VOL.107 . SUPPL.1 . No.3 . JUNE 2016 - Prospero...

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Vol. 107 June 2016 Suppl. 1 to No. 3

Vol. 107 - Suppl. 1 to No. 3 MINERVA MEDICA III

MINERVA MEDICA

CONTENTS

1Towards a multi-dimensional approach to COPDZanforlin A., Sorino C., Sferrazza Papa G. F.

7Improving donor lung suitability: from protective strategies to ex-vivo reconditioningSolidoro P., Schreiber A., Boffini M., Braido F., Di Marco F.

12The immunobiological and clinical role of vitamin D in obstructive lung diseasesSolidoro P., Bellocchia M., Facchini F.

PNEUMOLAB PROCEEDINGS 10

Vol. 107 - Suppl. 1 to No. 3 MiNerVa Medica 1

matory process leading to tissue damage with possible systemic effects.4 Moreover, defects of the mucociliary apparatus may be respon-sible 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 exertion-al dyspnea and chronic cough, while a persis-tent airflow limitation detected with spirom-etry 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.

chronic 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. Howev-er, other factors may contribute to the devel-opment of cOPd, such as poor lung growth, respiratory infections, and airway remodel-ling.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-metallopro-teinases (MMP-6, MMP-9), C-reactive protein (CRP), interleukins (IL-1, IL-6, IL-8) and fi-brinogen. These mediators sustain the inflam-

R E V I E WP N E U M O L A B P R O C E E D I N G S 1 0

Towards a multi-dimensional approach to cOPdAlessandro 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]

anno: 2016Mese: JuneVolume: 107No: 3rivista: Minerva Medicacod rivista: Minerva Med

Lavoro: 4512-MMtitolo breve: MULTI-DIMENSIONAL APPROACH TO COPDprimo autore: ZANFORLINpagine: 1-6citazione: Minerva Med 2016;07:1-6

a B S T r a c TChronic 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 signifi-cant radiological features of respiratory disease. This commentary article focuses on the possible future role of chest im-aging, including ultrasound of the respiratory muscles, integrated with additional functional tests, such as body plethys-mography 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 imag-ing - Tomography.

Minerva Medica 2016 June;107(Suppl. 1 to No. 3):1-6© 2016 ediZiONi MiNerVa MedicaThe online version of this article is located at http://www.minervamedica.it

ZANFORLIN MULTI-DIMENSIONAL APPROACH TO COPD

2 MiNerVa Medica June 2016

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 vol-umes 11 do not assess all aspects of the disease. an increase in bronchial vascularity, expressed in terms of both number of vessels and vascu-lar area, has been demonstrated in the central airways of symptomatic smokers with normal lung function compared to healthy non-smok-ers. 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 com-bines 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 phe-notype and clinical outcome. it suggests that a multidimensional approach to cOPd, which includes other diagnostic tools, might be im-plemented in the future.

Additional lung function tests in COPD

The assessment of forced ventilator flows and volumes is pivotal for the diagnosis and follow up of obstructive lung diseases. a de-crease 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 ob-structive nature of the ventilatory defect.14 re-cently, 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 smok-ers with normal spirometry have significantly impaired exercise capacity, emphysema or air-way thickening on chest cT scan. a possible explanation of these findings is that FEV1, FVc and their ratio may be normal in the early

However, this fixed cut-off may result in un-der-diagnosis of airflow obstruction in young people and over-diagnosis in the elderly due to an age-related changes in lung function. Pro-posed strategies for reducing the misclassifica-tion 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 het-erogeneous including parenchymal destruc-tion (emphysema) and airway inflammation with mucus production (chronic bronchitis). although frequent, other effects which include respiratory muscles dysfunction and pulmo-nary 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

“Early COPD” and the “GOLD 0” stage

Subjects with smoke exposure and chronic cough with phlegm, but normal post-broncho-dilator FeV1/FVC ratio, were previously clas-sified 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 rec-ommended.8, 9 due to scanty data support-ing 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

MULTI-DIMENSIONAL APPROACH TO COPD ZANFORLIN


therapy.11 a recent paper by regan et al.16 fo-cused 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/FVC<70% and FEV1≥80% pre-dicted). This report used data from the Genetic Epidemiology of COPD (COPDGene) Study, a multi-center study aimed to identify genetic factors in cOPd and to characterize pheno-types, and their association with susceptibil-ity genes. The study enrolled a large cohort of subjects, including people with COPD of ev-ery stage of severity and control groups.20 re-gan et al. aimed to identify signs of smoking-related disease provided by clinical data and radiological pathological findings in subjects without spirometric criteria for cOPd. The cT examination was based on quantitative analy-sis of emphysema severity and air trapping.16

The study revealed that many current or former smokers without spirometric criteria for cOPd present chronic cough, dyspnea, impairment of quality of life and reduction in 6-minute walking distance, and more than a half had emphysema or signs of airways dis-ease at cT scan. Thus, authors argued that this kind of patients might be affected by smoking-related disease undetected by spirometry. The clinical question raised is whether spirometry is sufficiently accurate for the assessment of cOPd. although the diagnosis of the disease should remain simple and readily available, other tests may improve patient characteriza-tion. as an example, the radiological evalu-ation may assess an increased airway thick-ness and detect the presence of emphysema. Furthermore, more than a half of the GOLD 0 group had at least one smoking-related impair-ment and 20% of the individuals of this subset were treated with medications to relieve symp-toms.16

Future perspective of chest imaging

The study of pulmonary diseases through conventional magnetic resonance imaging (MRI) has traditionally been considered very

phases of the cOPd due to a compensation in lung emptying from normal lung units, which should mask the decrease in flow from lung re-gions 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 maxi-mal expiration. This measurement is of major importance since rV tends to increase in the early phase of emphysema and with the sever-ity 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 monox-ide (CO) has gas properties similar to oxygen with a roughly 200 higher hemoglobin affin-ity. 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. Nota-bly, the reduction of dLCO in smokers is attrib-uted to the destruction of the pulmonary capil-lary 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 dis-ease 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 diagno-sis (such as acute heart failure) and to assess comorbidities. due to high biological and eco-nomic costs, chest computed tomography (cT scan) should be executed in selected patients, in case of diagnostic doubts or in the assess-ment of emphysema for lung volume reduction



cOPd. emphysema can be estimated through cT on the basis of a qualitative interpretation and quantitative evaluation of X-ray lung tis-sue attenuation beyond a specific threshold value (e.g., 2950 Hounsfield units) or a per-centile value of the distribution (e.g., lowest 15th percentile).27 Moreover, cT may provide important phenotype information by assess-ing regional and anatomical distributions of the emphysematous findings, which allow to differentiate centrilobular, panlobular, and paraseptal emphysema. For these reasons, chest CT is of major importance for detecting changes over time or in response to therapy in longitudinal studies and interventional trials of a1-antitrypsin deficiency 28 and severe emphy-sema.29, 30

