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MINERVA MEDICA Vol. 107

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CONTENTS

PNEUMOLAB PROCEEDINGS 10

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Towards a multi-dimensional approach to COPD Zanforlin A., Sorino C., Sferrazza Papa G. F.

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Improving donor lung suitability: from protective strategies to ex-vivo reconditioning Solidoro P., Schreiber A., Boffini M., Braido F., Di Marco F.

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The immunobiological and clinical role of vitamin D in obstructive lung diseases Solidoro P., Bellocchia M., Facchini F.

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MINERVA MEDICA

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© 2016 EDIZIONI MINERVA MEDICA The online version of this article is located at http://www.minervamedica.it

Minerva Medica 2016 June;107(Suppl. 1 to No. 3):1-6

REVIEW PNEUMOLAB PROCEEDINGS 10

Towards a multi-dimensional approach to COPD Alessandro ZANFORLIN  1  *, Claudio SORINO  2, Giuseppe F. SFERRAZZA PAPA  3 1Multidisciplinary Medical Department, San Luca Hospital, Trecenta, Rovigo, Italy; 2Department of Internal Medicine, University of Palermo, V. Cervello Hospital, Villa Sofia Hospitals, Palermo, Italy; 3Respiratory Unit, San Paolo Hospital, Dipartimento Scienze della Salute, Università degli Studi di Milano, Milan, Italy

*Corresponding author: Alessandro Zanforlin, Multidisciplinary Medical Department, San Luca Hospital, Viale Prof. U. Grisetti 265, Trecenta, 45027 Rovigo, Italy. E-mail: [email protected]

A B S T RAC T Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality worldwide. Clinical features of the disease include exertional dyspnea and chronic cough, while persistent airflow obstruction detected at spirometry is the defining element of the disease. Notably, subjects with smoke exposure and symptoms, but normal FEV1/FVC ratio (previously classified as “stage 0” by the GOLD classification), are not considered affected and do not require treatment according to guidelines. The recent GeneCOPD study suggested that a proportion of this population might present significant radiological features of respiratory disease. This commentary article focuses on the possible future role of chest imaging, including ultrasound of the respiratory muscles, integrated with additional functional tests, such as body plethysmography and diffusing capacity for carbon monoxide of the lungs (DLCO), in a multidimensional assessment of COPD. (Cite this article as: Zanforlin A, Sorino C, Sferrazza Papa GF. Towards a multi-dimensional approach to COPD. Minerva Med 2016;107:1-6) Key words: Chronic obstructive pulmonary disease - Plethysmography - Tobacco smoke pollution - Diagnostic imaging - Tomography.

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hronic obstructive pulmonary disease (COPD) is the third leading cause of mortality worldwide.1 This disease is mainly related to excessive lung damage by cigarette smoking and other noxious particles. However, other factors may contribute to the development of COPD, such as poor lung growth, respiratory infections, and airway remodelling.2 Chronic airway inflammation induced by the inhaled irritants is a key characteristic of COPD.3 This involve the accumulation of neutrophils, CD8+ T lymphocytes, B cells and macrophages, and the release of mediators such as tumour necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), matrix-metalloproteinases (MMP-6, MMP-9), C-reactive protein (CRP), interleukins (IL-1, IL-6, IL-8) and fibrinogen. These mediators sustain the inflam-

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matory process leading to tissue damage with possible systemic effects.4 Moreover, defects of the mucociliary apparatus may be responsible for the accumulation of inflammatory exudates in the lumen of airways.5 Smoking cessation may reduce the lung function decline, but in COPD patients there is a persistent airway inflammation also after quitting smoking.6 Clinical features of COPD include exertional dyspnea and chronic cough, while a persistent airflow limitation detected with spirometry is the functional hallmark of the disease. For many years, a post-bronchodilator forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) ratio lower than 0.70 has been used as criterion to establish the presence of an obstructive ventilatory defect.

