L and platelet count < 171 × 109/L. The accuracy of the prediction score was assessed by calculating the area under the curve (AUC) through logistic regression analysis. RESULTS: We included 131 cases and 160 controls. A score of 0 occurred in non-Legionella-related CAP patients only, a score of 5 and 6 in Legionella-related CAP patients only. A cut-off ≥ 4 resulted in a sensitivity of 58.8% and a specificity of 93.1%. The AUC was 0.89 (95% CI 0.86-0.93). The strongest predictors were elevated LDH, elevated CRP and hyponatremia. CONCLUSIONS: This multi-centre study validates the Legionella prediction score, an easily applicable diagnostic scoring system, in a large group of patients and finds high diagnostic accuracy. The score shows promise for future prospective validation and could contribute to targeted antibiotic treatment of suspected Legionella CAP.

Do-not-intubate status and COVID-19 mortality in patients admitted to Dutch non-ICU wards.

Mortality from COVID-19 has been particularly high in elderly patients on mechanical ventilation. Treatment outcomes for patients with do-not-intubate (DNI) status are unknown. One hundred patients admitted to the non-ICU ward during the "first wave" were retrospectively analyzed. Mortality rate was 49% in patients with a DNI order. This subgroup was characterized by significantly higher age, more comorbidity, and care dependency. Mortality among DNI patients was three times higher than other patients, but not higher than some of the published mortality rates for elderly mechanically ventilated patients. Advanced care planning is essential in COVID-19 to assist patient autonomy and prevent non-beneficial medical interventions.

Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Mucociliary clearance is dysfunctional in people with primary ciliary dyskinesia, resulting in the accumulation of dehydrated mucus in the airways that is difficult to clear. We undertook a study to assess the benefit on lung function of treatment with a nebulised epithelial sodium channel (ENaC) blocker, idrevloride, with or without hypertonic saline, in people with primary ciliary dyskinesia. METHODS: The CLEAN-PCD trial was a phase 2, randomised, double-blind, placebo-controlled crossover trial conducted at 32 tertiary adult and paediatric care centres and university hospitals in Canada, Denmark, Germany, Italy, the Netherlands, Poland, the UK, and the USA. People with a confirmed diagnosis of primary ciliary dyskinesia, aged 12 years or older, with a percentage of predicted FEV1 (ppFEV1) in the range of 40% to <90%, were randomly assigned in a 2:2:1:1 ratio (block size=6), stratified by ppFEV1 at screening, to one of four sequences: (1) idrevloride in hypertonic saline in treatment period 1 then hypertonic saline in treatment period 2; (2) hypertonic saline in treatment period 1 then idrevloride in hypertonic saline in treatment period 2; (3) idrevloride in treatment period 1 then placebo in treatment period 2; and (4) placebo in treatment period 1 then idrevloride in treatment period 2. The idrevloride dose was 85 µg and hypertonic saline was 4·2% NaCl. 3 mL of each study treatment was nebulised twice daily for 28 days in treatment periods 1 and 2; the two 28-day treatment periods were separated by a 28-day washout period. The primary endpoint was absolute change from baseline in ppFEV1 after 28 days. Safety assessments and reports of adverse events were made at clinic visits during each treatment period and by a follow-up telephone call 28 days after the last dose of study drug. Additionally, adverse events could be reported at a follow-up telephone call 3 days after the start of dosing and as they arose. Participants who received at least one dose of study drug were included in the safety analyses (safety set), and those who also had spirometry data were included in the efficacy analyses (full analysis set). The completed study is registered (EudraCT 2015-004917-26; ClinicalTrials.govNCT02871778). FINDINGS: Between Sep 14, 2016, and May 31, 2018, 216 patients were screened and 123 were randomly assigned to one of four crossover sequences. Across the two treatment periods, treatment with idrevloride in hypertonic saline was initiated in 80 patients and completed in 78 patients (all 78 had data available and were included in the analysis); hypertonic saline initiated in 81 patients and completed in 76 patients (75 had data available and were included in the analysis); idrevloride initiated in 37 patients and completed in 35 patients (34 had data available and were included in the analysis); and placebo initiated in 36 patients and completed in 34 patients (all 34 had data available and were included in the analysis). Greater absolute increases in ppFEV1 from baseline to 28 days of treatment were seen with idrevloride in hypertonic saline (least-squares mean absolute change from baseline 1·0 percentage points, 95% CI -0·4 to 2·4) than with hypertonic saline alone (least-squares mean absolute change from baseline of -0·5 percentage points, -2·0 to 0·9; difference 1·5 percentage points, 95% CI <0·1 to 3·0; p=0·044). There was no significant difference in ppFEV1 for the parallel comparison of idrevloride in hypertonic saline compared with placebo or the crossover comparison of idrevloride with placebo. Adverse events were similar across treatments (57 to 65% of patients). Cough occurred in a greater proportion of participants during treatments that contained idrevloride or hypertonic saline compared with placebo, and oropharyngeal pain occurred in a greater proportion of participants during idrevloride treatments than during treatment with hypertonic saline alone or placebo, whereas chest discomfort was more common during treatments that included hypertonic saline. INTERPRETATION: In this phase 2 crossover study, idrevloride in hypertonic saline was safe and associated with improved lung function over a 28-day period in people with primary ciliary dyskinesia compared with hypertonic saline alone. Larger, longer clinical studies are warranted to explore the potential benefits of idrevloride in combination with hypertonic saline in people with primary ciliary dyskinesia. FUNDING: Parion Sciences, under agreement with Vertex Pharmaceuticals.

