J.W.J. Lammers

Management of Lung Nodules Detected by Volume CT Scanning

BACKGROUND The use of multidetector computed tomography (CT) in lung-cancer screening trials involving subjects with an increased risk of lung cancer has highlighted the problem for the clinician of deciding on the best course of action when noncalcified pulmonary nodules are detected by CT. METHODS A total of 7557 participants underwent CT screening in years 1, 2, and 4 of a randomized trial of lung-cancer screening. We used software to evaluate a noncalcified nodule according to its volume or volume-doubling time. Growth was defined as an increase in volume of at least 25% between two scans. The first-round screening test was considered to be negative if the volume of a nodule was less than 50 mm(3), if it was 50 to 500 mm(3) but had not grown by the time of the 3-month follow-up CT, or if, in the case of those that had grown, the volume-doubling time was 400 days or more. RESULTS In the first and second rounds of screening, 2.6% and 1.8% of the participants, respectively, had a positive test result. In round one, the sensitivity of the screen was 94.6% (95% confidence interval [CI], 86.5 to 98.0) and the negative predictive value 99.9% (95% CI, 99.9 to 100.0). In the 7361 subjects with a negative screening result in round one, 20 lung cancers were detected after 2 years of follow-up. CONCLUSIONS Among subjects at high risk for lung cancer who were screened in three rounds of CT scanning and in whom noncalcified pulmonary nodules were evaluated according to volume and volume-doubling time, the chances of finding lung cancer 1 and 2 years after a negative first-round test were 1 in 1000 and 3 in 1000, respectively. (Current Controlled Trials number, ISRCTN63545820.)

Severity of obstructive airway disease and risk of osteoporotic fracture

The use of inhaled corticosteroids has been associated with a dose-related increased risk of fracture. This may be related to systemic absorption. However, several studies have found that patients with more severe reductions in pulmonary function had reduced bone mineral density, independent of inhaled corticosteroids. The objective of this study was to evaluate the relationship between disease severity and fracture risk. A large case–control study (108,754 cases) was conducted using data from the UK General Practice Research Database. It was found that higher doses of inhaled corticosteroids were associated with greater risks of fracture. The crude odds ratio of fracture among patients exposed to >1,600 μg beclomethasone equivalents per day was 1.95 (95% confidence interval (CI) 1.68–2.27). When adjustments were made for disease severity and use of bronchodilators, the initial dose–response relationship between inhaled corticosteroids and fracture risk disappeared (adjusted odds ratio of 1.19 (95% CI 1.01–1.41)). In conclusion, patients with severe obstructive airway disease are at risk of fracture. However, adequate adjustment for disease severity is essential when the association between the use of inhaled corticosteroids and risk of osteoporotic fracture is studied in observational research.

CT-quantified emphysema in male heavy smokers: association with lung function decline

Background Emphysema and small airway disease both contribute to chronic obstructive pulmonary disease (COPD), a disease characterised by accelerated decline in lung function. The association between the extent of emphysema in male current and former smokers and lung function decline was investigated. Methods Current and former heavy smokers participating in a lung cancer screening trial were recruited to the study and all underwent CT. Spirometry was performed at baseline and at 3-year follow-up. The 15th percentile (Perc15) was used to assess the severity of emphysema. Results 2085 men of mean age 59.8 years participated in the study. Mean (SD) baseline Perc15 was −934.9 (19.5) HU. A lower Perc15 value correlated with a lower forced expiratory volume in 1 s (FEV1) at baseline (r=0.12, p<0.001). Linear mixed model analysis showed that a lower Perc15 was significantly related to a greater decline in FEV1 after follow-up (p<0.001). Participants without baseline airway obstruction who developed it after follow-up had significantly lower mean (SD) Perc15 values at baseline than those who did not develop obstruction (−934.2 (17.1) HU vs −930.2 (19.7) HU, p<0.001). Conclusion Greater baseline severity of CT-detected emphysema is related to lower baseline lung function and greater rates of lung function decline, even in those without airway obstruction. CT-detected emphysema aids in identifying non-obstructed male smokers who will develop airflow obstruction.

N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease

The aim of this study was to evaluate the effect of oral N‐acetylcysteine in the prevention of re-hospitalisation for chronic obstructive pulmonary disease (COPD) exacerbations. Using the PHARmacoMOrbidity linkage (PHARMO) system the authors included all patients aged ≥55 yrs who had been dispensed medication, labelled for respiratory indications (anatomical therapeutic chemical (ATC) classification system: R03), between 1986–1998 and who had also been hospitalised for COPD (International Classification of Diseases (ICD)‐9: 491, 492, 496) in this time frame. These subjects were subsequently divided into two groups, those who had received N‐acetylcysteine following discharge from their first admission between 1986–1998 and those who had not. All the patients were studied starting from their initial discharge, until their first readmission, death or end of data collection period. The maximum follow-up period was 1 yr. A total of 1,219 patients, who were hospitalised for COPD between 1986–1998, were included in this study. After adjustment for disease severity, it was observed that the use of N‐acetylcysteine was significantly associated with a reduced risk of readmission. The readmission risk was significantly lower in patients with high average daily doses of N‐acetylcysteine. In conclusion it was observed that N‐acetylcysteine reduces the risk of re-hospitalisation for chronic obstructive pulmonary disease by ∼30% and that this risk reduction is dose-dependent.

Use of inhaled and oral glucocorticoids, severity of inflammatory disease and risk of hip/femur fracture: a population-based case-control study

Background.  Patients using higher dosages of inhaled or oral glucocorticoids (GCs) have an increased risk of hip/femur fractures. The role of the underlying disease in the aetiology of this increased risk has not been widely studied.

