Growing from common ground: nontuberculous mycobacteria and bronchiectasis.

Bronchiectasis and nontuberculous mycobacteria (NTM) are intricately intertwined, with NTM capable of being both a cause and consequence of bronchiectatic disease. This narrative review focuses on the common ground of bronchiectasis and NTM pulmonary disease (NTM-PD) in terms of diagnostic approach, underlying risk factors and treatment strategies. NTM-PD diagnosis relies on a combination of clinical, radiological and microbiological criteria. Although their epidemiology is complicated by detection and reporting biases, the prevalence and pathogenicity of NTM species vary geographically, with Mycobacterium avium complex and Mycobacterium abscessus subspecies most frequently isolated in bronchiectasis-associated NTM-PD. Diagnosis of nodular bronchiectatic NTM-PD should prompt investigation of host factors, including disorders of mucociliary clearance, connective tissue diseases and immunodeficiencies, either genetic or acquired. Treatment of NTM-PD in bronchiectasis involves a multidisciplinary approach and considers the (sub)species involved, disease severity and comorbidities. Current guideline-based antimicrobial treatment of NTM-PD is considered long, cumbersome and unsatisfying in terms of outcomes. Novel treatment regimens and strategies are being explored, including rifampicin-free regimens and inclusion of clofazimine and inhaled antibiotics. Host-directed therapies, such as immunomodulators and cytokine-based therapies, might enhance antimycobacterial immune responses. Optimising supportive care, as well as pathogen- and host-directed strategies, is crucial, highlighting the need for personalised approaches tailored to individual patient needs. Further research is warranted to elucidate the complex interplay between host and mycobacterial factors, informing more effective management strategies.

Antibiofilm activity of Prevotella species from the cystic fibrosis lung microbiota against Pseudomonas aeruginosa.

It is increasingly recognized that interspecies interactions may modulate the pathogenicity of Pseudomonas aeruginosa during chronic lung infections. Nevertheless, while the interaction between P. aeruginosa and pathogenic microorganisms co-infecting the lungs has been widely investigated, little is known about the influence of other members of the lung microbiota on the infection process. In this study, we focused on investigating the impact of Prevotella species isolated from the sputum of people with cystic fibrosis (pwCF) on biofilm formation and virulence factor production by P. aeruginosa. Screening of a representative collection of Prevotella species recovered from clinical samples showed that several members of this genus (8 out 10 isolates) were able to significantly reduce biofilm formation of P. aeruginosa PAO1, without impact on growth. Among the tested isolates, the strongest biofilm-inhibitory activity was observed for Prevotella intermedia and Prevotella nigrescens, which caused a reduction of up to 90% in the total biofilm biomass of several P. aeruginosa isolates from pwCF. In addition, a strain-specific effect of P. nigrescens on the ability of P. aeruginosa to produce proteases and pyocyanin was observed, with significant alterations in the levels of these virulence factors detected in LasR mutant strains. Overall, these results suggest that non-pathogenic bacteria from the lung microbiota may regulate pathogenicity traits of P. aeruginosa, and possibly affect the outcome of chronic lung infections.

Objective sputum colour assessment and clinical outcomes in bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes. METHODS: We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up. RESULTS: 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV1), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22-1.38; p<0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44-1.67; p<0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52-2.39; p<0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29-1.56; p<0.0001), 1.98 (95% CI 1.77-2.21; p<0.0001) and 3.05 (95% CI 2.25-4.14; p<0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01-1.24; p=0.027), for each increment in sputum purulence. CONCLUSION: Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis.

Baseline chest computed tomography for diagnosis of invasive aspergillosis in patients with acute myeloid leukaemia treated with intensive chemotherapy: A retrospective single-centre cohort study.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a relatively common infection in patients with acute myeloid leukaemia (AML), and is associated with high mortality rates. Optimising early detection is key to reduce the burden of IPA in this population. In this retrospective cohort study, we evaluated the added value of baseline chest CT before start of classical induction chemotherapy. METHODS: Adult patients receiving first-line intensive chemotherapy for AML were included if a baseline chest CT scan was available (±7 days). Data were collected from the electronic health record. IPA was classified using the EORTC/MSGERC 2020 consensus definitions. RESULTS: Between 2015 and 2019, 99 patients were included. During first-line treatment, 29/99 (30%) patients developed a probable IPA. Baseline chest CT was abnormal in 61/99 (62%) and 14/61 (23%) patients had typical radiological signs for IPA. An abnormal scan showed a trend towards higher risk for IPA (hazard ratio (HR): 2.12; 95% CI 0.95-4.84). Ground glass opacities were a strong predictor for developing IPA (HR 3.35: 95% CI 1.61-7.00). No probable/proven IPA was diagnosed at baseline; however, a bronchoalveolar lavage (BAL) at baseline was only performed in seven patients. Twelve-week mortality was higher in patients with IPA (7/26, 27% vs. 5/59, 8%; p = .024). CONCLUSION: Baseline chest CT scan could be an asset in the early diagnosis of IPA and contribute to risk estimation for IPA. In patients with an abnormal baseline CT, performing a BAL should be considered more frequently, and not only in patients with radiological findings typical for IPA.