T helper 17 cells are involved in the local and systemic inflammatory response in community-acquired pneumonia.

BACKGROUND: Recent findings in mouse models suggest that T helper (Th)17 cells, characterised by production of interleukin (IL)-17A and IL-22, are involved in the immunopathogenesis of pneumonia. OBJECTIVE: In this study, we aimed to identify the involvement of Th17 cells in human community-acquired pneumonia (CAP). DESIGN: Within 24 h of admission, T cells from peripheral blood (n=39) and bronchoalveolar lavage (BAL, n=20) of CAP patients and of 10 healthy individuals were analysed by intracellular flow cytometry for the production of various cytokines, including IL-17A and IL-22. Peripheral blood T cells were also analysed 7 and 30 days after admission. Th17 cytokine profiles were correlated with pneumonia severity index and microbial aetiology. RESULTS: In the BAL of CAP patients, proportions of IL-17A and IL-22 single positive, as well as IL-17A/IL-22 double positive CD4 T cells were significantly increased compared with healthy individuals. Significantly increased proportions of IL-17A/IL-22 double positive CD4 T cells in BAL were found in non-severe and severe CAP patients, as well as in pneumococcal and non-pneumococcal CAP. In the peripheral blood of CAP patients upon admission, we found significantly increased proportions of IL-17A/IL-22 double positive CD4 T cells. One week after admission, the proportions of these double positive cells were still significantly increased in CAP patients compared with healthy individuals. CONCLUSIONS: These data indicate that Th17 cells are engaged in the local and systemic immune response in human pneumonia. Especially, IL-17A/IL-22 double positive Th17 cells may be involved in the immunopathogenesis of CAP.

Local and systemic cytokine profiles in nonsevere and severe community-acquired pneumonia.

Local inflammatory responses in community-acquired pneumonia (CAP) remain insufficiently elucidated, especially in patients with nonsevere CAP. In this study we determined local and systemic cytokine responses in CAP patients and correlated these with disease severity and other clinical parameters. Levels of interleukin (IL)-6, IL-8, IL-10, IL-1ß, tumour necrosis factor-α, interferon (IFN)-γ, IL-22, IL-17A and IL-4 were determined in bronchoalveolar lavage fluid and serum of 20 CAP patients upon admission and 10 healthy individuals. Systemic cytokine levels were also measured on days 7 and 30. In bronchoalveolar lavage fluid of CAP patients, levels of IL-6, IL-8 and IFN-γ were significantly increased compared with healthy individuals, but no correlations with disease severity were found. Systemic levels of IL-6, IL-10 and IFN-γ were significantly higher in severe CAP patients than in nonsevere CAP patients and healthy individuals. Moreover, these cytokines showed a significant correlation with the pneumonia severity index. In the total group of CAP patients, systemic IL-8 and IL-22 levels were also increased compared with healthy individuals. We therefore conclude that IL-6, IL-10 and IFN-γ are important cytokines in CAP, although differences in disease severity upon admission are only reflected by systemic levels of these cytokines.

Incidence of viral respiratory pathogens causing exacerbations in adult cystic fibrosis patients.

Respiratory infections caused by respiratory viruses are common in paediatric cystic fibrosis (CF) patients and are associated with increased morbidity. There is only little data on the incidence of viral respiratory pathogens causing exacerbations in the adult CF patient population. In this observational pilot study we show, by using molecular as well as conventional techniques for viral isolation, that during 1 y a viral pathogen could be isolated in 8/24 (33%) adult CF patients who presented with a pulmonary exacerbation. This result shows that there is a considerable incidence of viral pathogens in pulmonary exacerbations in adult CF patients. Newly identified viruses such as pandemic influenza A/H1N1, human metapneumovirus, human bocavirus, and human coronavirus NL63 were not detected in our population, except for 1 human coronavirus NL63.

Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD.