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ZANFORLIN

MULTI-DIMENSIONAL APPROACH TO COPD

However, this fixed cut-off may result in under-diagnosis of airflow obstruction in young people and over-diagnosis in the elderly due to an age-related changes in lung function. Proposed strategies for reducing the misclassification of COPD comprise the use of the lower limit of normal (LLN) for FEV1/FVC, defined as the fifth percentile of a healthy reference population, or different FEV1/FVC thresholds for different age and gender groups (e.g, 0.65 in men and 0.67 in women after 65 years of age).7 The effects of smoking on the lungs are heterogeneous including parenchymal destruction (emphysema) and airway inflammation with mucus production (chronic bronchitis). Although frequent, other effects which include respiratory muscles dysfunction and pulmonary vascular remodeling are less known. However, a global patient evaluation, which takes in consideration also these aspects, may improve the assessment of the disease. Although simple spirometry remains the key test to confirm the diagnosis, other tests may be important to better characterize the disease. They comprise lung volumes measurement with body plethysmography, evaluation of lung diffusion capacity for carbon monoxide (DLCO), assessments of exercise capacity and health status, while also chest imaging may have a role evaluating the disease.2

was associated with smoking cessation and lower FEV1 decline), 39.8% remained stable (this group was associated in particular with persistent smoking, depressive symptoms and highest FEV1 decline), while 1.4% evolved in COPD. The measurement of lung flows and volumes 11 do not assess all aspects of the disease. An increase in bronchial vascularity, expressed in terms of both number of vessels and vascular area, has been demonstrated in the central airways of symptomatic smokers with normal lung function compared to healthy non-smokers. This suggest that angiogenic processes may occur in the airways of smokers without a direct relationship with airway obstruction.12 Moreover, the severity of airway obstruction may not correctly identify disease stages and guide different treatments.13 For this reason, the updated GOLD guidelines introduced a new method of assessing COPD which combines the severity of airflow obstruction with symptoms and rate of exacerbations.11 This is a first attempt to differentiate therapy in subjects with similar lung spirometry, but different phenotype and clinical outcome. It suggests that a multidimensional approach to COPD, which includes other diagnostic tools, might be implemented in the future.

“Early COPD” and the “gold 0” stage

The assessment of forced ventilator flows and volumes is pivotal for the diagnosis and follow up of obstructive lung diseases. A decrease of the FEV1/VC ratio below the LLN is the expression of a reduction in the speed at which the lungs empty and defines the obstructive nature of the ventilatory defect.14 Recently, Lutchmedial et al.15 found that among patients with emphysema on CT scan, only 86% had airway obstruction according to the lower limit of normal of FEV1/FVC. On this ground, Regan et al.16 found that many smokers with normal spirometry have significantly impaired exercise capacity, emphysema or airway thickening on chest CT scan. A possible explanation of these findings is that FEV1, FVC and their ratio may be normal in the early

Subjects with smoke exposure and chronic cough with phlegm, but normal post-bronchodilator FEV1/FVC ratio, were previously classified as “stage 0” by the GOLD document. Such individuals were not considered affected, but at risk of developing COPD. Thus, drug treatment was not suggested for this group, while smoking cessation was strongly recommended.8, 9 Due to scanty data supporting the evolution of the GOLD 0 stage into COPD, this group was removed from GOLD document in 2007.10 A recent large population study  8 found a GOLD 0 stage prevalence of 17%. At follow-up (mean 3.5 years), 58.8% of subjects resolved to no symptoms (this group

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Additional lung function tests in COPD

