Obstructive Lung Disease Linked to Occupational Exposures in Malawian Tobacco Farmers.

Nicotine and pesticide exposure in agricultural settings have been linked to the development of chronic respiratory disease in workers. However, this has not been extensively studied in Africa. The aim of this study was therefore to determine the prevalence of obstructive lung disease and its relationship to concurrent nicotine and pesticide exposure among small-scale tobacco farmers in Malawi. For this purpose, sociodemographic characteristics, occupational and environmental exposures were evaluated in relation to work-related respiratory symptoms and lung function impairment. A cross-sectional study was conducted enrolling 279 workers in flue-cured tobacco farms in Zomba, Malawi. The study instruments used for assessing the health outcomes were a standardised European Community Respiratory Health Survey II (ECRHS) questionnaire and Spirometry testing. The questionnaires were aimed at collecting relevant data on sociodemographic factors and self-reported respiratory health outcomes. Data were also collected on potential pesticide and nicotine exposures. Spirometry was done to evaluate objective respiratory impairment in accordance with American Thoracic Society guidelines. The mean age of participants was 38 years with 68% being male. The prevalence of work-related ocular nasal symptoms, chronic bronchitis, and work-related chest symptoms was 20%, 17%, and 29%, respectively. Airflow limitation (FEV1/FVC <70%) was found in 8% of workers. Self-reported exposure to pesticides varied from 72%- to 83%, whilst the prevalence of recent green tobacco sickness was 26%. Tasks linked to nicotine exposure, such as sowing (OR: 2.5; CI 1.1-5.7) and harvesting (OR: 2.6; CI 1.4-5.1), were significantly associated with work-related chest symptoms. Pesticide application (OR:1.96; CI 1.0-3.7) was associated with an increased risk of work-related oculonasal symptoms. Duration of pesticide exposure was also associated with obstructive impairment FEV1/FVC

Dietary phenotype and advanced glycation end-products predict WTC-obstructive airways disease: a longitudinal observational study.

BACKGROUND: Diet is a modifier of metabolic syndrome which in turn is associated with World Trade Center obstructive airways disease (WTC-OAD). We have designed this study to (1) assess the dietary phenotype (food types, physical activity, and dietary habits) of the Fire Department of New York (FDNY) WTC-Health Program (WTC-HP) cohort and (2) quantify the association of dietary quality and its advanced glycation end product (AGE) content with the development of WTC-OAD. METHODS: WTC-OAD, defined as developing WTC-Lung Injury (WTC-LI; FEV1 < LLN) and/or airway hyperreactivity (AHR; positive methacholine and/or positive bronchodilator response). Rapid Eating and Activity Assessment for Participants-Short Version (REAP-S) deployed on 3/1/2018 in the WTC-HP annual monitoring assessment. Clinical and REAP-S data of consented subjects was extracted (7/17/2019). Diet quality [low-(15-19), moderate-(20-29), and high-(30-39)] and AGE content per REAP-S questionnaire were assessed for association with WTC-OAD. Regression models adjusted for smoking, hyperglycemia, hypertension, age on 9/11, WTC-exposure, BMI, and job description. RESULTS: N = 9508 completed the annual questionnaire, while N = 4015 completed REAP-S and had spirometry. WTC-OAD developed in N = 921, while N = 3094 never developed WTC-OAD. Low- and moderate-dietary quality, eating more (processed meats, fried foods, sugary drinks), fewer (vegetables, whole-grains),and having a diet abundant in AGEs were significantly associated with WTC-OAD. Smoking was not a significant risk factor of WTC-OAD. CONCLUSIONS: REAP-S was successfully implemented in the FDNY WTC-HP monitoring questionnaire and produced valuable dietary phenotyping. Our observational study has identified low dietary quality and AGE abundant dietary habits as risk factors for pulmonary disease in the context of WTC-exposure. Dietary phenotyping, not only focuses our metabolomic/biomarker profiling but also further informs future dietary interventions that may positively impact particulate matter associated lung disease.

