Jan Zieliński

Residential radon and risk of lung cancer : A combined analysis of 7 north american case-control studies

Background: Underground miners exposed to high levels of radon have an excess risk of lung cancer. Residential exposure to radon is at much lower levels, and the risk of lung cancer with residential exposure is less clear. We conducted a systematic analysis of pooled data from all North American residential radon studies. Methods: The pooling project included original data from 7 North American case–control studies, all of which used long-term α-track detectors to assess residential radon concentrations. A total of 3662 cases and 4966 controls were retained for the analysis. We used conditional likelihood regression to estimate the excess risk of lung cancer. Results: Odds ratios (ORs) for lung cancer increased with residential radon concentration. The estimated OR after exposure to radon at a concentration of 100 Bq/m3 in the exposure time window 5 to 30 years before the index date was 1.11 (95% confidence interval = 1.00–1.28). This estimate is compatible with the estimate of 1.12 (1.02–1.25) predicted by downward extrapolation of the miner data. There was no evidence of heterogeneity of radon effects across studies. There was no apparent heterogeneity in the association by sex, educational level, type of respondent (proxy or self), or cigarette smoking, although there was some evidence of a decreasing radon-associated lung cancer risk with age. Analyses restricted to subsets of the data with presumed more accurate radon dosimetry resulted in increased estimates of risk. Conclusions: These results provide direct evidence of an association between residential radon and lung cancer risk, a finding predicted using miner data and consistent with results from animal and in vitro studies.

Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia.

BACKGROUND: To date only two controlled studies have been published on the effects of domiciliary oxygen treatment on survival in patients with chronic obstructive pulmonary disease (COPD) with advanced respiratory failure. The survival in such patients despite oxygen treatment remains poor. The prescription of long term oxygen therapy (LTOT) in less severe disease remains controversial. The aim of this study was to evaluate the rationale for prescribing oxygen to patients with COPD with moderate hypoxaemia. METHODS: One hundred and thirty five patients with COPD, with PaO2 7.4-8.7 kPa (56-65 mmHg) and advanced airflow limitation (mean (SD) forced expiratory volume in one second (FEV1) 0.83 (0.28) 1), were randomly allocated to a control (n = 67) and LTOT (n = 68) group. The patients were followed every three months for at least three years or until death. RESULTS: The cumulative survival rate was 88% at one year, 77% at two years, and 66% at three years. No significant differences were found in survival rates between patients treated with LTOT and controls, nor did longer oxygen use (over 15 hours per day) improve survival. Younger age, better spirometric values, and higher body mass index predicted better survival. CONCLUSIONS: Domiciliary oxygen treatment does not prolong survival in patients with COPD with moderate hypoxaemia. Airway limitation seems to determine survival in this group of patients.

A Combined Analysis of North American Case-Control Studies of Residential Radon and Lung Cancer