The routine clinical use of cT examinations is limited by the potential risks of radiation exposure and economic costs. To address the first limitation, X-ray dose-reduction strategies specific to thoracic imaging have been devel-oped, the most important of these is the use of iterative reconstruction methods.31

as a future perspective, it is desirable that imaging techniques could also assess regional ventilation and its changes over time and in response to bronchodilators. The provided in-sights could help to explain the heterogeneity in patient’s responses to treatment yet unde-tected by FeV1 changes.

Discussion

Several questions remains unanswered in the assessment of cOPd. Firstly, does the presence of airway obstruction (the “O” in COPD) is sufficient to characterize the dis-ease?32 Secondly, what clinical significance should be attributed to the radiologic or other functional tests alterations in subjects without airflow obstruction?

To date, there is no evidence that CT-defined emphysema corresponds to a clinical entity worthy of medical treatment.33 However, in-creasing evidence suggest that the effects of therapy for cOPd cannot be measured only through FeV1. For instance, the reduction of hyperinflation and RV is one of the main ben-

difficult due to technical challenges such as the continuous movement of the respiratory system. However, recent technical improve-ments might allow new applications for Mri in cOPd. For instance, by examining different relaxation signals that are inherent to differ-ent tissues and combining this with contrast-enhanced Mr, it is possible to differentiate inflammation 21 from smooth muscle remodel-ing, edema, or mucus deposition.21, 22 Nowa-days, the use of Mri in cOPd remains a re-search tool. However, these findings may open new horizons in this research field.

despite the innovation of considering early radiologic findings of disease in the lung and airways, regan et al.16 did not assessed respi-ratory muscles. it has been demonstrated that inspiratory muscle strength decreases with in-creasing the degree of airflow obstruction, and it also has a correlation with dyspnea, walking distance and blood gases during exercise. Thus, inspiratory muscle strength may be an impor-tant factor in assessing the disease severity and the burden of cOPd.23 Since it is a dynamic evaluation, ultrasound permits to assess respi-ratory muscles. echodensitometric changes of both inspiratory and expiratory muscles have been observed in cOPd patients compared to controls, mainly between cOPd patients with modified Medical Research Council (mMRC) dyspnea score equal to 0 (i.e. no breathless-ness) and patients with mMRC 1-3, showing a correlation between increasing muscle sclero-sis and worsening of symptoms.24 Smargiassi et al. have shown that diaphragm thickness correlates with body fat-free mass, and vari-ability of muscle thickness may be related to hyperinflation.25 Moreover, the ultrasound analysis of diaphragmatic excursion has been correlated with bronchial obstruction, showing a delayed diaphragm relaxation during forced expiration in patient with airflow obstruction.26 Such data suggest that the use of ultrasound may shed light on the difficult task of muscle testing in cOPd.

in recent years, multidetector cT measure-ments have been applied to the evaluation of lung disease, leading to a better understand-ing of the airway and tissue abnormalities of

MULTI-DIMENSIONAL APPROACH TO COPD ZANFORLIN


4. Barnes PJ. immunology of asthma and chronic obstruc-tive pulmonary disease. Nat Rev Immunol 2008;8:183-92.

5. Hogg JC. Pathophysiology of airflow limitation in chron-ic obstructive pulmonary disease. Lancet 2004;364:709-21.

6. Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. Effect of 1-yearsmoking cessation on airway inflammation in COPD andasymptomatic smokers. Eur Respir J 2005;26:835-45.

7. Sorino c, Battaglia S, Scichilone N, Pedone c, antonelli-incalzi r, Sherrill d, et al. diagnosis of airway obstruc-tion in the elderly: contribution of the Sara study. int JChron Obstruct Pulmon Dis 2012;7:389-95.

8. Brito-Mutunayagam R1, Appleton SL, Wilson DH, Ruf-fin RE, Adams RJ; North West Adelaide Cohort HealthStudy Team. Global initiative for chronic ObstructiveLung Disease stage 0 is associated with excess FEV(1)decline in a representative population sample. chest2010;138:605-13.

9. Global Initiative for Chronic Obstructive Lung Disease.Global Strategy for the diagnosis, Management, andPrevention of chronic Obstructive Pulmonary disease,NHLBI/WHO Workshop Report. Bethesda, MD: Nation-al Institutes of Health, NHLBI; 2001.

10. rabe KF, Hurd S, anzueto a, Barnes PJ, Buist Sa, cal-verley P, et al. Global initiative for chronic Obstructive Lung Disease. Global strategy for the diagnosis, manage-ment, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532-55.

11. Global Strategy for the diagnosis, Management and Pre-vention of cOPd, Global initiative for chronic Obstruc-tive Lung Disease (GOLD) 2015 [Internet]. Available at:www.goldcopd.org [cited 2016, Apr 22].

12. calabrese c, Bocchino V, Vatrella a, Marzo c, Guarino c, Mascitti S, et al. evidence of angiogenesis in bron-chial biopsies of smokers with and without airway ob-struction. Respir Med 2006;100:1415-22.

13. Verhage TL, Heijdra YF, Molema J, Daudey L, Dekhui-jzen PN, Vercoulen JH. Adequate Patient Characteriza-tion in COPD: Reasons to Go Beyond GOLD Classifica-tion. Open Respir Med J 2009;3:1-9.

14. Pellegrino r, Viegi G, Brusasco V, crapo rO, Burgos F,casaburi r, et al. interpretative strategies for lung func-tion tests. Eur Respir J 2005;26:948-68.

15. Lutchmedial SM, Creed WG, Moore AJ, Walsh RR,Gentchos GE, Kaminsky DA. How common is airflowlimitation in patients with emphysema on cT scan of thechest? Chest 2015;148:176-84.