Characteristics in Stages of Change and Decisional Balance among Smokers: The Burden of Obstructive Lung Diseases (BOLD)-Australia Study.

Smoking cessation remains a health promotion target. Applying the Transtheoretical Model to Australian Burden of Obstructive Lung Diseases (BOLD) data, we examined differences in stages of change (SoC) and readiness to quit decisional behaviours. Factors were identified likely to influence readiness of smokers, ≥40 years old, to quit. Analysis was restricted to current smokers classified to one of three stages: pre-contemplation (PC), contemplation (C) or preparation (P) to quit. Their ability to balance positive and negative consequences was measured using decisional balance. Among 314 smokers, 43.0% females and 60.8% overweight/obese, the distribution of SoC was: 38.1% PC, 38.3% C and 23.5% P. Overweight/obesity was associated with readiness to quit in stages C and P and there were more negative than positive attitudes towards smoking in those stages. Males were significantly heavier smokers in PC and C stages. Females used smoking cessation medication more frequently in PC stage, were more embarrassed about smoking and had greater negative reinforcements from smoking. Age started smoking and factors related to smoking history were associated with readiness to quit and increased the odds of being in stage C or P. An overweight/obese smoker was likely to be contemplating or preparing to quit. In these stages, smokers have more negative attitudes toward smoking. Starting smoking later, taking advice on cessation from health providers and using quit medications indicate increased readiness to quit. Evaluating these factors in smokers and developing cessation gain-framed messages may prove useful to healthcare providers.

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

PURPOSE OF REVIEW: Hundreds of millions of people worldwide are exposed to arsenic via contaminated water. The goal of this study was to identify whether arsenic-associated lung function deficits resemble obstructive- or restrictive-like lung disease, in order to help illuminate a mechanistic pathway and identify at-risk populations. RECENT FINDINGS: We recently published a qualitative systematic review outlining the body of research on arsenic and non-malignant respiratory outcomes. Evidence from several populations, at different life stages, and at different levels of exposure showed consistent associations of arsenic exposure with chronic lung disease mortality, respiratory symptoms, and lower lung function levels. The published review, however, only conducted a broad qualitative description of the published studies without considering specific spirometry patterns, without conducting a meta-analysis, and without evaluating the dose-response relationship. We searched PubMed and Embase for studies on environmental arsenic exposure and lung function. We performed a meta-analysis using inverse-variance-weighted random effects models to summarize adjusted effect estimates for arsenic and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Across nine studies, median water arsenic levels ranged from 23 to 860 µg/L. The pooled estimated mean difference (MD) comparing the highest category of arsenic exposure (ranging from > 11 to > 800 µg/L) versus the lowest (ranging from < 10 to < 100 µg/L) for each study for FEV1 was - 42 mL (95% confidence interval (CI) - 70, - 16) and for FVC was - 50 mL (95% CI - 63, - 37). Three studies reported effect estimates for FEV1/FVC, for which there was no evidence of an association; the pooled estimated MD was 0.01 (95% CI - 0.005, 0.024). This review supports that arsenic is associated with restrictive impairments based on inverse associations between arsenic and FEV1 and FVC, but not with FEV1/FVC. Future studies should confirm whether low-level arsenic exposure is a restrictive lung disease risk factor in order to identify at-risk populations in the USA.

Occupational exposures to solvents and metals are associated with fixed airflow obstruction.

Objectives This study investigated the associations between occupational exposures to solvents and metals and fixed airflow obstruction (AO) using post-bronchodilator spirometry. Methods We included 1335 participants from the 2002-2008 follow-up of the Tasmanian Longitudinal Health Study. Ever-exposure and cumulative exposure-unit (EU) years were calculated using the ALOHA plus job exposure matrix (JEM). Fixed AO was defined as post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) <0.7 and FEV 1/FVC

Astragalin Inhibits Allergic Inflammation and Airway Thickening in Ovalbumin-Challenged Mice.