Cohort studies have consistently shown underground miners exposed to high levels of radon to be at excess risk of lung cancer, and extrapolations based on those results indicate that residential radon may be responsible for nearly 10–15% of all lung cancer deaths per year in the United States. However, case-control studies of residential radon and lung cancer have provided ambiguous evidence of radon lung cancer risks. Regardless, alpha-particle emissions from the short-lived radioactive radon decay products can damage cellular DNA. The possibility that a demonstrated lung carcinogen may be present in large numbers of homes raises a serious public health concern. Thus, a systematic analysis of pooled data from all North American residential radon studies was undertaken to provide a more direct characterization of the public health risk posed by prolonged radon exposure. To evaluate the risk associated with prolonged residential radon exposure, a combined analysis of the primary data from seven large scale case-control studies of residential radon and lung cancer risk was conducted. The combined data set included a total of 4081 cases and 5281 controls, representing the largest aggregation of data on residential radon and lung cancer conducted to date. Residential radon concentrations were determined primarily by α-track detectors placed in the living areas of homes of the study subjects in order to obtain an integrated 1-yr average radon concentration in indoor air. Conditional likelihood regression was used to estimate the excess risk of lung cancer due to residential radon exposure, with adjustment for attained age, sex, study, smoking factors, residential mobility, and completeness of radon measurements. Although the main analyses were based on the combined data set as a whole, we also considered subsets of the data considered to have more accurate radon dosimetry. This included a subset of the data involving 3662 cases and 4966 controls with α-track radon measurements within the exposure time window (ETW) 5–30 yr prior to the index date considered previously by Krewski et al. (2005). Additional restrictions focused on subjects for which a greater proportion of the ETW was covered by measured rather than imputed radon concentrations, and on subjects who occupied at most two residences. The estimated odds ratio (OR) of lung cancer generally increased with radon concentration. The OR trend was consistent with linearity (p = .10), and the excess OR (EOR) was 0.10 per Bq/m3 with 95% confidence limits (−0.01, 0.26). For the subset of the data considered previously by Krewski et al. (2005), the EOR was 0.11 (0.00, 0.28). Further limiting subjects based on our criteria (residential stability and completeness of radon monitoring) expected to improve radon dosimetry led to increased estimates of the EOR. For example, for subjects who had resided in only one or two houses in the 5–30 ETW and who had α-track radon measurements for at least 20 yr of this 25-yr period, the EOR was 0.18 (0.02, 0.43) per 100 Bq/m3. Both estimates are compatible with the EOR of 0.12 (0.02, 0.25) per 100 Bq/m3 predicted by downward extrapolation of the miner data. Collectively, these results provide direct evidence of an association between residential radon and lung cancer risk, a finding predicted by extrapolation of results from occupational studies of radon-exposed underground miners. E. G. Létourneau and J. B. Schoenberg have retired; J. A. Stolwijk holds an emeritus position. We acknowledge the helpful input of the following individuals who served on the International Steering Committee for the North American combined analysis: Ken Chadwick (CEC Radiation Protection Program), Susan Conrath (U.S. Environmental Protection Agency), Sarah Darby (Oxford University), Evan Douple (U.S. National Academy of Sciences), Colin Muirhead (UK National Radiation Protection Board), and Susan Rose (U.S. Department of Energy). Salary support for Drs. Field, Lynch, and Steck was provided in part by grant numbers R01 ES05653 and P30 ES05605 from the National Institute of Environmental Health Sciences, NIH and grant number R01 CA85942 from the National Cancer Institute, NIH. This research was supported by grants from the Canadian Institutes of Health Research (formerly the Medical Research Council of Canada) and the Natural Sciences and Engineering Research Council of Canada to D. Krewski, who currently holds the NSERC/SSHRC/McLaughlin Chair in Population Health Risk Assessment at the University of Ottawa. Financial support for the meetings of the Analysis Team and the Steering Committee was also provided by Health Canada and the U.S. Department of Energy. We are grateful to Dr. Huixia Jiang for assistance with the combined analysis, and to Jackie Monaghan for technical assistance in preparing this report.

Prevalence, severity and underdiagnosis of COPD in the primary care setting

Background: Chronic obstructive pulmonary disease (COPD) is a common disease with a steadily increasing prevalence and mortality. However, recent epidemiological estimates differ depending on the population studied and methods used. Aim: To investigate the prevalence, severity and burden of COPD in a primary care setting. Methods: From 4730 patients registered in a single primary care practice, all 2250 patients aged 40 years or more were invited to participate. Participants completed a questionnaire on smoking, respiratory symptoms, education and social status. A physical examination was followed by pre- and post-bronchodilator (BD) spirometry. Results: Of the eligible patients, 1960 (87%) participated. 92% of spirometric tests met the ATS criteria. Airflow limitation was demonstrated in 299 (15%) of the participants pre-BD and in 211 (11%) post-BD. COPD was diagnosed in 183 patients (9.3%). Of these patients, the degree of post-BD airflow limitation was mild in 30.6%, moderate in 51.4%, severe in 15.3% and very severe in 2.7%. Only 18.6% of these patients had previously been diagnosed with COPD; almost all of these had severe or very severe airflow limitation. As a result of the study, a diagnosis of asthma was made in 122 patients. Conclusions: The prevalence and underdiagnosis of COPD in adult patients in this primary care setting made case finding worthwhile. Large numbers of newly detected patients were symptomatic and needed treatment. Limiting investigations to smokers would have reduced the number of COPD diagnoses by 26%.