16. Regan EA, Lynch DA, Curran-Everett D, Curtis JL, Aus-tin JH, Grenier Pa, et al. Genetic epidemiology of cOPd(COPDGene) Investigators. Clinical and radiologic dis-ease in smokers with normal spirometry. JaMa internMed 2015;175:1539-49.

17. Pellegrino r, Brusasco V. On the causes of lung hy-perinflation during bronchoconstriction. Eur Respir J1997;10:468-75.

18. Harvey BG, Strulovici-Barel Y, Kaner RJ, Sanders A,Vincent TL, Mezey JG, et al. cOPd with obstruction risk for smokers with normal spirometry/reduced diffusioncapacity. Eur Respir J 2015;46:1589-97.

19. Global Initiative for Chronic Obstructive Lung Disease.Global strategy for the diagnosis, management and pre-vention of chronic obstructive pulmonary disease: NHL-BI/WHO workshop report, updated 2005. Bethesda, MD:National Heart, Lung and Blood Institute, 2005.

20. Regan EA, Hokanson JE, Murphy JR, Make B, Lynchda, Beaty TH, et al. Genetic epidemiology of cOPd(COPDGene) study design. COPD 2010;7:32-43.

21. Vogel-claussen J1, renne J, Hinrichs J, Schönfeld c,

efits of treatment with bronchodilators, which results in a reduction of breathlessness and im-proved exercise tolerance.

Tan et al. showed that events similar to exac-erbations of cOPd (acute worsening of respi-ratory symptoms) can occur in subjects with-out spirometric evidence of cOPd or asthma and are associated with significant health and socioeconomic outcomes. This may increase the respiratory burden in the community and contribute to incorrect diagnosis of asthma or cOPd.34 On the other hand, it is worth to em-phasize that the use of a fixed FEV1/FVC ra-tio <0.70 to define airflow limitation has been associated to the risk overdiagnosis, particu-larly in the elderly.35 in the Sara cohort it was found that about 15% of healthy subjects aged >65 years may have an FeV1/FVC<0.70.7 all these findings support the utility of integrat-ing clinical, functional and imaging aspects of smoking-related lung disease. This approach should permit to identify on the one hand indi-viduals with low exposure to cigarette smoke, few symptoms, but expiratory flows close to the normal limits (risk of over-diagnosis and over-treatment); on the other hand, there are smokers, or former smokers, with respiratory symptoms and the presence of alteration at ad-ditional function test undetected at spirometry.

Conclusions

in conclusion, although cOPd is an under-diagnosed condition which requires spirometry to be confirmed, the integration of spirometry with additional functional tests, such as body plethysmography and dLCO, and chest imaging may increase patient characterization and help to identify the early stage of the disease.

References

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2. rennard Si, drummond MB. early chronic obstructivepulmonary disease: definition, assessment, and preven-tion. Lancet 2015;385:1778-88.

3. Sorino c, Scichilone N, augugliaro G, Bellia V. Mecha-nisms in chronic obstructive pulmonary disease: com-parison with asthma. Minerva Pneumol 2009;48:15-29.



augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials us-ing computed tomography densitometry. respir res 2010;11:136.

29. coxson HO, Nasute Fauerbach PV, Storness-Bliss c, Müller NL, Cogswell S, Dillard DH, Computed tomog-raphy assessment of lung volume changes after bronchial valve treatment. Eur Respir J 2008;32:1443-50.

30. Sciurba Fc, ernst a, Herth FJ, Strange c, criner GJ,Marquette cH, et al. VeNT Study research Group. arandomized study of endobronchial valves for advancedemphysema. N Engl J Med 2010;363:1233-44.

31. Coxson HO, Leipsic J, Parraga G, Sin DD. Using pul-monary imaging to move chronic obstructive pulmo-nary disease beyond FeV1. am J respir crit care Med2014;190:135-44.

32. Mannino dM, Make BJ. is it time to move beyond the“O” in early COPD? Eur Respir J 2015;46:1535-53.

33. Sorino c, d’amato M, Steinhilber G, Patella V, corsicoaG. Spirometric criteria to diagnose airway obstructionin the elderly: fixed ratio vs. lower limit of normal. Min-erva Med 2015 Jan 14. [Epub ahead of print].

34. Tan Wc, Bourbeau J, Hernandez P, chapman Kr, cowie r, FitzGerald JM, Marciniuk dd, et al.; CanCOLD Col-laborative research Group. exacerbation-like respiratory symptoms in individuals without chronic obstructive pul-monary disease: results from a population-based study.Thorax 2014;69:709-17.

35. Swanney MP, Ruppel G, Enright PL, Pedersen OF, CraporO, Miller Mr, et al. Using the lower limit of normalfor the FeV1/FVC ratio reduces the misclassification ofairway obstruction. Thorax 2008;63:1046-51.

Gutberlet M, Schaumann F, et al. Quantification of pulmonary inflammation after segmental allergen chal-lenge using turbo-inversion recovery-magnitude mag-netic resonance imaging. am J respir crit care Med 2014;189:650-7.

22. Ley-Zaporozhan J, Ley S, Kauczor HU. Proton MRI inCOPD. COPD 2007;4:55-65.

23. Kabitz HJ, Walterspacher S, Walker d, Windisch W.inspiratory muscle strength in chronic obstructive pul-monary disease depending on disease severity. clin Sci(Lond) 2007;113:243-9.

24. Makarevich AE, Lemiasheuskaya SS, Poctavcev AJ,Lemeschewskij AI, Nedvedz M. The dynamics of respi-ratory muscle changes during the progression of chron-ic obstructive pulmonary disease. adv clin exp Med2014;23:381-94.

25. Smargiassi A, Inchingolo R, Tagliaboschi L, Di MarcoBerardino a, Valente S, et al. Ultrasonographic assess-ment of the diaphragm in chronic obstructive pulmonarydisease patients: relationships with pulmonary functionand the influence of body composition - a pilot study.Respiration 2014;87:364-71.

26. Zanforlin a, Smargiassi a, inchingolo r, di Marco Be-rardino a, Valente S, ramazzina e. Ultrasound analysisof diaphragm kinetics and the diagnosis of airway ob-struction: the role of the M-mode index of obstruction.Ultrasound Med Biol 2014;40:1065-71.