Lung inflammation and oxidative stress are the major contributors to the development of obstructive pulmonary diseases. Macrophages are involved in pulmonary inflammation and alveolar damage in emphysema. Astragalin is an anti-inflammatory flavonoid present in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited inflammatory cell infiltration induced by 20 µM H2O2 and blocked airway thickening and alveolar emphysema induced by 20 µg of ovalbumin (OVA) in mice. OVA induced mouse pulmonary MCP-1, and H2O2 enhanced the expression of MCP-1/ICAM-1/αv integrin in bronchial airway epithelial BEAS-2B cells. Such induction was inhibited by supplying 10-20 mg/kg of astragalin to OVA-challenged mice and 1-20 µM astragalin to oxidant-stimulated cells. Oral administration of 20 mg/kg of astragalin reduced the induction of F4/80/CD68/CD11b in airways of mice challenged with OVA. Additionally, emphysema tissue damage was observed in OVA-exposed alveoli. Mast cell recruitment in the airway subepithelium was blocked by supplementing astragalin to OVA-challenged mice. Orally treating 20 mg/kg of astragalin reduced α-SMA induction in inflammation-occurring airways and appeared to reverse airway thickening and constriction induced by an OVA episode. These results revealed that astragalin may improve airway thickening and alveolar destruction with blockade of allergic inflammation in airways. Therefore, astragalin may be a therapeutic agent antagonizing asthma and obstructive pulmonary diseases.

Obstructive pulmonary function impairment among Korean male workers exposed to organic solvents, iron oxide dust, and welding fumes.

We evaluated spirometric obstructive pulmonary function impairment among workers who were occupationally exposed to organic solvents, iron oxide dust, or welding fumes. Data were collected from records of periodic health examinations of workers. In total, 448 Korean male workers were enrolled and classified into three exposure groups: exposure to organic solvents, iron oxide dust, or welding fumes. Logistic regression analysis was performed to evaluate the association between occupational exposure and pulmonary function. Compared to exposure to organic solvents, exposure to iron oxide dust was significantly associated with obstructive pulmonary function impairment (odds ratio [OR], 9.61; 95% confidence interval [CI], 2.20-41.97). The group exposed to welding fumes did not show a significantly higher OR compare to those exposed to organic solvents (OR, 2.83; 95% CI, 0.74-10.8). These results suggest that exposure to iron oxide dust has a greater association with obstructive pulmonary function impairment than exposure to organic solvents or welding fumes.

Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice.

The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P < .001). Survival proportions were significantly increased in GLP-1R agonist-treated mice (P < .01). SFTPB and SFTPA were down-regulated and the expression of inflammatory cytokines were increased in mice with obstructive lung disease, but levels were largely unaffected by GLP-1R agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression.

Perinatal exposure to nicotine and implications for subsequent obstructive lung disease.

Many diseases are due to gene-environment or epigenetic-environment interactions resulting in a change in the program that controls tissue structure and function. Changes in the in utero and external environment during perinatal development due to parental smoking, or nicotine exposure, may reduce the capacity of the offspring to protect themselves against environmental stressors. Nicotine is genotoxic and also induces reactive oxygen species [ROS] production. It also reduces the antioxidant capacity of the lung. The lungs of the offspring are therefore developing in an environment of an oxidant-antioxidant imbalance with the concomitant adverse effects of the oxidants and nicotine on cell integrity. Consequently, they are more prone to develop respiratory diseases such as asthma and emphysema later in life. The use of NRT by pregnant or lactating females is therefore not an appropriate strategy to quit smoking.

Parenchymal and airway diseases caused by asbestos.