Quantitative Computed Tomography in COPD: Possibilities and Limitations

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is characterized by chronic airflow limitation. Unraveling of this heterogeneity is challenging but important, because it might enable more accurate diagnosis and treatment. Because spirometry cannot distinguish between the different contributing pathways of airflow limitation, and visual scoring is time-consuming and prone to observer variability, other techniques are sought to start this phenotyping process. Quantitative computed tomography (CT) is a promising technique, because current CT technology is able to quantify emphysema, air trapping, and large airway wall dimensions. This review focuses on CT quantification techniques of COPD disease components and their current status and role in phenotyping COPD.

CT-quantified emphysema distribution is associated with lung function decline

Emphysema distribution is associated with chronic obstructive pulmonary disease. It is, however, unknown whether computed tomography (CT)-quantified emphysema distribution (upper/lower lobe) is associated with lung function decline in heavy (former) smokers. 587 male participants underwent lung CT and pulmonary function testing at baseline and after a median (interquartile range) follow-up of 2.9 (2.8–3.0) yrs. The lungs were automatically segmented based on anatomically defined lung lobes. Severity of emphysema was automatically quantified per anatomical lung lobe and was expressed as the 15th percentile (Hounsfield unit point below which 15% of the low-attenuation voxels are distributed (Perc15)). The CT-quantified emphysema distribution was based on principal component analysis. Linear mixed models were used to assess the association of emphysema distribution with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), FEV1 and FVC decline. Mean±sd age was 60.2±5.4 yrs, mean baseline FEV1/FVC was 71.6±9.0% and overall mean Perc15 was -908.5±20.9 HU. Participants with upper lobe-predominant CT-quantified emphysema had a lower FEV1/FVC, FEV1 and FVC after follow-up compared with participants with lower lobe-predominant CT-quantified emphysema (p=0.001), independent of the total extent of CT-quantified emphysema. Heavy (former) smokers with upper lobe-predominant CT-quantified emphysema have a more rapid decrease in lung function than those with lower lobe-predominant CT-quantified emphysema.

Nitric oxide diffusing capacity versus spirometry in the early diagnosis of emphysema in smokers

The diffusion capacity for nitric oxide (DLNO) is independent of pulmonary capillary blood volume and equals the membrane diffusing capacity. Therefore the DLNO could be more sensitive in detecting alveolar destruction than the DLCO. We measured flow-volumes curves, DLNO, DLCO, the transfer coefficients KNO (DLNO/VA) and KCO (DLCO/VA) and performed computed tomography (CT) scans in 263 randomly selected heavy smokers. Subjects with areas > or =1% of the total lung volume showing an attenuation <-950 Hounsfield Units were considered to have emphysema. In 36 subjects emphysema was diagnosed with CT, a low KNO was present in 94 subjects, and in 95 subjects a FEV1/FVC ratio <70% was seen. The area under the ROC curve for detection CT-based emphysema was 0.894 for the KNO, 0.822 for the KCO and 0.795 for FEV1/FVC, meaning that the KNO has a slightly higher sensitivity to detect emphysema than the KCO and FEV1/FVC. The positive predictive value of KNO however was low (34.7%), while the negative predictive value of KNO was very high (98.2%), indicating an emphysema exclusion test. The DLNO/DLCO ratio is significantly higher in the study group compared to normal subjects.

Association of the transfer coefficient of the lung for carbon monoxide with emphysema progression in male smokers

A decreased transfer coefficient of the lung for carbon monoxide (KCO) is associated with emphysema. We evaluated whether in heavy smokers, baseline KCO was associated with the progression of computed tomography (CT)-detected emphysema, and the progression of airflow limitation. Heavy smokers, mean±sd 41.3±18.7 pack-yrs, participating in a lung cancer screening trial underwent diffusion testing and CT scanning of the lungs. CT scanning was repeated after median (25th–75th percentile) 2.8 (2.7–3.0) yrs and emphysema was assessed by lung densitometry using the 15th percentile. The association between KCO at baseline with progression of emphysema and lung function decline was assessed by multiple linear regression, correcting for baseline CT-quantified emphysema severity and forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), age, height, body mass index, pack-yrs and smoking status (current or former smoker). 522 participants aged 60.1±5.4 yrs were included. Mean±sd 15th percentile was -938±19, absolute FEV1/FVC was 71.6±9% and KCO was 1.23±0.25, which is 81.8±16.5% of predicted. By interpolation, a one sd (0.25) lower KCO value at baseline predicted a 1.6 HU lower 15th percentile and a 0.78% lower FEV1/FVC after follow-up (p<0.001). A lower baseline KCO value is independently associated with a more rapid progression of emphysema and airflow limitation in heavy smokers.

Blinded and uniform cause of death verification in a lung cancer CT screening trial

Disease-specific mortality is the final outcome of a lung cancer screening trial, therefore cause of death verification is crucial. The use of death certificates for this purpose is debated because of bias, inaccurate completion and incorrect ante mortem diagnoses. A cause of death evaluation process was designed to ensure a uniform and unbiased determination of the graduation of certainty that lung cancer was the underlying cause of death. An independent clinical expert committee will review the medical files of all deceased participants once diagnosed with lung cancer and will make use of a flow chart and predetermined criteria. A pilot study of fifty cases was conducted to determine the performance of this process and to compare the outcome with the official death certificates. The independent review has shown an agreement of 90% (kappa 0.65), which demonstrates a uniform classification. The sensitivity and specificity of the death certificates for lung cancer specific mortality were 95.2 and 62.5%. This demonstrates a limited distinctive character of the death certification process in lung cancer patients. Our results imply that the final outcome of a lung cancer screening trial cannot reliably be established without predetermined criteria and an independent review of blinded cases.