27. coxson HO. Quantitative chest tomography in cOPd research: chairman’s summary. Proc am Thorac Soc 2008;5:874-7.

28. Stockley ra, Parr dG, Piitulainen e, Stolk J, StoelBC, Dirksen A. Therapeutic efficacy of a-1 antitrypsin

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: April 15, 2016. - Manuscript accepted: April 12, 2016. - Manuscript received: April 6, 2016.


quest and the offer, and the challenge of choos-ing the best donor for the best recipient still remains the main problem in managing a lung transplant waiting list. Because of these limits, a high number of potential recipients still die waiting for a transplant,1 reason why the main aim in the field is to increase the donors’ pool. in 2011, only 21% of lungs from donors were

Lung transplant is a therapeutic option forend stage lung diseases but only a limited

number of lung grafts is considered suitable for transplantation within the donors’ pool. Moreover, patients quickly deteriorating while on the waiting list cannot be bridged for long periods to lung transplant. Because of this delicate balance, the mismatch between the re-

improving donor lung suitability: from protective strategies to ex-vivo reconditioning

Paolo SOLidOrO 1 *, annia ScHreiBer 2, Massimo BOFFiNi 3, Fulvio BraidO 4, Fabiano di MarcO 5

1Unit of Pneumology, department of cardiovascular and Thoracic Surgery, città della Salute e della Scienza di Torino University Hospital, Turin, italy; 2respiratory intensive care Unit and Pulmonary rehabilitation Unit, Salvatore Maugeri Foundation, Pavia, italy; 3cardiac Surgery division, department of Surgical Sciences, città della Salute e della Scienza di Torino University Hospital, Turin, italy; 4allergy and respiratory diseases, department of internal Medicine (diMi), irccS San Martino di Genova University Hospital, Genoa, italy; 5Unit of Pneumology, department of Health Sciences, Università degli Studi di Milano, San Paolo Hospital, Milan, italy*corresponding author: Paolo Solidoro, Unit of Pneumology, department of cardiovascular and Thoracic Surgery, città della Salute e della Scienza di Torino University Hospital, c.so Bramante, 88, 10126 Turin, italy. e-mail: [email protected]

anno: 2016Mese: JuneVolume: 107No: 3rivista: Minerva Medicacod rivista: Minerva Med

Lavoro: 4513-MMtitolo breve: iMPrOViNG dONOr LUNG SUiTaBiLiTYprimo autore: SOLidOrOpagine: 7-11citazione: Minerva Med 2016;07:7-11

a B S T r a c TLung transplant is a therapeutic option for end stage lung diseases, but only a limited number of lung grafts is considered suitable for transplantation. it has been recently suggested an approach to improve and maximize donor lung suitability, namely ventilation strategies to prevent lung damage and preserve function before transplantation. in potential lung donor patients, the use of lung-protective ventilatory strategies may protect against and at least partially reverse some conditions, such as ventilator-induced lung injury, atelectasis and neurogenic pulmonary edema, resulting in improved donor organ procurement. The novelty recently proposed lies in the integration of ventilatory strategies of previous stud-ies, using an algorithmic approach for the management of potential donors, based on their clinical response and PaO2/FiO2 ratio. This approach could be further improved by using lung ultrasound (LUS) which demonstrated to be more accurate than bedside chest radiography in detecting and distinguishing different degrees of aeration loss, and could be useful in the evaluation of alveolar recruitment following the application of PeeP or after performing any recruitment maneuver. Finally, the close future is the exploration of ex-vivo reconditioning which introduces the exciting concept of both a protective ventilation and a protective perfusion, reducing the risk of ventilation associated damage, and, on the other hand, washing out potential inflammatory cytokines by low volume high oncotic pressure perfusion, managing the risk of edema by capillary leakage. addressing these challenges will allow more patients with end-stage lung disease access to a lung transplant.(Cite this article as: Solidoro P, Schreiber A, Boffini M, Braido F, Di Marco F. Improving donor lung suitability: from protec-tive strategies to ex-vivo reconditioning. Minerva Med 2016;_______)Key words: Perfusion - Lung transplantation - Respiration, artificial.

Minerva Medica 2016 June;107(Suppl. 1 to No. 3):7-11© 2016 ediZiONi MiNerVa MedicaThe online version of this article is located at http://www.minervamedica.it


SOLidOrO iMPrOViNG dONOr LUNG SUiTaBiLiTY


this risk is the measurement of the stress index at the bedside.12 anyway, this NPe scenario could not be completely corrected in vivo by ventilation and fluid management, as assessed by a low PaO2/FiO2 ratio, and the choice of an ex vivo lung perfusion (eVLP) management could be optimal in unsuccessful case to give a second chance to the donor’s lung. Thanks to EVLP, a more complete six hours’ follow-up can be applied, which allows a more complex monitoring of the status of the lung, including compliance and resistance data.

A new “protective” way: EVLP

The close future is the exploration of ex-vivo reconditioning: in fact the eVLP intro-duce the exciting concept of both a protective ventilation and a protective perfusion, reduc-ing the risk of ventilation associated damage, and, on the other hand, washing out potential inflammatory cytokines by low volume high oncotic pressure perfusion, managing the risk of edema by capillary leakage.13, 14 in addi-tion, eVLP enables re-expansion of atelectatic areas, clearance of secretions through serial bronchoscopy, clot removal with the ex vivo perfusate, maintenance of normothermic met-abolic function, and closer monitoring of the status of the lung through serial evaluations of radiographs, blood gases analysis, and lung mechanics evaluation. eVLP also holds prom-ise for pharmacologic manipulation of the lung, not only through the use of antibiotics, but also with agents aimed at enhancing fluid clearance, as well as gene therapy to promote lung repair.15

A useful algorithmic approach

in their paper, Bansal et al.7 explore an im-portant approach to improve and maximize donor lung suitability, namely ventilation strategies to prevent lung damage and pre-serve function before transplantation. Besides the already well-known effects on survival in patients with full-blown ardS,16 previous pa-pers have demonstrated the benefits of using a strategy of low-tidal volume (Vt) ventilation

transplanted.2 However, the majority of donor organs (64.4%) were deemed incompatible be-cause of lung damage that generally predates but in some instances supervenes following brain death.