Bronchiectasis and asthma: Data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: Asthma is commonly reported in patients with a diagnosis of bronchiectasis. OBJECTIVE: The aim of this study was to evaluate whether patients with bronchiectasis and asthma (BE+A) had a different clinical phenotype and different outcomes compared with patients with bronchiectasis without concomitant asthma. METHODS: A prospective observational pan-European registry (European Multicentre Bronchiectasis Audit and Research Collaboration) enrolled patients across 28 countries. Adult patients with computed tomography-confirmed bronchiectasis were reviewed at baseline and annual follow-up visits using an electronic case report form. Asthma was diagnosed by the local investigator. Follow-up data were used to explore differences in exacerbation frequency between groups using a negative binomial regression model. Survival analysis used Cox proportional hazards regression. RESULTS: Of 16,963 patients with bronchiectasis included for analysis, 5,267 (31.0%) had investigator-reported asthma. Patients with BE+A were younger, were more likely to be female and never smokers, and had a higher body mass index than patients with bronchiectasis without asthma. BE+A was associated with a higher prevalence of rhinosinusitis and nasal polyps as well as eosinophilia and Aspergillus sensitization. BE+A had similar microbiology but significantly lower severity of disease using the bronchiectasis severity index. Patients with BE+A were at increased risk of exacerbation after adjustment for disease severity and multiple confounders. Inhaled corticosteroid (ICS) use was associated with reduced mortality in patients with BE+A (adjusted hazard ratio 0.78, 95% CI 0.63-0.95) and reduced risk of hospitalization (rate ratio 0.67, 95% CI 0.67-0.86) compared with control subjects without asthma and not receiving ICSs. CONCLUSIONS: BE+A was common and was associated with an increased risk of exacerbations and improved outcomes with ICS use. Unexpectedly we identified significantly lower mortality in patients with BE+A.

Effect of 18 months elexacaftor-tezacaftor-ivacaftor on body mass index and glycemic control in adults with cystic fibrosis.

BACKGROUND & AIMS: Malnutrition and cystic fibrosis related diabetes (CFRD) are common comorbidities in cystic fibrosis (CF). Cystic fibrosis transmembrane regulator (CFTR) modulators have shown beneficial effects on respiratory status. This study aims to determine the effect of elexacaftor-tezacaftor-ivacaftor (ETI) on body mass index (BMI) and glycemic control. METHODS: A retrospective, observational study of a cohort of 17 adult CF patients was conducted at the CF reference center of Ghent University Hospital. BMI evolution was analyzed 18 months before and 0, 3, 6, 12 and 18 months after the start of ETI. The evolution of insulin dependence and the 2 h oral glucose tolerance test (OGTT) results were described until 36 months after start of ETI, in a small subgroup of ten patients with CFRD or impaired glucose tolerance (IGT). RESULTS: A significant increase in mean BMI of 1.2 kg/m2 (±1.3 SD) was observed. Most weight gain was observed in the first 3 months after starting treatment. This effect was sustained during the observed period of 18 months. Six patients had insulin dependent CFRD, of which three were able to stop insulin after starting ETI. Two patients with CFRD treated with dietary measures showed an initial normalization of the 2 h OGTT, but deterioration at 36 month follow-up. CONCLUSIONS: After initiation of ETI an increase in BMI was observed in adults with CF. ETI can have a beneficial impact on glucose metabolism in patients with CFRD, leading to a possible need for reduction or cessation of insulin therapy.

Pooling isolates to address the diversity in antimicrobial susceptibility of Pseudomonas aeruginosa in cystic fibrosis.