Screening for and early detection of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a substantially underdiagnosed disorder, with the diagnosis typically missed or delayed until the condition is advanced. Spirometry is the most frequently used pulmonary function test and enables health professionals to make an objective measurement of airflow obstruction and assess the degree to which it is reversible. As a diagnostic test for COPD, spirometry is a reliable, simple, non-invasive, safe, and non-expensive procedure. Early diagnosis of COPD should provide support for smoking cessation initiatives and lead to reduction of the societal burden of the disease, but definitive confirmation of both proves elusive. Despite substantial effort and investment, implementation of quality spirometry is deficient because of several hurdles and limitations, described in this Review. All in all, spirometry is recognised as the essential test for diagnosis and monitoring of COPD.

Smokers with airway obstruction are more likely to quit smoking

Background: Chronic obstructive pulmonary disease (COPD), usually caused by tobacco smoking, is one of the leading causes of morbidity and mortality. Smoking cessation at an early stage of the disease usually stops further progression. A study was undertaken to determine if diagnosis of airway obstruction was associated with subsequent success in smoking cessation, as advised by a physician. Methods: 4494 current smokers (57.4% men) with a history of at least 10 pack-years of smoking were recruited from 100 000 subjects screened by spirometric testing for signs of airway obstruction. At the time of screening all received simple smoking cessation advice. 1177 (26.2%) subjects had airway obstruction and were told that they had COPD and that smoking cessation would halt rapid progression of their lung disease. No pharmacological treatment was proposed. After 1 year all subjects were invited for a follow up visit. Smoking status was assessed by history and validated by exhaled carbon monoxide level. Results: Nearly 70% attended a follow up visit (n = 3077): 61% were men, mean (SD) age was 52 (10) years, mean (SD) tobacco exposure 30 (17) pack-years, and 33.3% had airway obstruction during the baseline examination. The validated smoking cessation rate in those with airway obstruction was 16.3% compared with 12.0% in those with normal spirometric parameters (p = 0.0003). After correction for age, sex, nicotine dependence, number of cigarettes smoked daily, and lung function, success in smoking cessation was predicted by lower lung function, lower nicotine dependence, and lower tobacco exposure. Conclusions: Simple smoking cessation advice combined with spirometric testing resulted in good 1 year cessation rates, especially in subjects with airway obstruction.

There Is No Relationship between Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea Syndrome: A Population Study

Background: Both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSAS) are common diseases. Some recent studies suggest an increased prevalence of COPD among subjects with OSAS. Objectives: The study objective was to evaluate whether there is an epidemiological relationship between COPD and OSAS in a random population sample. Materials and Methods: The study population, 356 males (53%) and 320 females, mean age 56.6 ± 8.2 years (range 41–72), was selected from a voting list for parliamentary election in Warsaw. The investigation included lung diseases and smoking history with polysomnography and spirometry. Results: OSAS was diagnosed in 76 subjects (11.3%), 59 males (8.8%) and 17 females (2.5%), mean apnea/hypopnea index (AHI) was 25.3 ± 16.1, mean overnight SaO2 92.1 ± 3.3%, minimum SaO2 76.9 ± 9.4%, and SaO2 <90% = 18.9 ± 23.9% of total sleep time. COPD was diagnosed in 72 subjects (10.7%), 39 males and 33 females. Severity of airflow limitation was assessed according to European Respiratory Society (ERS) guidelines: mild in 70%, moderate in 22%, and severe in 8%. In 7 subjects (9.2% of OSAS population, 1% of total population) OSAS and COPD overlapped. Polysomnographic variables were compared between overlap (overlap syndrome, OS) and OSAS subjects. In the OS mean AHI was 19.0 versus 25.3 in OSAS (nonsignificant), mean SaO2 89.6 versus 92.3% in OSAS (p < 0.005), and time spent in SaO2 <90% was 25.4 versus 18.2% in OSAS (p = 0.04). Conclusions: COPD in subjects with OSAS was as frequent as in the general population. In the OS group mean arterial blood saturation was lower and time spent in desaturation was longer than in OSAS. The presented data suggest a more severe course of sleep-disordered breathing in subjects with coexisting COPD.

Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP

Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHIP) on chromosome 4q31 have been strongly associated with pulmonary function levels and moderate-to-severe chronic obstructive pulmonary disease (COPD). However, whether the effects of variants in this region are related to HHIP or another gene has not been proven. We confirmed genetic association of SNPs in the 4q31 COPD genome-wide association study (GWAS) region in a Polish cohort containing severe COPD cases and healthy smoking controls (P = 0.001 to 0.002). We found that HHIP expression at both mRNA and protein levels is reduced in COPD lung tissues. We identified a genomic region located ∼85 kb upstream of HHIP which contains a subset of associated SNPs, interacts with the HHIP promoter through a chromatin loop and functions as an HHIP enhancer. The COPD risk haplotype of two SNPs within this enhancer region (rs6537296A and rs1542725C) was associated with statistically significant reductions in HHIP promoter activity. Moreover, rs1542725 demonstrates differential binding to the transcription factor Sp3; the COPD-associated allele exhibits increased Sp3 binding, which is consistent with Sp3s usual function as a transcriptional repressor. Thus, increased Sp3 binding at a functional SNP within the chromosome 4q31 COPD GWAS locus leads to reduced HHIP expression and increased susceptibility to COPD through distal transcriptional regulation. Together, our findings reveal one mechanism through which SNPs upstream of the HHIP gene modulate the expression of HHIP and functionally implicate reduced HHIP gene expression in the pathogenesis of COPD.

The European sleep apnoea database (ESADA) –report from 22 European sleep laboratories

The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 program. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5103 patients (1426 females, age 51.8±12.6 years, 79.4% with AHI≥5 events·hr−1) were included from March 15, 2007 to August 1, 2009. Morbid obesity (BMI≥35 kg·m−2) was present in 21.1% of males and 28.6% of women. Cardiovascular, metabolic, and pulmonary comorbidities were frequent (49.1, 32.9 and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 vs. 29.1±26.3 events·hour−1, p<0.0001). The ESADA is a rapidly growing multicentric patient cohort that enables unique outcome research opportunities and genotyping. The first cross sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSAS.The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 programme. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5,103 patients (1,426 females, mean±sd age 51.8±12.6 yrs, 79.4% with apnoea/hypopnoea index (AHI) ≥5 events·h−1) were included from March 15, 2007 to August 1, 2009. Morbid obesity (body mass index ≥35 kg·m−2) was present in 21.1% of males and 28.6% of females. Cardiovascular, metabolic and pulmonary comorbidities were frequent (49.1%, 32.9% and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 versus 29.1±26.3 events·h−1, p<0.0001). The ESADA is a rapidly growing multicentre patient cohort that enables unique outcome research opportunities and genotyping. The first cross-sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSA.

The adequacy of oxygenation in COPD patients undergoing long-term oxygen therapy assessed by pulse oximetry at home

It is probable that some daily activities may cause marked falls in arterial oxygen saturation (SaO2) in patients undergoing long-term oxygen therapy (LTOT), despite good oxygenation at rest. We estimated the adequacy of LTOT in 34 randomly selected chronic obstructive pulmonary disease (COPD) patients at home by monitoring SaO2 continuously over 24 h. The subjects were also asked to complete a questionnaire listing frequent daily activities. Despite almost normal mean SaO2 (94%) at the beginning of recording (O2 2 l.min-1, at rest) the subjects studied spent 6.9 h below an SaO2 of 90%, with minimum SaO2 of 61%. On average we observed 10 episodes of desaturation in each patient over 24 h, both while breathing air and oxygen. The comparison of SaO2 recordings and questionnaires revealed the highest number of desaturations during sleep, followed by naps, watching the television, eating, washing and talking. The oxygen flow rate prescribed, based on blood gas measurements at rest, did not protect 85% of the patients studied from deep falls in SaO2 during daily life. An increase oxygen flow during some activities and during sleep is suggested.