Potential mechanisms of lung damage be-fore brain death include trauma, resuscitation maneuvers, mechanical ventilation, aspira-tion of blood or gastric content, pneumonia, or fluid management; after brain death lungs are at risk for the development of injury result-ing from the onset of neurogenic pulmonary edema (NPe), well recognized as a sequel of central nervous system injury, but poorly un-derstood and, perhaps, underdiagnosed.3, 4 How brain death is related to NPe is not com-pletely clear and it seems to involve complex hemodynamic and inflammatory pathways as a transient sympathetic storm associated to a sympathetic mediated alteration in pulmonary capillary permeability. The pulmonary edema is one of the most important consequences of a tissue fluid distribution up to 72% of the circu-lating blood volume after brain death.5

a review of 12.054 lung allograft recipients from the UNOS database reported similar sur-vival in recipients who received lungs that had PaO2 /FiO2 ratio <200 and recipients who re-ceived lungs with PaO2 /FiO2 ratio >300, sug-gesting that, as a single characteristic PaO2 /FiO2 ratio is not an accurate predictor of donor lung quality, recipient outcome, or both.6

Protective ventilation

a recent article 7 pointed out the role of a protective ventilation in managing potential lung donors, translating pathophysiologic con-cepts from the ardS ventilatory approach, studied both in retrospective 8-10 and prospec-tive studies.11

donor lungs, like all mechanical ventilated lungs, are at risk of developing atelectasis. Fundamental goal is preventing it by positive end-expiratory pressure (PeeP) aimed at lung recruitment. However, this beneficial effect could be associated to the risk of alveolar pres-sure related overdistention caused by exces-sive pressures. One potential way to mitigate

iMPrOViNG dONOr LUNG SUiTaBiLiTY SOLidOrO


lowing the recruitment maneuver, the venti-lator setting is returned to the prerecruitment values. as suggested by angel et al.,11 a re-cruitment maneuver is considered successful if both a persistent PaO2/FiO2 value of >300 mmHg and a significant improvement in chest radiograph findings are achieved. If neither of these conditions is satisfied, the potential do-nor is deemed unsuitable.

Ultrasounds: a new point of view

In our view, Bansal’s et al. approach could be further improved by using lung ultrasound (LUS). This emerging, non-invasive, highly repeatable, bedside technique can give real-time information on the density of the lung pe-riphery and has been demonstrated to be more accurate than bedside chest radiography in de-tecting and distinguishing different degrees of aeration loss.20, 21

In this specific setting, it would be poten-tially useful for the early detection of aeration loss, which could be relevant in relation to the subsequent development of lung injury and unsuitability of the organ.

Furthermore, by the means of an aeration and re-aeration ultrasound score (LUS Score), developed with the aim of providing quantifi-able comparable measures of changes in aera-tion, LUS may enable measurement of the de-gree of lung aeration at a precise moment and its successive changes over time (for instance, before and after treating atelectasis, pneumo-nia or pulmonary edema) thereafter monitor-ing the evolution of that specific condition.22, 23

another great potential of lung ultrasound in this setting lies in its ability to evaluate al-veolar recruitment following the application of PeeP 24 or after performing any recruitment maneuver. LUS would also enable the clini-cian to identify and treat the phenomenon of tidal recruitment, namely the repetitive open-ing and closing of collapsed alveoli during the mechanical respiratory cycle, which is a proposed dynamic mechanism of ventilator-induced lung injury (ViLi), even in previously healthy lungs.25 adding sonographic informa-tion on lung recruitment and de-recruitment to

also in patients at risk of developing ardS,17 more generally, in all critically ill patients,18 and even in patients with normal lung function following intubation.19

in potential lung donor patients, the use of lung-protective ventilatory strategies may therefore protect against and at least partially reverse some of the aforementioned condi-tions, such as ventilator-induced lung injury, atelectasis and NPe, resulting in improved do-nor organ procurement.

Basically lung-protective ventilation strat-egies — both Volume-control Ventilation (VcV) and Pressure-control Ventilation (PcV) — aim to: 1) prevent over-distension by adjusting a tidal volume of 6-8 mL/kg of ideal body weight (iBW) and a plateau pres-sure of 30 cmH2O; 2) induce and maintain al-veolar recruitment by the means of a PeeP of 8-10 cmH20; and 3) prevent oxygen toxicity by setting the FiO2 at the lowest level to keep an oxygen saturation (SpO2) of 92-95%.

as previously discussed, in a randomized controlled trial by Mascia et al. 11 protective ventilation resulted in a greater than twofold increase in the number of eligible and har-vested lungs in comparison with conventional ventilation. Other, mainly retrospective, stud-ies reported almost superimposable results.9, 10

The novelty proposed by Bansal et al. lies in the way they integrate the ventilatory strate-gies of previous studies 9-11 and propose an al-gorithmic approach for the management of po-tential donors, based on their clinical response and PaO2/FiO2 ratio.

According to Bansal’s algorithm, after start-ing standard protective ventilation with an initial FiO2 of 1.0, successive steps depend on the patient’s resultant PaO2/FiO2 ratio. if it remains >300 mmHg, FiO2should be reduced to the lowest value that permits a SpO2 of 92%-95%. On the contrary, in case of a per-sistent PaO2/FiO2 <300 mmHg and/or in the presence of atelectasis or pulmonary edema of any origin, a recruitment maneuver should be performed. Using either VcV or PcV, the ma-neuver mainly consists of maintaining a PeeP of 15 cmH2O (with a final plateau pressure <30 cmH2O) and a FiO2 of 1.0 for 2 hours. Fol-

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deemed unsuitable may be salvaged, contrib-uting to an increased procurement of lungs for transplantation.