IMPORTANCE: People with cystic fibrosis (pwCF) often suffer from chronic lung infections with Pseudomonas aeruginosa. While antibiotics are still commonly used to treat P. aeruginosa infections, there is a high discordance between in vitro and in vivo antibiotic efficacy, which contributes to suboptimal antibiotic therapy. In the present study, we found that isolates from the same sputum sample had highly diverse antibiotic resistance profiles [based on the minimal inhibitory concentration (MIC)], which may explain the reported discrepancy between in vitro and in vivo antibiotic efficacy. Through systematic analysis, we report that pooling nine isolates per sputum sample significantly decreased intrasample diversity in MIC and influenced clinical interpretation of antibiotic susceptibility tests compared to single isolate testing. Hence, pooling of isolates may offer a solution to obtain a consistent MIC test result and could lead to optimizing antibiotic therapy in pwCF and other infectious diseases where diversity in antibiotic resistance is observed.

A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19.

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.

Commensal bacteria of the lung microbiota synergistically inhibit inflammation in a three-dimensional epithelial cell model.

Patients with chronic lung disease suffer from persistent inflammation and are typically colonized by pro-inflammatory pathogenic bacteria. Besides these pathogens, a wide variety of commensal species is present in the lower airways but their role in inflammation is unclear. Here, we show that the lung microbiota contains several species able to inhibit activation of the pro-inflammatory NF-κB pathway and production of interleukin 8 (IL-8), triggered by lipopolysaccharide (LPS) or H2O2, in a physiologically relevant three-dimensional (3D) lung epithelial cell model. We demonstrate that the minimal dose needed for anti-inflammatory activity differs between species (with the lowest dose needed for Rothia mucilaginosa), and depends on the type of pro-inflammatory stimulus and read out. Furthermore, we evaluated synergistic activity between pairs of anti-inflammatory bacteria on the inhibition of the NF-κB pathway and IL-8 secretion. Synergistic anti-inflammatory activity was observed for 4/10 tested consortia. These findings indicate that various microbiota members can influence lung inflammation either alone or as a consortium. This information can contribute to a better understanding of the lung microbiota in chronic lung disease development and process, and could open up new avenues for treatment.

In-hospital antibiotic use for severe chronic obstructive pulmonary disease exacerbations: a retrospective observational study.

BACKGROUND: The use of antibiotics in mild to severe acute exacerbations of chronic obstructive pulmonary disease (COPD) remains controversial. AIM: To explore in-hospital antibiotic use in severe acute exacerbations of COPD (AECOPD), to analyze determinants of in-hospital antibiotic use, and to investigate its association with hospital length of stay (LOS) and in-hospital mortality. METHODS: A retrospective, observational study was conducted in Ghent University Hospital. Severe AECOPD were defined as hospitalizations for AECOPD (ICD-10 J44.0 and J44.1) discharged between 2016 and 2021. Patients with a concomitant diagnosis of pneumonia or 'pure' asthma were excluded. An alluvial plot was used to describe antibiotic treatment patterns. Logistic regression analyses identified determinants of in-hospital antibiotic use. Cox proportional hazards regression analyses were used to compare time to discharge alive and time to in-hospital death between antibiotic-treated and non-antibiotic-treated AECOPD patients. RESULTS: In total, 431 AECOPD patients (mean age 70 years, 63% males) were included. More than two-thirds (68%) of patients were treated with antibiotics, mainly amoxicillin-clavulanic acid. In multivariable analysis, several patient-related variables (age, body mass index (BMI), cancer), treatment-related variables (maintenance azithromycin, theophylline), clinical variables (sputum volume and body temperature) and laboratory results (C-reactive protein (CRP) levels) were associated with in-hospital antibiotic use independent of sputum purulence, neutrophil counts, inhaled corticosteroids and intensive care unit of which CRP level was the strongest determinant. The median hospital LOS was significantly longer in antibiotic-treated patients (6 days [4-10]) compared to non-antibiotic-treated patients (4 days [2-7]) (p < 0.001, Log rank test). This was indicated by a reduced probability of hospital discharge even after adjustment for age, sputum purulence, BMI, in-hospital systemic corticosteroid use and forced expiratory volume in one second (FEV1) (adjusted hazard ratio 0.60; 95% CI 0.43; 0.84). In-hospital antibiotic use was not significantly associated with in-hospital mortality. CONCLUSIONS: In this observational study in a Belgian tertiary hospital, in-hospital antibiotic use among patients with severe AECOPD was determined by the symptom severity of the exacerbation and the underlying COPD severity as recommended by the guidelines, but also by patient-related variables. Moreover, in-hospital antibiotic use was associated with a longer hospital stay, which may be linked to their disease severity, slower response to treatment or 'harm' due to antibiotics. TRIAL REGISTRATION: Number: B670201939030; date of registration: March 5, 2019.

