Systemic antibiotics for Pseudomonas aeruginosa infection in outpatients with non-hospitalised exacerbations of pre-existing lung diseases: a randomised clinical trial.

BACKGROUND: The effect of dual systemic antibiotic therapy against Pseudomonas aeruginosa in patients with pre-existing lung disease is unknown. To assess whether dual systemic antibiotics against P. aeruginosa in outpatients with COPD, non-cystic fibrosis (non-CF) bronchiectasis, or asthma can improve outcomes. METHODS: Multicenter, randomised, open-label trial conducted at seven respiratory outpatient clinics in Denmark. Outpatients with COPD, non-CF bronchiectasis, or asthma with a current P. aeruginosa-positive lower respiratory tract culture (clinical routine samples obtained based on symptoms of exacerbation not requiring hospitalisation), regardless of prior P. aeruginosa-status, no current need for hospitalisation, and at least two moderate or one hospitalisation-requiring exacerbation within the last year were eligible. Patients were assigned 1:1 to 14 days of dual systemic anti-pseudomonal antibiotics or no antibiotic treatment. Primary outcome was time to prednisolone or antibiotic-requiring exacerbation or death from day 20 to day 365. RESULTS: The trial was stopped prematurely based in lack of recruitment during the COVID-19 pandemic, this decision was endorsed by the Data and Safety Monitoring Board. Forty-nine outpatients were included in the study. There was a reduction in risk of the primary outcome in the antibiotic group compared to the control group (HR 0.51 (95%CI 0.27-0.96), p = 0.037). The incidence of admissions with exacerbation within one year was 1.1 (95%CI 0.6-1.7) in the dual antibiotic group vs. 2.9 (95%CI 1.3-4.5) in the control group, p = 0.037. CONCLUSIONS: Use of dual systemic antibiotics for 14 days against P. aeruginosa in outpatients with chronic lung diseases and no judged need for hospitalisation, improved clinical outcomes markedly. The main limitation was the premature closure of the trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03262142, registration date 2017-08-25.

Targeted AntiBiotics for Chronic pulmonary diseases (TARGET ABC): can targeted antibiotic therapy improve the prognosis of Pseudomonas aeruginosa-infected patients with chronic pulmonary obstructive disease, non-cystic fibrosis bronchiectasis, and asthma? A multicenter, randomized, controlled, open-label trial.

BACKGROUND: Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. METHODS: This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20-365 from study allocation and (ii) days alive and without exacerbation within days 20-365 from the study allocation. DISCUSSION: This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03262142 . Registered on August 25, 2017.

Tuberculosis screening among newly arrived asylum seekers in Denmark.

BACKGROUND: Tuberculosis (TB) screening programmes among asylum seekers tend to focus on chest radiography (CXR) for early diagnosis, whereas knowledge on sputum examination is limited. We evaluated active TB screening using CXR and sputum culture among asylum seekers arriving in Denmark. In addition, we assessed the coverage of a voluntary health assessment. METHODS: Between 1 February 2017 and 31 March 2019, all newly arrived asylum seekers in Denmark ≥ 18 years from TB high-incidence countries or risk groups, who attended a voluntary general health assessment, were offered active TB screening with CXR and spot sputum examination. Sputum samples were examined by culture and smear microscopy. RESULTS: Coverage of the general health assessment was 65.1%. Among 1,154 referred for active TB screening, 923 (80.0%) attended. Of these, 854 were screened by CXR and one case of active TB was identified equivalent to a yield of 0.12%. Sputum samples were collected from 758 and one M. tuberculosis culture-positive TB case (also identified by CXR) was identified, equivalent to a yield of 0.13%. No cases were found by sputum culture screening only. In addition, screening found three cases of malignant disease. CONCLUSION: We suggest that TB screening should focus on asylum seekers from TB high-incidence countries. Furthermore, early health assessments should be of high priority to ensure migrant health.

The Association between Use of ICS and Psychiatric Symptoms in Patients with COPD-A Nationwide Cohort Study of 49,500 Patients.

