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.

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.

Aggregatibacter is inversely associated with inflammatory mediators in sputa of patients with chronic airway diseases and reduces inflammation in vitro.

BACKGROUND: Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD. METHODS: Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients. RESULTS: We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1ß levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability. CONCLUSIONS: These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients.

Aspergillus and the Lung.

The filamentous fungus Aspergillus causes a wide spectrum of diseases in the human lung, with Aspergillus fumigatus being the most pathogenic and allergenic subspecies. The broad range of clinical syndromes that can develop from the presence of Aspergillus in the respiratory tract is determined by the interaction between host and pathogen. In this review, an oversight of the different clinical entities of pulmonary aspergillosis is given, categorized by their main pathophysiological mechanisms. The underlying immune processes are discussed, and the main clinical, radiological, biochemical, microbiological, and histopathological findings are summarized.

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.

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.

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.

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.

Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial.

BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear. METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) - 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified. CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.

Conceptions of the pathophysiology of happy hypoxemia in COVID-19.

In their letter-to-the-editor entitled "Misconceptions of pathophysiology of happy hypoxemia and implications for management of COVID-19", Tobin et al. (Respir Res 21:249, 2020) debated our views on happy hypoxemia in COVID-19 (Respir Res 21:198, 2020). We thank the authors for their interesting comments and alternative viewpoints, and we would like to clarify several important aspects raised.

Early resuscitation orders in hospitalized oldest-old with COVID-19: A multicenter cohort study.

BACKGROUND: In particular older people are at risk of mortality due to corona virus disease 2019 (COVID-19). Advance care planning is essential to assist patient autonomy and prevent non-beneficial medical interventions. AIM: To describe early (taken within 72 h after hospital admission) resuscitation orders in oldest-old hospitalized with COVID-19. SETTING/PARTICIPANTS: A cohort of patients aged 80 years and older admitted to the acute hospital in March and April 2020 with COVID-19 were retrospectively recruited from 10 acute hospitals in Belgium. Recruitment was done through a network of geriatricians. RESULTS: Overall, 766 octogenarians were admitted of whom 49 were excluded because no therapeutic relationship with the geriatrician and six because of incomplete case report form. Early decisions not to consider intensive care admission were taken in 474/711 (66.7%) patients. This subgroup was characterized by significantly higher age, higher number of comorbidities and higher frailty level. There was a significant association between the degree of the treatment limitation and the degree of premorbid frailty (p < 0.001). Overall in-hospital mortality was 41.6% in patients with an early decision not to consider intensive care admission (67.1% in persons who developed respiratory failure vs 16.7% in patients without respiratory failure (p < 0.001)). Of 104 patients without early decision not to consider intensive care admission but who developed respiratory failure, 59 were eventually not transferred to intensive care unit with in-hospital mortality of 25.4%; 45 were transferred to the intensive care unit with mortality of 64.4%. CONCLUSIONS: Geriatricians applied all levels of treatment in oldest-old hospitalized with COVID-19. Early decisions not to consider intensive care admission were taken in two thirds of the cohort of whom more than 50% survived to hospital discharge by means of conservative treatment.

Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. INTERPRETATION: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. FUNDING: Vertex Pharmaceuticals.

The pathophysiology of 'happy' hypoxemia in COVID-19.

The novel coronavirus disease 2019 (COVID-19) pandemic is a global crisis, challenging healthcare systems worldwide. Many patients present with a remarkable disconnect in rest between profound hypoxemia yet without proportional signs of respiratory distress (i.e. happy hypoxemia) and rapid deterioration can occur. This particular clinical presentation in COVID-19 patients contrasts with the experience of physicians usually treating critically ill patients in respiratory failure and ensuring timely referral to the intensive care unit can, therefore, be challenging. A thorough understanding of the pathophysiological determinants of respiratory drive and hypoxemia may promote a more complete comprehension of a patient's clinical presentation and management. Preserved oxygen saturation despite low partial pressure of oxygen in arterial blood samples occur, due to leftward shift of the oxyhemoglobin dissociation curve induced by hypoxemia-driven hyperventilation as well as possible direct viral interactions with hemoglobin. Ventilation-perfusion mismatch, ranging from shunts to alveolar dead space ventilation, is the central hallmark and offers various therapeutic targets.