The scarcity of donors can be faced by other different methods, all with potential disadvan-tages: the use of marginal donors, non-heart beating donors, adapting size by living lobar and split lung transplantation or by volume reduction.27 donor criteria have evolved over the years, resulting in organs that were pre-viously considered unacceptable now being commonly used. The terms “marginal” and, more recently, “extended criteria” organs are common lexicon in organ procurement. Many of these extended-criteria lungs are due to lib-eralization of acceptable prior smoking history as well as increasing acceptance of lungs from older donors.28

an exciting new approach to the organ do-nor shortage issue is the emerging science of tissue engineering and the creation of bioarti-ficial lungs. This involves repopulating a de-nuded lung matrix with stems cells, other ap-propriate cell lines, or both.29, 30

despite waxing and waning enthusiasm over the years, xenotransplantation remains just a promising approach to address the do-nor/recipient imbalance.31 a protective ven-tilation strategy to prevent lung damage and preserve function before transplantation has been proposed. LUS appears to be a promis-ing technique for improving the number of do-nor lungs suitable for lung transplantation and their outcomes. However, further studies are needed to evaluate the additional advantage of using this technique in comparison and in combination with pre-existing or future tools in this specific setting. Finally, EVLP seems to be the real bridge between the in vivo pro-tective mechanical ventilation/perfusion and other ex vivo orthotopic and bioartificial ap-proaches.

References

1. Boffini M, Ricci D, Ranieri VM, Rinaldi M. A bridgeover troubled waters. Transpl int 2015;28:284-5.

2. israni aK, Zaun da, rosendale Jd, Snyder JJ, KasiskeBL. OPTN/SrTr 2011 annual data report: deceased

Basal’s et al. approach may be useful in the further optimization of the ventilator setting and lead to more successful procurement and use of donor lungs. However, it is important to keep in mind that LUS cannot give any in-formation on alveolar over-distension. in fact, due to ultrasound reverberation phenomena, the LUS patterns of a normal and an increased air content of the lung are indistinguishable.26 Thus, the use of LUS in the management of potential lung donors appears to be a promis-ing technique for improving the number of do-nor lungs suitable for lung transplantation and their outcomes. However, further studies are needed to evaluate the additional advantage of using LUS in comparison and in combination with pre-existing or future tools in this specific setting.

Conclusions

efforts to expand the donor lung pool must be focused on both protecting potential or-gans and defining accurate preprocurement measurements of donor quality. retrospective analysis of the UNOS database suggests that suitable lungs are being discarded, and ran-domized controlled trials are needed to expand the current criteria for donor lung suitability. addressing these challenges will allow more patients with end stage lung disease access to a lung transplant. The future of lung trans-plantation appears promising, with different fields of progress. Careful management must be exercised to lower lung injury just from the moment of intubation. after brain death systemic inflammatory response can poten-tially damage the lungs. Traditionally, donor management protocols implemented by organ procurement organizations have used tidal volumes (Vt) ranging from 10 to 15 mL/kg. a changing paradigm suggests us to manage ventilation in a different way changing from a traditional patient to a potential lung donor. in fact, despite its limitations, the meta-analysis by Serpa Neto et al.17 demonstrated that lower Vt (6-8 mL/kg iBW) were associated to better clinical outcomes in patients without ardS. By this way, many of the lungs that are usually

iMPrOViNG dONOr LUNG SUiTaBiLiTY SOLidOrO


espósito dc, Pasqualucci Mde O, et al. association be-tween use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JaMa 2012;308:1651-9.

18. Lellouche F, Lipes J. Prophylactic protective ventilation:lower tidal volumes for all critically ill patients? inten-sive care Med 2013;39:6-15.

19. Futier e, constantin JM, Paugam-Burtz c, Pascal J, eurin M, Neuschwander a, et al; iMPrOVe Study Group. atrial of intraoperative low-tidal-volume ventilation in ab-dominal surgery. N engl J Med 2013;369:428-37.

20. Volpicelli G, elbarbary M, Blaivas M, Lichtenstein da,Mathis G, Kirkpatrick aW et al. international Liaisoncommittee on Lung Ultrasound (iLc-LUS) for the in-ternational consensus conference on Lung Ultrasound(icc-LUS). international evidence-based recommenda-tions for point-of-care lung ultrasound. intensive careMed 2012;38:577-91

21. Xirouchaki N, Magkanas e, Vaporidi K, Kondili e, Pla-taki M, Patrianakos a, et al. Lung ultrasound in critically ill patients: comparison with bedside chest radiography.intensive care Med 2011;37:1488-93.

22. Bouhemad B, Zhang M, Lu Q, rouby JJ. clinical review: Bedside lung ultrasound in critical care practice. critcare 2007;11:205.

23. Bouhemad B, Liu ZH, arbelot c, Zhang M, Ferarri F,Le-Guen M, et al. Ultrasound assessment of antibiotic-induced pulmonary reaeration in ventilator-associatedpneumonia. crit care Med 2010;38:84-92.

24. Bouhemad B, Brisson H, Le-Guen M, arbelot c, Lu Q,rouby JJ. Bedside Ultrasound assessment of Positiveend-

25. expiratory Pressure-induced Lung recruitment. am J respir crit care Med 2011;183:341-7.

26. Tusman G, acosta c, Nicola M, esperatti M, Bohm SH,Suarez-Sipmann F. real-time images of tidal recruitmentusing lung ultrasound. crit Ultrasound J 2015;7:19.

27. Volpicelli G. Lung Sonography. J Ultrasound Med2013;32:165-71.

28. Boffini M, Ranieri VM, Rinaldi M. Lung transplantation:is it still an experimental procedure? curr Opin crit care2010;16:53-61.

29. Taghavi S, Jayarajan S, Komaroff e, Horai T, Brann S,cordova F, et al. double-lung transplantation can besafely performed using donors with heavy smoking his-tory. ann Thorac Surg 2013;95:1912-7; discussion 1917-8.

30. Ott Hc, clippinger B, conrad c, Schuetz c, Pomer-antseva i, ikonomou L, et al. regeneration and ortho-topic transplantation of a bioartificial lung. Nat Med2010;16:927-33.

31. calle ea, Ghaedi M, Sundaram S, Sivarapatna a, Tseng MK, Niklason Le. Strategies for whole lung tissue engi-neering. ieee Trans Biomed eng 2014;61:1482-96.

32. Griesemer a, Yamada K, Sykes M. Xenotransplantation:immunological hurdles and progress toward tolerance.immunol rev 2014;258:241-58.

organ donation. am J Transplant 2013;13 Suppl 1:179-98.