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ZANFORLIN

phases of the COPD due to a compensation in lung emptying from normal lung units, which should mask the decrease in flow from lung regions with low constant time. The above mentioned studies highlight that spirometry has intrinsic limitations that may be overcome through the combined use of other functional tests. Body plethysmography permits to assess the residual volume (RV), the gas remaining in the lung at the end of a maximal expiration. This measurement is of major importance since RV tends to increase in the early phase of emphysema and with the severity of COPD due to loss or lung elastic recoil, airway closure, or stiffness of the chest wall.17 While spirometry measures ventilation, the DLCO assesses gas exchanges. Carbon monoxide (CO) has gas properties similar to oxygen with a roughly 200 higher hemoglobin affinity. CO uptake is regulated by the conductance properties of the alveolar-capillary membrane and capillary blood volume. Thus, a reduction in DLCO may be caused by any affection of these components. The test is standardized and it should be used in the clinical assessment of obstructive and restrictive lung diseases. Notably, the reduction of DLCO in smokers is attributed to the destruction of the pulmonary capillary bed and alveoli, which is the main feature of emphysema.5 Recently, Harvey et al.18 on a cohort of smokers with normal spirometry found that among those with low DLCO, 22% developed COPD, whereas only 3% developed obstruction among those with normal DLCO. In conclusion, in the clinical suspicion of the disease DLCO seems to be sensitive to detect early emphysema. The role of imaging in COPD assessment Imaging techniques are mainly static and have a marginal role in the diagnosis of COPD. Chest X-ray is useful for differential diagnosis (such as acute heart failure) and to assess comorbidities. Due to high biological and economic costs, chest computed tomography (CT scan) should be executed in selected patients, in case of diagnostic doubts or in the assessment of emphysema for lung volume reduction

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therapy.11 A recent paper by Regan et al.16 focused on the clinical and radiological features of smokers with a normal post-broncodilator FEV1/FVC ratio.19 This group, corresponding to the above mentioned “GOLD 0” stage, has been compared with never smokers and GOLD 1 group (FEV1/FVC100  nmol/l) have been suggested to be necessary for optimal immune function and respiratory outcomes.8 By these definitions, it has been estimated that 1 billion people worldwide have vitamin D deficiency or insufficiency,6 so 25-hydroxy vitamin D deficiency is a health problem worldwide. Vitamin D deficiency or insufficiency is due to an inadequate sun exposure to maintain adequate vitamin D,9 clothes that shield most of the skin from the sun,10 skin pigmentation, season, aging, sunscreen use, and air pollution,11 obesity,12 pregnancy, and breastfeeding.13 To minimize such deficiency, in many countries — but not in Italy — many kinds of food and drinks are available which are fortified with vitamin D. The role of vitamin D in the bone metabolism has been known for over two hundred years, while in the last years the association between vitamin D deficiency and a lot of disease has been described, such as: malabsorption due to chronic inflammatory bowel disease, celiac enteropathy, total or subtotal gastrectomy, pathologies of the biliary secretion, intestinal bacterial pollution, kidney failure, cancer, diabetes, autoimmune disorders, hypertension, atherosclerosis, muscle weakness, and neuronal disorders has been reported.6 Many studies have been demonstrating the role of vitamin D in airway disease. Immunological effects of vitamin D on COPD As recently published, many in-vitro and invivo studies suggest a potential involvement of vitamin D in numerous pathogenic processes in respiratory disease.14 The biologically active form of vitamin D is produced in the lungs by airway epithelial cells, macrophages, and neutrophils, which express both α1-hydroxilase and VDR. Therefore, macrophages express a truncated, catabolically inactive form of 24-hydroxilase, thereby preventing catabolism of 1,25-dihy-

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SOLIDORO IMMUNOBIOLOGICAL AND CLINICAL ROLE OF VITAMIN D

droxyvitamin D; in this way macrophages may maintain an overproduction of 1,25-dihydroxyvitamin D, which could promote innate effector functions. The active form of vitamin D has anti-inflammatory effects due to inhibition of NF-κB and mitogen-activated protein kinase (MAPK) activity. NF-κB and MAPK activity lead to the enhanced secretion of a number of inflammatory cytokines and chemokines, including interleukin-1β (IL-1β), IL-6, IL-8, TNF-α, and monocyte chemoattractant protein-1. In response to these inflammatory signals, neutrophils, monocytes, and T lymphocytes rapidly migrate into the lungs and further promote the inflammatory response. Hence, 1,25 vitamin D decrease the inflow of inflammatory cells producing the decreased expression of proinflammatory cytokine, chemokines,14 antiapototic factors as well as enzyme involved in the generation of pro-inflammatory mediation such as COX-2.15 Vitamin D can reduce oxidative stress, NFκB and p38 MAPK pathways related, by inhibiting antiprotease activity, impairing antimicrobial defenses, increasing the release of TGF-β 16 and acting on nuclear factor erythroid 2-related factor 2 (Nrf2, a transcriptional regulator of most antioxidant genes). These effects of vitamin D on Nrf2 might also have implications for the phagocytic capacity of alveolar macrophages.14 Vitamin D plays a preventive role against infection: 1,-25-dihydroxy vitamin D increased the maturation and proliferation of monocytes into macrophages 17 and promotes the production of cathelicidin and defensin-β2, by upregulating their transcription.18 These peptides are produced by several cell types in the lungs such as airway epithelial cells, macrophages and neutrophils. Cathelicidin and defensin-β2 are very effective in killing both Gram-positive and -negative antibiotic-resistant strains, such as Pseudomonas and Staphylococcus aureus, and different viruses.19 They also suppress inflammation,20 and subsequently reduce the severity of infection. Berg et al. demonstrated that low 25-hydroxyvitamin D serum levels were associated