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified COPD, age ≥40 years, and no previous cancer. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder were assessed by Cox proportional hazards models. We observed a dose-dependent increase in the risk of antidepressant-use with ICS cumulated dose (HR 1.05, 95% CI 1.03-1.07, p = 0.0472 with low ICS exposure, HR 1.10, 95% CI 1.08-1.12, p < 0.0001 with medium exposure, HR 1.15, 95% CI 1.11-1.15, p < 0.0001 with high exposure) as compared to no ICS exposure. We found a discrete increased risk of admission to psychiatric hospitals in the medium and high dose group (HR 1.00, 95% CI 0.98-1.03, p = 0.77 with low ICS exposure, HR 1.07, 95% CI 1.05-1.10, p < 0.0001 with medium exposure, HR 1.13, 95% CI 1.10-1.15, p < 0.0001 with high exposure). The association persisted when stratifying for prior antidepressant use. Thus, exposure to ICS was associated with a small to moderate increase in antidepressant-use and psychiatric admissions.

Depressive symptoms among patients with COPD according to smoking status: a Danish nationwide case-control study of 21 184 patients.

INTRODUCTION: Depressive symptoms appear more often among patients with COPD and are associated with reduced disease control and increased mortality. Both smoking and COPD increase the risk of depressive symptoms. Whether smoking cessation among COPD patients affects the occurrence of depressive symptoms is unknown. We hypothesised that smoking cessation in patients with COPD leads to reduced use of antidepressants and fewer admissions to psychiatric hospitals with depression, anxiety or bipolar disorder. METHODS: We conducted a nationwide retrospective case-control study, in patients from The Danish Register for COPD with spirometry-verified COPD, age ≥40 years, a history of smoking and absence of cancer. Consistent smokers were matched 1:1 with ex-smokers using a propensity score model. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder both descriptively was assessed by Cox proportional hazard models. RESULTS: We included 21 184 patients. A total of 2011 consistent smokers collected antidepressant prescriptions compared with 1821 ex-smokers. Consistent smoking was associated with increased risk of filling prescription on antidepressants (HR 1.4, 95% CI 1.3-1.5, p<0.0001) and with increased risk of psychiatric hospital admission with either depression, anxiety or bipolar disorder (HR 2.0, 95% CI 1.6-2.5). The associations persisted after adjustment for former use of antidepressants. CONCLUSION: Consistent smoking among COPD patients was associated with increased use of antidepressants and admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder, compared to smoking cessation.

Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype.

α1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α1-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.

Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling.

RATIONALE: As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES: Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS: A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). MEASUREMENTS AND MAIN RESULTS: Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. CONCLUSIONS: No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

Screening for TB by sputum culture in high-risk groups in Copenhagen, Denmark: a novel and promising approach.

INTRODUCTION: Evidence on screening high-risk groups for TB by mobile X-ray in low-incidence countries is building, but knowledge on other possible screening methods is limited. In this retrospective study we report results from a community based programme screening for TB by spot sputum culture. METHODS: On seven occasions, from September 2012 through June 2014, we offered TB screening to all persons present at 11 locations where socially marginalised people gather in Copenhagen. Spot sputum samples from participants were examined by smear microscopy and culture. Genotype, nucleic acid amplification test and chest X-ray were done if TB was found. RESULTS: Among 1075 participants, we identified 36 cases of TB. Twenty-four cases (66.7%) were identified at the first screening of each participant, that is, the prevalence of TB was 2233/100 000. Thirty-five (97%) of the TB cases were culture-positive and seven (19.4%) were smear-positive. Twelve out of 21 (57.1%) cases tested were nucleic acid amplification test positive. Twenty-eight (77.8%) had chest X-ray suggestive of TB. All patients with TB started treatment, 30 (83.3%) had a successful outcome. DISCUSSION: Screening for TB by spot sputum culture is possible and a promising alternative to mobile X-ray in a community based screening programme. 22.2% did not have chest X-ray suggestive of TB and would not have been identified using mobile X-ray. Most of the TB cases were smear-negative, suggesting that they were identified at an early, less infectious stage, which is essential in order to prevent transmission and gain infection control.

Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. METHODS: The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 µM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS: Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). INTERPRETATION: Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. FUNDING: CSL Behring.

[Lung cancer screening with low dose CT requires careful consideration].