Glycemic indices at night measured by CGM are predictive for a lower pulmonary function in adults but not in children with cystic fibrosis.

INTRODUCTION: In patients with cystic fibrosis (CF), it is still unclear to which extent glucose abnormalities - preceding the diagnosis of cystic fibrosis related diabetes (CFRD) - are associated with pulmonary and nutritional outcome parameters. This study related circadian glycemic patterns to clinical outcomes in a group of CF patients not previously diagnosed with diabetes. METHODS: Continuous glucose monitoring (CGM) readings (7 days) of 47 CF patients (26 children, 21 adults) with an impaired oral glucose tolerance test (OGTT) (n = 25) and/or increased Hb1Ac (> 5.5%) were analyzed. Biometric, pulmonary function and clinical parameters were retrospectively collected over a period of 1 year before (T-1) and 1 year after (T + 1) CGM (T0). RESULTS: 96% (45/47) of CGM readings showed glucose values > 140 mg/dL ≥ 4.5% of the time and at least one ≥ 200 mg/dL. In the pediatric cohort, no significant associations were found between CGM parameters and pulmonary and nutritional outcome parameters. In the adult cohort, an area under the curve (AUC) > 140 mg/dL and%-time > 140 mg/dL during the night were associated with a lower forced expiratory volume in 1 s (FEV1)% predicted (pp) at time of evaluation but not with change in FEV1pp. CONCLUSION: This is the first study reporting the circadian glycemic pattern in children and adults at risk for CFRD. In the adult cohort an association between detection of abnormal glucose exposure and a lower FEV1pp was found. Our results support continued screening for glucose intolerance in patients with CF.

Video-assisted thoracic surgery in critically ill COVID-19 patients on venovenous extracorporeal membrane oxygenation.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) leads to thoracic complications requiring surgery. This is challenging, particularly in patients supported with venovenous extracorporeal membrane oxygenation (VV-ECMO) due to the need for continuous therapeutic anticoagulation. We aim to share our experience regarding the safety and perioperative management of video-assisted thoracic surgery for this specific population. METHODS: Retrospective, single-center study between November 2020 and January 2022 at the ICU department of a 1.061-bed tertiary care and VV-ECMO referral center during the COVID-19 pandemic. RESULTS: 48 COVID-19 patients were supported with VV-ECMO. A total of 14 video-assisted thoracic surgery (VATS) procedures were performed in seven patients. Indications were mostly hemothorax (85.7%). In eight procedures heparin was stopped at least 1 h before incision. A total of 10 circuit changes due to clot formation or oxygen transfer failure were required in six patients (85.7%). One circuit replacement seemed related to the preceding VATS procedure, although polytransfusion might be a contributing factor. None of the mechanical complications was fatal. Four VATS-patients (57.1%) died, of which two (50%) immediately perioperatively due to uncontrollable bleeding. All three survivors were treated with additional transarterial embolization. CONCLUSION: (1) Thoracic complications in COVID-19 patients on VV-ECMO are common. (2) Indication for VATS is mostly hemothorax (3) Perioperative mortality is high, mostly due to uncontrollable bleeding. (4) Preoperative withdrawal of anticoagulation is not directly related to a higher rate of ECMO circuit-related complications, but a prolonged duration of VV-ECMO support and polytransfusion might be. (5) Additional transarterial embolization to control postoperative bleeding may further improve outcomes.

Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment.

GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22).

EQUAL CPA Score 2022: a tool to measure guideline adherence for chronic pulmonary aspergillosis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) can complicate underlying pulmonary diseases, and clinical management of CPA is challenging. Guidelines support clinicians but due to the complexity of the disease they can be difficult to adhere to. OBJECTIVES: To map current guideline recommendations for the clinical management of CPA into a scoring tool to facilitate and quantify guideline adherence in clinical practice. METHODS: Recommendations for diagnosis, treatment and follow-up of CPA presented in the current ESCMID/ERS/ECMM and CPAnet guidance documents were assembled and weighed on the basis of their strength of recommendation and level of evidence. RESULTS: Twenty-seven recommendations were identified, resulting in a total maximum EQUAL CPA Score of 51. For diagnostics (ScoreMax = 27), a strong emphasis on expert consultation, culture, direct microscopy, histopathology, serology and imaging was reflected in respective points, whereas molecular techniques and susceptibility testing count into the diagnostics score to a lesser extent.Ten treatment recommendations (ScoreMax = 14), including antifungal therapy, therapeutic drug monitoring and treatment duration, were identified. Surgery, where indicated, adds three points. For refractory disease or intolerance of first-line antifungal treatment, optimal second-line treatment added another two points.During follow-up (ScoreMax = 10), response assessment via imaging gave three points, while culture and serology added two points each to the ScoreMax. CONCLUSION: The EQUAL CPA Score intents to be used as a comprehensive tool for measuring guideline adherence. If adherence to current guidelines is associated with clinical outcome, this will be assessed in future studies.