3. Baumann a1, audibert G, Mcdonnell J, Mertes PM.Neurogenic pulmonary edema. acta anaesthesiol Scand2007;51:447-55.

4. Barklin A. Systemic inflammation in the brain-dead or-gan donor. acta anaesthesiol Scand 2009;53:425-35.

5. Novitzky d, Wicomb WN, rose aG, cooper dK, rei-chart B. Pathophysiology of pulmonary edema follow-ing experimental brain death in the chacma baboon. annThorac Surg 1987;43:288-94.

6. Zafar F, Khan MS, Heinle JS, adachi i, McKenzie ed,Schecter MG, et al. does donor arterial partial pressureof oxygen affect outcomes after lung transplantation? areview of more than 12,000 lung transplants. J Thoraccardiovasc Surg 2012;143:919-25.

7. Bansal r, esan a, Hess d, angel LF, Levine SM, George T, et al. Mechanical Ventilatory Support in PotentialLung donor Patients. chest 2014;146:220-7.

8. Matuschak GM. Optimizing ventilatory support of thepotential organ donor during evolving brain death: maxi-mizing lung availability for transplantation. crit careMed 2006;34:548-9.

9. angel LF, Levine dJ, restrepo Mi, Johnson S, Sakoe, carpenter a, et al. impact of a lung transplanta-tion donor-management protocol on lung donation and recipient outcomes. am J respir crit care Med 2006;174:710-6.

10. Kirschbaum ce, Hudson S. increasing organ yieldthrough a lung management protocol. Prog Transplant2010;20:28-32.

11. Mascia L, Pasero d, Slutsky aS, arguis MJ, BerardinoM, Grasso S, et al. effect of a lung protective strategyfor organ donors on eligibility and availability of lungsfor transplantation: a randomized controlled trial. JaMa 2010;304:2620-7.

12. Grasso S, Stripoli T, de Michele M, Bruno F, MoschettaM, angelelli G, et al. ardSnet ventilator protocol andalveolar hyperinflation: role of positive end-expiratorypressure. am J respir crit care Med 2007;176:761-7.

13. Boffini M, Ricci D, Barbero C, Bonato R, Ribezzo M,Mancuso e, et al. ex vivo lung perfusion increases thepool of lung grafts: analysis of its potential and realimpact on a lung transplant program. Transplant Proc2013;45:2624-6.

14. Boffini M, Ricci D, Bonato R, Fanelli V, Attisani M,ribezzo M, et al. incidence and severity of primary graftdysfunction after lung transplantation using rejectedgrafts reconditioned with ex vivo lung perfusion. eur Jcardiothorac Surg 2014;46:789-93.

15. Nathan S.d. The Future of Lung Transplantation. chest2015;147:309-16.

16. The acute respiratory distress Syndrome Network.Ventilation with lower tidal volumes as compared withtraditional tidal volumes for acute lung injury and theacute respiratory distress syndrome. N engl J Med2000;342:1301-8.

17. Serpa Neto a, cardoso SO, Manetta Ja, Pereira VG,


12 Minerva Medica June 2016

different nutrients and airway disease has been evaluated. among those, vitamin d has re-ceived particular attention, probably because of its multiple functions.

vitamin d has been shown in recent studies to play a role in asthma and cOPd pathogen-esis by acting on innate and adaptive immune system and on inflammation.

The aim of this study is to review the role of vitamin d in asthma and cOPd.

Vitamin D metabolism

vitamin d is a fat-soluble vitamin. Few foods (fatty fish, cod liver oil, eggs, etc.) con-tain it naturally, so the dietary intake of vita-

asthma and chronic obstructive pulmonarydisease (COPD) are chronic obstructive

airways diseases characterized by heightened airway inflammation, airway hyper-respon-siveness with high incidence and prevalence. it was estimated that over 300 million of peo-ple suffer from asthma 1 and, in approximately 50% of cases, the disease is not optimally con-trolled, even in developed countries. cOPd is the fourth leading cause of death worldwide, prevalence and mortality rates are still increas-ing.2 The costs of asthma and cOPd are large-ly due to uncontrolled disease, and are likely to rise as their prevalence and severity are likely to increase.

in the last years, the association between

The immunobiological and clinical role of vitamin d in obstructive lung diseases

Paolo SOLidOrO 1 *, Michela BeLLOccHia 1, Fabrizio FaccHini 2

1Pulmonary Medicine Unit, department of cardiovascular and Thoracic Surgery, città della Salute e della Scienza University Hospital, University of Turin, Turin, italy; 2Pulmonary Medicine Unit, vittorio veneto Hospital, Treviso, italy*corresponding author: Paolo Solidoro, Pulmonary Medicine Unit, department of cardiovascular and Thoracic Surgery, città dellaSalute e della Scienza University Hospital, University of Turin, c.so Bramante 88, 10126 Turin, italy. e-mail: [email protected]

anno: 2016Mese: Junevolume: 107no: 3rivista: Minerva Medicacod rivista: Minerva Med

Lavoro: 4514-MMtitolo breve: iMMUnOBiOLOGicaL and cLinicaL rOLe OF viTaMin dprimo autore: SOLidOrOpagine: 12-9citazione: Minerva Med 2016;07:12-9

a B S T r a c Tvitamin d is a fat-soluble vitamin, which is obtained by conversion of 7-dehydrocholesterol in the skin by Uv ray and by diet. its role on bone mineralization has been known for over two hundred years, while its non-skeletal effects have been acknowledged only in the last few years. The discovery of important vitamin d properties on the innate and adaptive immune system created a lot of interest in a potential role of vitamin D on diseases characterized by heightened inflam-mation and oxidative response, and impaired antimicrobial response, such as asthma and chronic obstructive pulmonary disease (COPD). Recent studies have demonstrated that vitamin D and its deficiency have a number of biological effects which are potentially important in altering the pathogenesis and severity of both asthma and cOPd. vitamin d may improve lung function and response to steroids therapy, reduce airway remodeling and disease exacerbations. The aim of this study is to review the role of vitamin d in asthma and cOPd.(Cite this article as: Solidoro P, Bellocchia M, Facchini F. The immunobiological and clinical role of vitamin d in obstructive lung diseases. Minerva Med 2016;_______)Key words: 25-hydroxyvitamin d, asthma, cOPd, treatment of asthma, treatment of cOPd, vitamin d.