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with the severity of computed tomography– defined emphysema.21 This might be because vitamin D plays a critical role in tissue repair and remodeling: 1,25-dihydroxy vitamin D has been showed a potential inhibitory effect in expression of several matrix metalloproteinases in monocytes and alveolar macrophages, in proliferation and activation of murine fibroblasts and in reduction of expression of extracellular matrix proteins by these fibroblasts.22 These observations suggest that under TGFbeta1 stimulation, 1,25-dihydroxy vitamin D inhibits the pro-fibrotic phenotype of lung fibroblasts and epithelial cells. Vitamin D status, lung function and exacerbation in COPD There are several cross-sectional and longitudinal studies that demonstrated the positive association between vitamin D serum levels and lung function, as assessed by forced expiratory volume in 1 second (FEV1);21, 23-27 while the role of vitamin D on lung function decline has been evaluated in few longitudinal studies. Kunisaki et al. followed 196 continuous smokers with COPD during 6 years and found no difference in baseline 25(OH)D levels between patients with rapid and slow decline in FEV1.28 This is in contrast to the findings of a large population-based study, where lower 25(OH)D levels were associated with faster decline in FEV1 in 1647 COPD patient,29 and to a community-based sample of 626 elderly men followed for 20 years, the combination of current smoking and vitamin D deficiency was significantly associated with a faster decline in FEV1.26 Finally, Persson et al. showed that severe vitamin D deficiency was associated with the decline in lung function.30 The role of vitamin D on acute exacerbation of the disease is still debated. In a secondary analysis of a prospective cohort study of Kunisaki el al., performed in exacerbation-prone COPD patients,28 no association was found between baseline vitamin D levels and subsequent risk of acute exacerbations; negative results have also been reported in a primary care setting 31 and in a London COPD cohort.32

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These results were probably due to the fact that some patients in the study were already taking vitamin D supplementation at baseline for osteopenia or osteoporosis. Hence, of course, once supplemented, vitamin D levels no longer reflected the underlying COPD severity. In a second analysis of a study by Kunisaki et al.28 excluding those patients taking supplements, Heulens et al.33 demonstrated that patients with vitamin D levels below 10 ng/mL had the shortest time to first exacerbation and experienced the highest number of COPD acute exacerbation. Similar positive results were observed in our study,34 where severe vitamin D deficiency was related to more frequent disease exacerbations and hospital admission for acute exacerbation of the disease independently of patients’ characteristics and comorbidities. Recently, Zhang et al. published a metaanalysis of case-control study analyzing the relationship of vitamin D on asthma and COPD. It showed that vitamin D insufficiency at baseline is not associated with increased odds ratio of COPD exacerbation.35 The vitamin D add on has recently demonstrated effects on disease control. To date, two double-blind, randomized placebo-controlled trials were performed to analyze the effect of vitamin D supplementation on the incidence of exacerbations in COPD patients. Lehouck et al. randomized 182 patients with moderate to very severe COPD with history of recent exacerbations to receive 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year. They did not show significant differences among two groups in the median time to first exacerbation, exacerbation rates, FEV1, hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency at baseline (serum vitamin D levels