PURPOSE OF REVIEW: The extensive industrial use of asbestos for many decades has been linked to development of benign and malignant pleuropulmonary disease. This review summarizes newer evidence and ongoing controversies that exist in the literature regarding asbestos-related parenchymal and airway diseases. RECENT FINDINGS: Asbestosis represents a significant respiratory problem despite the improvement in the workplace hygiene and a decrease in use of asbestos. The management of asbestosis remains challenging as currently there is no specific treatment. The role of asbestos exposure alone as a cause of chronic airway obstruction remains uncertain. The relationship between lung cancer and asbestos exposure alone and in combination with smoking has also been investigated. The benefit of screening for asbestos-related pleuropulmonary disease remains uncertain as does the use of computed tomography scanning for the purpose of screening. SUMMARY: Future studies will help clarify the clinical issues and shape screening strategies for asbestos-exposed individuals.

Occupational exposure and pulmonary function of jute mill workers in Sunsari, Nepal.

Most workers of building, pottery, timber, food and mine industries suffer from non-specific lung diseases and ventilatory disorders. There are many such industries operative in Sunsari, Nepal and so far no study has been reported on pulmonary function of jute mill workers of this region, who are also exposed to dust as other workers in similar types of industries. A brief clinical sheet regarding age, occupational particulars, smoking habits and presence or absence of respiratory symptoms was recorded for each worker. Spirometric parameters were recorded using an electronic spirometer. The group consisted of 95 male workers with mean age 28.43 +/- 7.58 yrs, weight 53.77 +/- 8.70 kg and height 164.83 +/- 6.82 cm. The study indicated an overall reduction in FVC, FEV1, PEFR, FEF25-75% and MVV. FEV1/FVC was within the normal range. Further division of workers into smokers and non-smokers, showed comparatively more decline in PEFR, FEF 25.0-75.0% and FEV1/ FVC in smokers. From this study, it can be concluded that exposure of jute dust leads to combined types of spirometric deficit revealing restrictive or obstructive diseases.

Cigarette smoking and diffuse lung disease.

Cigarette smoke, a toxic collection of more than 4000 chemicals generated from combustion of tobacco plant leaves, is known to cause several respiratory ailments, including chronic bronchitis, emphysema and lung cancer, and is associated with an increase in respiratory infections. In addition, cigarette smoking is considered a principal aetiological factor responsible for the development of certain diffuse interstitial and bronchiolar lung diseases, namely respiratory bronchiolitis-interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP) and adult pulmonary Langerhans' cell histiocytosis (PLCH). Although not exclusively seen in cigarette smokers, substantial clinical and epidemiological data support a central role for smoking as the primary causative agent of most RB-ILD, DIP and PLCH. Additional evidence in support of cigarette smoke as a primary aetiological agent in RB-ILD, DIP and PLCH is the observation that smoking cessation may lead to disease improvement, while recurrence of these disorders has been observed to occur in the transplanted lung upon re-exposure to tobacco smoke. Furthermore, histopathological changes of respiratory bronchiolitis, DIP and PLCH (with or without co-existent emphysema) may be found on lung biopsy in the same individual, implicating smoking as a common inciting agent of these diverse lesions. Recent studies also suggest a role for cigarette smoking as a potential co-factor in the development of acute eosinophilic pneumonia, usual interstitial pneumonia and rheumatoid arthritis-associated interstitial lung disease. In the current review, we propose a novel classification that takes into account the complex relationship between cigarette smoking and diffuse lung diseases. Investigation on the role of smoking as a potential causative factor or modifier of these diverse diffuse lung diseases is important, as smoking cessation utilizing state-of-the-art tobacco cessation efforts should be a central part of therapy, while pharmacotherapy with corticosteroids or other immune modifying agents should be reserved for selected patients.

Pulmonary function abnormalities and airway irritation symptoms of metal fumes exposure on automobile spot welders.