Altered intravenous drug disposition in people living with cystic fibrosis: A meta-analysis integrating top-down and bottom-up data.

Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top-down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom-up). This was done through meta-analyses and meta-regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case-by-case basis.

Prospective longitudinal evaluation of hospitalised COVID-19 survivors 3 and 12 months after discharge.

Background: Long-term outcome data of coronavirus disease 2019 (COVID-19) survivors are needed to understand their recovery trajectory and additional care needs. Methods: A prospective observational multicentre cohort study was carried out of adults hospitalised with COVID-19 from March through May 2020. Workup at 3 and 12 months following admission consisted of clinical review, pulmonary function testing, 6-min walk distance (6MWD), muscle strength, chest computed tomography (CT) and quality of life questionnaires. We evaluated factors correlating with recovery by linear mixed effects modelling. Results: Of 695 patients admitted, 299 and 226 returned at 3 and 12 months, respectively (median age 59 years, 69% male, 31% severe disease). About half and a third of the patients reported fatigue, dyspnoea and/or cognitive impairment at 3 and 12 months, respectively. Reduced 6MWD and quadriceps strength were present in 20% and 60% at 3 months versus 7% and 30% at 12 months. A high anxiety score and body mass index correlated with poor functional recovery. At 3 months, diffusing capacity for carbon monoxide (D LCO) and total lung capacity were below the lower limit of normal in 35% and 18%, decreasing to 21% and 16% at 12 months; predictors of poor D LCO recovery were female sex, pre-existing lung disease, smoking and disease severity. Chest CT improved over time; 10% presented non-progressive fibrotic changes at 1 year. Conclusion: Many COVID-19 survivors, especially those with severe disease, experienced limitations at 3 months. At 1 year, the majority showed improvement to almost complete recovery. To identify additional care or rehabilitation needs, we recommend a timely multidisciplinary follow-up visit following COVID-19 admission.

Prevalence of Chronic Pulmonary Aspergillosis in Patients Suspected of Chest Malignancy.

Chronic pulmonary aspergillosis (CPA) is a potentially life-threatening fungal lung infection, and recent research suggests CPA to be more common than previously considered. Although CPA mimics other lung diseases including pulmonary cancer, awareness of this disease entity is still sparse. This study aimed to investigate the prevalence of CPA in a population of patients under suspicion of having lung cancer. We conducted a retrospective cohort study of 1200 patients and manually collected individual health record data from previous cancer examinations, with retrospective CPA status assessment using international criteria. Among 992 included patients, 16 (1.6%) fulfilled diagnostic criteria for CPA retrospectively, of whom 15 were undiscovered at initial lung cancer examination. The prevalence of CPA in this study population was 50 times higher than the reported prevalence of the overall European population. Our findings indicate that CPA is often missed in patients suspected of malignancy in the chest. Therefore, CPA should be kept in mind as a significant differential diagnosis.

Urinary sodium/creatinine ratio is a predictor for fractional sodium excretion and related to age in patients with cystic fibrosis.

Electrolyte disturbances are common in patients with cystic fibrosis (CF). Current guidelines on monitoring sodium status are based on research in a small group of infants and require blood sampling. The aim of this study was to evaluate urinary salt parameters as a surrogate for sodium-status in different age-groups. Blood and urine samples for electrolytes were collected from 222 patients followed at the Ghent University Hospital CF-center. Fractional sodium excretion (FENa) and several urinary parameters were calculated. Clinical characteristics did not differ according to sodium status, defined as FENa <0.5%. ROC analysis demonstrated that sodium/creatinine ratio (UNa/Creat) predicted the sodium status most accurately with high sensitivity and specificity (97 and 91% respectively). The UNa/Creat cut-off predicting a FENa <0.5% differed significantly according to age. The UNa/Creat is an excellent marker for the sodium status defined as a FENa <0.5%. However, different cut-offs according to age category should be applied.

Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.

BACKGROUND: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation. METHODS: We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40-90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972. FINDINGS: Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [-46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1). INTERPRETATION: The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population. FUNDING: Vertex Pharmaceuticals.

Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 µg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 µg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 µg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program.