Haemoptysis as the first presentation of COVID-19: a case report.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic that profoundly challenges healthcare systems all over the world. Fever, cough and fatigue are the most commonly reported clinical symptoms. CASE PRESENTATION: A 58-year-old man presented at the emergency department with acute onset haemoptysis. On the fifth day after admission, he developed massive haemoptysis. Computed tomography (CT) angiography of the chest revealed alveolar haemorrhage, more prominent in the left lung. Flexible bronchoscopy confirmed bleeding from the left upper lobe, confirmed by a bronchial arteriography, which was successfully embolized. Nasopharyngeal swabs (NPS) tested for SARS-CoV-2 using real-time polymerase chain reaction (RT-PCR) repeatedly returned negative. Surprisingly, SARS-CoV-2 was eventually detected in bronchoalveolar lavage (BAL) fluid. CONCLUSIONS: Life-threatening haemoptysis is an unusual presentation of COVID-19, reflecting alveolar bleeding as a rare but possible complication. This case emphasises the added value of bronchoscopy with BAL in the diagnostic work-up in case of high clinical suspicion and negative serial NPS in patients presenting with severe symptoms.

Clinical relevance of pulmonary non-tuberculous mycobacterial isolates in three reference centres in Belgium: a multicentre retrospective analysis.

BACKGROUND/OBJECTIVES: Assessing the clinical relevance of non-tuberculous mycobacteria (NTM) isolated from respiratory samples can be challenging. The epidemiology and pathogenicity of NTM species vary geographically. We aimed to outline the clinical relevance and associated radiological patterns of NTM species isolated in Belgium. METHODS: We performed a retrospective multicentre analysis of all patients identified from the laboratory database with > 1 respiratory sample growing NTM from January 2010 through December 2017. We collected clinical, radiological and microbiological data through medical record review and assessed clinical relevance according to ATS/IDSA criteria for NTM pulmonary disease (NTM-PD). RESULTS: Of the 384 unique patients, 60% were male, 56% had a smoking history and 61% had pre-existing lung disease. Mycobacterium avium complex (MAC), M. gordonae and M. xenopi were the most frequently isolated species: 53, 15 and 8% respectively. 43% of patients met ATS/IDSA criteria, of whom 28% presented with fibrocavitary disease. Weight loss, fever, nodular bronchiectatic and fibrocavitary lesions on chest CT, and a positive acid-fast bacilli (AFB) stain were significantly associated with NTM-PD. The species with the highest pathogenic potential were M. abscessus (11/12), M. malmoense (6/7) and M. intracellulare (41/64). CONCLUSION: In our study, MAC was the most commonly isolated NTM species, but M. abscessus and M. malmoense showed the highest probability of being clinically relevant. Clinical relevance varied not only by species but also by radiological findings on chest CT and AFB staining. Clinicians should consider these elements in their treatment decision making. Prospective data including clinical outcome are needed to provide more robust evidence.

Development and validation of an LC tandem MS assay for the quantification of ß-lactam antibiotics in the sputum of cystic fibrosis patients.

OBJECTIVES: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data. METHODS: Ultra-performance LC coupled to tandem MS was used. A single sample can be measured in 2.5 min with multiple reaction monitoring in positive electrospray ionization mode. Deuterated internal standards were used and a concentration range of 0.7-160 mg/L was covered. The method was validated according to the EMA guideline on analytical method validation. RESULTS: The boundaries within which a reliable measurement in CF sputum can be performed were determined. A few constraints are linked to the instability of the antibiotics in sputum. Piperacillin showed limited stability at room temperature and during freeze-thaw cycles. Autosampler instability was observed after 15 h for aztreonam at low concentrations. CONCLUSIONS: The method allows a reliable measurement of the selected antibiotics, if precautions are taken regarding the limited stability of piperacillin at room temperature. Due to freeze-thaw instability, piperacillin should always be analysed on the day of sampling. Quick review of the analytical data and reanalysis are needed as low concentrations of aztreonam are not stable in the autosampler.

Risk factors and impact of allergic bronchopulmonary aspergillosis in Pseudomonas aeruginosa-negative CF patients.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a major complication in cystic fibrosis (CF) patients. Risk factors for ABPA and clinical deterioration in CF patients, negative for Pseudomonas aeruginosa (Pa), were explored. METHODS: We performed a retrospective case-control study in 73 Pa-negative patients. Each patient was matched with 2 controls for age, gender, pancreas sufficiency, DeltaF508 mutation (homozygous or heterozygous), and Pa colonization. RESULTS: Median FEV1 at the year of diagnosis (index year) was significantly lower in patients with ABPA. The median of cumulative values of FEV1 and FVC before the index year was not significantly different. After the index year, the median of cumulative data for FEV1 and FVC was significantly lower; there were significantly more hospitalization days and more IV antibiotic days compared to controls. Comparing pre- and post-index year data in patients with ABPA, significantly more hospitalization days and more IV antibiotic days were observed after the index year. During the period preceding the index year, significantly more ABPA patients were treated with rhDNase and inhaled corticosteroids. CONCLUSIONS: Bronchial damage cannot be considered as a facilitating factor for ABPA. ABPA causes a significant increase in bronchial damage. In patients with ABPA, further bronchial damage can be controlled by an increase in hospitalization days and use of IV antibiotics. rhDNase and inhaled corticosteroids were associated with the development of ABPA.

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.