Results from the American National Lung Screening Trial (NLST) show a significant reduction in lung cancer and all-cause mortality in a high risk population screened with annual low-dose CT. Handling of pulmonary nodules, false positive tests, overdiagnosis, psychosocial consequences and cost-efficiency etc. are all aspects that require careful consideration. This paper gives an overview of the current knowledge on these issues. Before a recommendation can be made, we need an overall evaluation of both the benefits and harms in CT screening for lung cancer.

[Lung cancer screening with low-dose CT - Danish and international results].

Lung cancer is the cancer type that causes the largest number of deaths in Denmark. With advances in medical imaging and widespread use of computed tomography (CT), it is possible to detect even small abnormalities in lung tissue. This has led to a great interest in lung cancer screening with low-dose CT and launching of randomised screening trials worldwide. This paper gives an overview of the current lung cancer screening trials in Denmark and internationally and focuses on main lung cancer findings and mortality results.

Profuse coarse pulmonary nodules in a patient with lymphangioleiomyomatosis: thirty-three years of follow-up.

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by progressive cystic destruction of the lungs. We present an unusual radiological presentation of lymphangioleiomyomatosis in a patient followed for 33 years with profuse coarse lung nodules in addition to the classical cystic lesions. We believe that this report might support the case for considering LAM a low-malignant neoplasm.

CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT.

BACKGROUND: The effects of low-dose CT screening on disease stage shift, mortality and overdiagnosis are unclear. Lung cancer findings and mortality rates are reported at the end of screening in the Danish Lung Cancer Screening Trial. METHODS: 4104 men and women, healthy heavy smokers/former smokers were randomised to five annual low-dose CT screenings or no screening. Two experienced chest radiologists read all CT scans and registered the location, size and morphology of nodules. Nodules between 5 and 15 mm without benign characteristics were rescanned after 3 months. Growing nodules (>25% volume increase and/or volume doubling time<400 days) and nodules >15 mm were referred for diagnostic workup. In the control group, lung cancers were diagnosed and treated outside the study by the usual clinical practice. RESULTS: Participation rates were high in both groups (screening: 95.5%; control: 93.0%; p<0.001). Lung cancer detection rate was 0.83% at baseline and mean annual detection rate was 0.67% at incidence rounds (p=0.535). More lung cancers were diagnosed in the screening group (69 vs. 24, p<0.001), and more were low stage (48 vs 21 stage I-IIB non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC), p=0.002), whereas frequencies of high-stage lung cancer were the same (21 vs 16 stage IIIA-IV NSCLC and extensive stage SCLC, p=0.509). At the end of screening, 61 patients died in the screening group and 42 in the control group (p=0.059). 15 and 11 died of lung cancer, respectively (p=0.428). CONCLUSION: CT screening for lung cancer brings forward early disease, and at this point no stage shift or reduction in mortality was observed. More lung cancers were diagnosed in the screening group, indicating some degree of overdiagnosis and need for longer follow-up.

Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor.

Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.

The Danish randomized lung cancer CT screening trial--overall design and results of the prevalence round.

INTRODUCTION: Lung cancer screening with low dose computed tomography (CT) has not yet been evaluated in randomized clinical trials, although several are underway. METHODS: In The Danish Lung Cancer Screening Trial, 4104 smokers and previous smokers from 2004 to 2006 were randomized to either screening with annual low dose CT scans for 5 years or no screening. A history of cigarette smoking of at least 20 pack years was required. All participants have annual lung function tests, and questionnaires regarding health status, psychosocial consequences of screening, smoking habits, and smoking cessation. Baseline CT scans were performed in 2052 participants. Pulmonary nodules were classified according to size and morphology: (1) Nodules smaller than 5 mm and calcified (benign) nodules were tabulated, (2) Noncalcified nodules between 5 and 15 mm were rescanned after 3 months. If the nodule increased in size or was larger than 15 mm the participant was referred for diagnostic workup. RESULTS: At baseline 179 persons showed noncalcified nodules larger than 5 mm, and most were rescanned after 3 months: The rate of false-positive diagnoses was 7.9%, and 17 individuals (0.8%) turned out to have lung cancer. Ten of these had stage I disease. Eleven of 17 lung cancers at baseline were treated surgically, eight of these by video assisted thoracic surgery resection. CONCLUSIONS: Screening may facilitate minimal invasive treatment and can be performed with a relatively low rate of false-positive screen results compared with previous studies on lung cancer screening.