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary and systemic inflammation. Both CD4+ and CD8+ T-lymphocytes play a key role in COPD pathogenesis, but cytokine profiles in circulating T-lymphocytes have not been well characterised. Here we report the analysis of peripheral blood T-cells from 30 stable COPD patients and 10 healthy never-smokers for interferon (IFN)-γ, interleukin (IL)-4, tumour necrosis factor (TNF)-α and the T-helper 17 cytokines IL-17A, IL-17F and IL-22 by intracellular flow cytometry. We found significantly increased proportions of IFN-γ+ and TNF-α+ CD8+ T-cells in COPD patients, when compared with healthy controls. This was most evident in patients with less severe disease. In contrast, expression profiles in circulating CD4+ T-cells were similar in COPD patients and healthy controls for all cytokines tested, except for IL-17F. COPD patients with more severely reduced diffusing capacity had lower proportions of IL-17A+ CD4+ T-cells. Proportions of IL-22+ cells in the CD4+ memory T-cell population were significantly increased in active smokers, when compared with past smokers. Collectively, this comprehensive cytokine analysis of circulating T-cells in COPD patients revealed a correlation for CD8+ T-cells between Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and IFN-γ or TNF-α expression, but not for CD4+ T-cells.

Recommendations for antibacterial therapy in adults with COVID-19 - an evidence based guideline.

SCOPE: The Dutch Working Party on Antibiotic Policy constituted a multidisciplinary expert committee to provide evidence-based recommendation for the use of antibacterial therapy in hospitalized adults with a respiratory infection and suspected or proven 2019 Coronavirus disease (COVID-19). METHODS: We performed a literature search to answer four key questions. The committee graded the evidence and developed recommendations by using Grading of Recommendations Assessment, Development, and Evaluation methodology. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: We assessed evidence on the risk of bacterial infections in hospitalized COVID-19 patients, the associated bacterial pathogens, how to diagnose bacterial infections and how to treat bacterial infections. Bacterial co-infection upon admission was reported in 3.5% of COVID-19 patients, while bacterial secondary infections during hospitalization occurred up to 15%. No or very low quality evidence was found to answer the other key clinical questions. Although the evidence base on bacterial infections in COVID-19 is currently limited, available evidence supports restrictive antibiotic use from an antibiotic stewardship perspective, especially upon admission. To support restrictive antibiotic use, maximum efforts should be undertaken to obtain sputum and blood culture samples as well as pneumococcal urinary antigen testing. We suggest to stop antibiotics in patients who started antibiotic treatment upon admission when representative cultures as well as urinary antigen tests show no signs of involvement of bacterial pathogens after 48 hours. For patients with secondary bacterial respiratory infection we recommend to follow other guideline recommendations on antibacterial treatment for patients with hospital-acquired and ventilator-associated pneumonia. An antibiotic treatment duration of five days in patients with COVID-19 and suspected bacterial respiratory infection is recommended upon improvement of signs, symptoms and inflammatory markers. Larger, prospective studies about the epidemiology of bacterial infections in COVID-19 are urgently needed to confirm our conclusions and ultimately prevent unnecessary antibiotic use during the COVID-19 pandemic.

Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19).

Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients (17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5-11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4-17.2). Multivariate analyses identify viral loads above 7 log10 RNA copies/mL (odds ratio [OR] of 14.7 (CI 3.57-58.1; p < 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p < 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.

The radiological diagnosis of bronchiectasis: what's in a name?

Diagnosis of bronchiectasis is usually made using chest computed tomography (CT) scan, the current gold standard method. A bronchiectatic airway can show abnormal widening and thickening of its airway wall. In addition, it can show an irregular wall and lack of tapering, and/or can be visible in the periphery of the lung. Its diagnosis is still largely expert based. More recently, it has become clear that airway dimensions on CT and therefore the diagnosis of bronchiectasis are highly dependent on lung volume. Hence, control of lung volume is required during CT acquisition to standardise the evaluation of airways. Automated image analysis systems are in development for the objective analysis of airway dimensions and for the diagnosis of bronchiectasis. To use these systems, clear and objective definitions for the diagnosis of bronchiectasis are needed. Furthermore, the use of these systems requires standardisation of CT protocols and of lung volume during chest CT acquisition. In addition, sex- and age-specific reference values are needed for image analysis outcome parameters. This review focusses on today's issues relating to the radiological diagnosis of bronchiectasis using state-of-the-art CT imaging techniques.

Prevalence and abundance of selected genes conferring macrolide resistance genes in COPD patients during maintenance treatment with azithromycin.