BACKGROUND: Spot or resistance welding has been considered less hazardous than other types of welding. Automobile manufacturing is a major industry in Taiwan. Spot and arc welding are common processes in this industry. The respiratory effects on automobile spot welders exposed to metal fumes are investigated. METHODS: The cohort consisted of 41 male auto-body spot welders, 76 male arc welders, 71 male office workers, and 59 assemblers without welding exposure. Inductivity Coupled Plasma Mass Spectrophotometer (ICP-MS) was applied to detect metals' (zinc, copper, nickel) levels in the post-shift urine samples. Demographic data, work history, smoking status, and respiratory tract irritation symptoms were gathered by a standard self-administered questionnaire. Pulmonary function tests were also performed. RESULTS: There were significantly higher values for average urine metals' (zinc, copper, nickel) levels in spot welders and arc welders than in the non-welding controls. There were 4 out of 23 (17.4%) abnormal forced vital capacity (FVC) among the high-exposed spot welders, 2 out of 18 (11.1%) among the low-exposed spot welders, and 6 out of 130 (4.6%) non-welding-exposed workers. There was a significant linear trend between spot welding exposure and the prevalence of restrictive airway abnormalities (P = 0.036) after adjusting for other factors. There were 9 out of 23 (39.1%) abnormal peak expiratory flow rate (PEFR) among high-exposed spot welders, 5 out of 18 (27.8%) among the low-exposed spot welders, and 28 out of 130 (21.5%) non-welding-exposed workers. There was a borderline significant linear trend between spot welding exposure and the prevalence of obstructive lung function abnormalities (P = 0.084) after adjusting for other factors. There was also a significant dose-response relationship of airway irritation symptoms (cough, phlegm, chronic bronchitis) among the spot welders. Arc welders with high exposure status also had a significant risk of obstructive lung abnormalities (PEFR reduction). There was also a significant dose-response relationship of airway irritation symptoms (cough, phlegm, chest tightness, and chronic bronchitis) among the arc welders. CONCLUSIONS: These findings suggest that restrictive and obstructive lung abnormalities, and airway irritation symptoms are associated with spot and arc welding exposures.

The role of alveolar macrophages in the pathogenesis of recurrent airway obstruction in horses.

When challenged with allergens and pro-inflammatory agents, such as Aspergillus fumigatus (AF), hay dust solution (HDS) and lipopolysaccharide (LPS), the innate immune response will not only activate the immune system but also increase the amount of pro-inflammatory cytokines in the bronchoalveolar space. The aim of this study was to assess the response of equine alveolar macrophages to different aerosolized challenges and to investigate the differences in this response between horses susceptible or nonsusceptible to recurrent airway obstruction (RAO). Seven susceptible and 5 nonsusceptible horses were challenged with saline, LPS, HDS, or AF, and bronchoalveolar lavage (BAL) cytology, total cell counts, and lung function were assessed. In addition, alveolar macrophages were isolated 6 and 24 hours after challenge, and macrophage mRNA expression of tumor necrosis factor (TNF)-alpha and interleukins (IL) IL-1beta, IL-6, IL-8, and IL-10 were measured by means of real-time (RT) polymerase chain reaction (PCR). There was a significant difference in lung function, neutrophil ratios, and total cell counts in the bronchoalveolar lavage fluid between RAO-susceptible and nonsusceptible horses. In addition, the expression of TNF-alpha, IL-1beta, and IL-8 by alveolar macrophages after challenges were higher in susceptible horses, than in nonsusceptible horses. In contrast, I1-6, considered an anti-inflammatory cytokine, showed a higher expression in nonsusceptible horses 6 hours after inhalation challenge with allergens and pro-inflammatory antigens. These data suggest that the differences between susceptible and nonsusceptible horses to RAO are not only dependent on adaptive immunity but also start with an innate immune response.

A novel orally active inhibitor of HLE.

Human leukocyte elastase (HLE) is a serine proteinase, capable of degrading a variety of structural matrix proteins. SSR69071 2-[(4-isopropyl-6-methoxy-1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methoxy]-9-(2-piperidin-1-ylethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one was selected as a novel orally active HLE inhibitor for treatment of chronic obstructive pulmonary diseases, asthma, emphysema, cystic fibrosis and several inflammatory diseases (WO 01/44245 A1) (J. Pharm. Exp. Ther., submitted for publication).

Drug-induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration.