OBJECTIVES: Maintenance treatment with macrolide antibiotics has shown to be effective in reducing exacerbations in COPD patients. A major concern with prolonged treatment with antibiotics is the development of bacterial resistance. In this study we determined the effect of azithromycin on the development and acquisition of resistance to macrolides in the nasopharyngeal flora in COPD patients. METHODS: This study was part of the COLUMBUS trial, a randomised, double-blind, placebo-controlled trial to measure the effect of maintenance treatment with azithromycin in 92 COPD patients on the exacerbation rates during a 12-month period. In order to determine resistance to macrolides, we used a targeted metagenomic approach to measure the presence and relative abundance of specific macrolide resistance genes ermB, ermF and mefA in throat samples collected at different time-points during this 12-month period. RESULTS: There was no increased risk for acquisition of macrolide resistance genes in the azithromycin group compared to the placebo group in COPD patients. However, loss of the macrolide resistance gene ermB was increased overtime in the placebo treated group compared to the azithromycin group (n = 5 for the placebo group versus n = 0 for the azithromycin group at 12 months; p = 0.012). The change in relative abundance of the three macrolide-resistance genes showed that all but one (ermF) increased during treatment with azithromycin. CONCLUSIONS: The acquisition rate of macrolide resistance genes in COPD patients treated with azithromycin maintenance therapy was limited, but the relative abundance of macrolide resistance genes increased significantly over time compared to placebo. This study was part of the COLUMBUS trial ( Clinicaltrials.gov , NCT00985244 ).

[Use of antibiotics for asthma and COPD exacerbation]. / Antibioticagebruik bij astma- en COPD-exacerbaties.

Most patients with asthma do not receive antibiotics when they experience an exacerbation. In contrast, most patients with COPD exacerbations do indeed receive antibiotics. However, studies have shown that while some subgroups of patients with asthma or COPD may benefit from antibiotics, others do not. In this era of antibiotic stewardship, it is of crucial importance to use objective criteria when deciding whether or not to give antibiotics. Biomarkers, such as procalcitonin, could be helpful when making this decision. There is a clear need for well-designed and high-quality studies with enough power to evaluate the usage of these kinds of biomarkers.

Blood eosinophil count and GOLD stage predict response to maintenance azithromycin treatment in COPD patients with frequent exacerbations.

INTRODUCTION: Maintenance treatment with macrolides are useful in preventing COPD exacerbations. We investigated which characteristics of COPD patients with frequent exacerbations predicted the best response to maintenance treatment with azithromycin. METHODS: This study was part of the COLUMBUS trial, a prospective randomized, double-blind, placebo-controlled study in 92 COPD patients with frequent exacerbations. During the 1-year treatment period, follow-up data were collected for spirometry, mMRC scores, sputum cultures and blood inflammatory markers. RESULTS: In the azithromycin group a significant lower number of exacerbations per patient was observed in patients with the following characteristics: baseline blood eosinophil count ≥2.0% (x̄ = 1.26), compared to an eosinophil count < 2.0% (x̄ = 2.50; p = 0.02), GOLD stage 1-2 (x̄ = 1.06), versus GOLD stage 4 (x̄ = 2.62; p = 0.02) and GOLD group C (x̄ = 0.45) compared to group D (x̄ = 2.18; p < 0.01). Moreover, the number of hospitalizations was significantly lower in patients, with a blood eosinophil count ≥2.0% (x̄ = 0.26) compared to an eosinophil count < 2.0% (x̄ = 0.90; p = 0.01) and in GOLD stages 1-2 (x̄ = 1.06) compared to stage 4 (x̄ = 2.62; p = 0.04). CONCLUSION: In conclusion, azithromycin maintenance treatment appears to be effective in COPD patients with frequent exacerbations, who are either classified in GOLD stage 1-2 or GOLD C and those with a blood eosinophil count of ≥2.0%.

Home videos of cystic fibrosis patients using tobramycin inhalation powder: Relation of flow and cough.

BACKGROUND: Many cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa are on maintenance tobramycin inhalation therapy. Cough is reported as a side effect of tobramycin inhalation powder (TIP) in 48% of the patients. Objectives of this study were to investigate the association between the inspiratory flow of TIP and cough and to study the inhalation technique. We hypothesized that cough is related to a fast inhalation. MATERIALS AND METHODS: In this prospective observational study, CF patients ≥ 6 years old on TIP maintenance therapy from four Dutch CF centers were visited twice at home. Video recordings were obtained and peak inspiratory flow (PIF) was recorded while patients inhaled TIP. Between the two home visits, the patients made three additional videos. CF questionnaire-revised, spirometry data, and computed tomography scan were collected. Two observers scored the videos for PIF, cough, and mistakes in inhalation technique. The associations between PIF and cough were analyzed using a logistic mixed-effects model accounting for FEV1 % predicted and capsule number. RESULTS: Twenty patients were included, median age 22 (18-28) years. No significant associations were found between PIF and cough. The risk of cough was highest after inhalation of the first capsule when compared to the second, third, and fourth capsule (P ≤ .015). Fourteen patients (70%) coughed at least once during TIP inhalation. A breath-hold of less than 5 seconds after inhalation and no deep expiration before inhalation were the most commonly observed mistakes. CONCLUSION: PIF is not related to cough in CF patients using TIP.