BACKGROUND: Sustained-release bupropion is commonly used for the symptomatic relief of depressive illness and as an adjuvant in smoking cessation therapy. OBJECTIVE: To report a case of bupropion-induced drug rash with eosinophilia and systemic symptoms syndrome, including acute hepatitis, obstructive lung disease, and myositis. METHODS: After the patient discontinued use of bupropion, serologic tests, muscle biopsies, pulmonary function tests, a chest x-ray examination, venous Doppler ultrasounds, and an electrocardiogram were performed. RESULTS: On discontinuation of bupropion and prolonged systemic corticosteroid therapy, there was complete resolution of symptoms. CONCLUSIONS: To our knowledge, this is the first reported case of drug rash with eosinophilia and systemic symptoms syndrome induced by bupropion therapy. We report this case to notify clinicians of the potential serious multisystem complications that can occur with sustained-release bupropion therapy.

Role of underlying pulmonary obstruction in short-term airway response to metal working fluid exposure: a reanalysis.

BACKGROUND: Among epidemiologic studies that found evidence for associations between exposures to metal working fluids (MWF) and pulmonary function impairments, one found effects restricted to workers with fixed obstruction at baseline. We reanalyzed a previously published study on MWF exposure and cross-shift pulmonary function to further evaluate this finding. METHODS: Pulmonary function was measured cross-shift on Monday and Friday in 131 male automotive workers. Quantitative personal MWF exposure data were available. Those with an FEV(1)/FVC ratio of

Pulmonary function of workers exposed to ammonia: a study in the Eastern Province of Saudi Arabia.

To determine the effect of chronic exposure to ammonia on pulmonary function among ammonia workers, 77 workers were randomly selected from an ammonia factory in the Eastern Province of Saudi Arabia and 355 were selected as controls from the administrative staffs of four industrial groups in Eastern Province. Spirometry was carried out and FEV1, FVC, and FEV1/FVC% were calculated. The ammonia level in the working environment was determined spectrophotometrically. 30% of the air samples had ammonia concentrations that exceeded the threshold limit value. Significant reductions in FEV1 % predicted and FVC % predicted were observed in ammonia workers exposed to higher cumulative ammonia levels (above 50 mg/m3-years). FEV1% predicted and FEV1/FVC% were significantly lower in symptomatic than in asymptomatic workers in the exposed group. These findings may raise the possibility that exposure to a high cumulative ammonia level produces a combined restrictive/obstructive ventilatory defect.

Evaluation of diffusing capacity in patients with a restrictive lung disease.

BACKGROUND: In healthy volunteers, the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) decreases and DLCO normalized per liter alveolar volume (VA; DLCO/VA) increases if VA is decreased. We hypothesized that comparison of DLCO/VA with its predicted value at predicted total lung capacity (TLC) will result in an underestimation of the diffusion disorder in patients with a restrictive lung disease, if a similar relationship exists between DLCO/VA and lung volume as found in healthy volunteers. OBJECTIVE: To test this hypothesis, we studied total gas transfer DLCO and DLCO/VA as functions of VA in patients who developed a restrictive lung disease and a diffusion disorder in a short period of time. DESIGN: An observational survey. SETTING: Pulmonary function department. PATIENTS: Thirteen patients without any initial pulmonary pathology who developed the mentioned pulmonary pathology due to bleomycin treatment. INTERVENTIONS: Bleomycin treatment. MEASUREMENTS AND RESULTS: We performed the single-breath test at various VA levels before, during, and after bleomycin treatment. In the majority of the patients, the DLCO vs VA relationship remained parabolic, but shifted downwards during therapy. Therefore, the linear DLCO/VA vs VA relationship shifted downwards, while the negative slope was not changed, indicating the development of a decreased gas transfer. Six patients also developed a volume restriction. CONCLUSIONS: The agreement of the data with the hypothesis increased its probability. Consequently, to evaluate a diffusion disorder, DLCO/VA at a lower actual TLC of patients with a lung restriction should be compared to a reference DLCO/VA at a lung volume equal to the actual TLC.