Minerva Medica 2016 June;107(Suppl. 1 to No. 3):12-9© 2016 ediZiOni Minerva MedicaThe online version of this article is located at http://www.minervamedica.it


iMMUnOBiOLOGicaL and cLinicaL rOLe OF viTaMin d SOLidOrO

vol. 107 - Suppl. 1 to no. 3 Minerva Medica 13

sufficiency of vitamin D, and a level of 30 ng/ml or greater (or >75 nmol/L) as sufficient vitamin d.7 However, higher 25-hydroxy vi-tamin d levels (e.g. >100 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 de-ficiency is a health problem worldwide.

Vitamin D deficiency or insufficiency is due to an inadequate sun exposure to maintain ad-equate vitamin d,9 clothes that shield most of the skin from the sun,10 skin pigmentation, sea-son, aging, sunscreen use, and air pollution,11 obesity,12 pregnancy, and breastfeeding.13

To minimize such deficiency, in many coun-tries — 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 metab-olism has been known for over two hundred years, while in the last years the association be-tween 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 gastrecto-my, pathologies of the biliary secretion, intes-tinal bacterial pollution, kidney failure, cancer, diabetes, autoimmune disorders, hypertension, atherosclerosis, muscle weakness, and neuro-nal 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 in-vivo 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. There-fore, macrophages express a truncated, cata-bolically inactive form of 24-hydroxilase, thereby preventing catabolism of 1,25-dihy-

min d is not enough to satisfy the metabolic needs. Most of cholecalciferol or vitamin d3 is produced in the skin from 7-dehydrocholes-terol by ultraviolet B exposure. Sensible sun exposure can provide an adequate amount of vitamin d, which is stored in body fat and re-leased during the winter, when it cannot be ac-tivated by sun.3

vitamin d from the diet or dermal synthesis is biologically inactive and requires dihydrox-ylation to become a metabolic active form: 1-25-dihydroxy vitamin d, also known as cal-citriol. The first vitamin D hydroxylation oc-curs in the liver in order to produce 25-hydroxy vitamin d, also known as calcidiol. calcidiol is the stored form of vitamin d, and its systemic status is reliably indicated by the serum level of 25-hydroxyvitamin d.4 calcidiol is then con-verted by CYP27B1 (1α-hydroxylase) into the biologically-active 1-25-dihydroxy vitamin d; this reaction occurs mainly in the kidneys, but also in extrarenal sites.5 in the kidneys, cY-P27B1 expression and thus 1,25-dihydroxyvi-tamin d production are regulated by calcium, phosphorus, and their regulating hormones (including parathyroid hormone), which regu-late bone metabolism. negative feedback is provided by 1,25-dihydroxyvitamin d itself through downregulation of cYP27B1 and upregulation of CYP24A1 (24-hydroxylase), which catalyzes the first step in vitamin D catabolism, thereby preventing the excessive production of 1,25-dihydroxyvitamin d.

This vitamin form performs biologic func-tions by binding to the vitamin d receptor (VDR). VDR complex binds to specific ge-nomic sequences (vitamin d response ele-ments) in the promoter region of target genes, whereby gene expression is regulated. in this way, 1-25-dihydroxy vitamin d performs en-docrine, paracrine and autocrine functions.6

Vitamin D deficiency

although there is no universal consen-sus on the criteria for optimal serum levels of 25-hydroxyvitamin d, usually a level of 25-hydroxy vitamin d of 21 to 29 ng/mL (or 30 to 50 nmol/L) is considered a relative in-

SOLidOrO iMMUnOBiOLOGicaL and cLinicaL rOLe OF viTaMin d


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 metalloprotein-ases in monocytes and alveolar macrophages, in proliferation and activation of murine fibro-blasts and in reduction of expression of extra-cellular matrix proteins by these fibroblasts.22 These observations suggest that under TGF-beta1 stimulation, 1,25-dihydroxy vitamin d inhibits the pro-fibrotic phenotype of lung fi-broblasts and epithelial cells.

Vitamin D status, lung function and exacerbation in COPD

There are several cross-sectional and longi-tudinal studies that demonstrated the positive association between vitamin d serum levels and lung function, as assessed by forced expi-ratory volume in 1 second (FEV1);21, 23-27 while the role of vitamin d on lung function decline has been evaluated in few longitudinal stud-ies. Kunisaki et al. followed 196 continuous smokers with cOPd during 6 years and found no difference in baseline 25(OH)D levels be-tween 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 se-vere 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 Kuni-saki el al., performed in exacerbation-prone cOPd patients,28 no association was found between baseline vitamin d levels and sub-sequent risk of acute exacerbations; negative results have also been reported in a primary care setting 31 and in a London cOPd cohort.32

droxyvitamin d; in this way macrophages may maintain an overproduction of 1,25-dihy-droxyvitamin d, which could promote innate effector functions.

The active form of vitamin d has anti-in-flammatory 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 inflam-matory cytokines and chemokines, including interleukin-1β (iL-1β), IL-6, IL-8, TNF-α, and monocyte chemoattractant protein-1. in re-sponse to these inflammatory signals, neutro-phils, 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 pro-inflammatory cytokine, chemokines,14 antiap-ototic factors as well as enzyme involved in the generation of pro-inflammatory mediation such as cOX-2.15

vitamin d can reduce oxidative stress, nF-κB and p38 MaPK pathways related, by in-hibiting antiprotease activity, impairing anti-microbial defenses, increasing the release of TGF-β 16 and acting on nuclear factor erythroid 2-related factor 2 (nrf2, a transcriptional regu-lator of most antioxidant genes). These effects of vitamin d on nrf2 might also have impli-cations for the phagocytic capacity of alveolar macrophages.14

vitamin d plays a preventive role against in-fection: 1,-25-dihydroxy vitamin d increased the maturation and proliferation of monocytes into macrophages 17 and promotes the produc-tion of cathelicidin and defensin-β2, by up-regulating 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-posi-tive and -negative antibiotic-resistant strains, such as Pseudomonas and Staphylococcus aureus, and different viruses.19 They also sup-press inflammation,20 and subsequently reduce the severity of infection.

Berg et al. demonstrated that low 25-hy-droxyvitamin d serum levels were associated



120,000 iU vitamin d3) or placebo group for 1 year. vitamin d3 compared to placebo did not affect time to first moderate or severe ex-acerbation, but vitamin d3 add-on protected against moderate or severe exacerbation, in patients with cOPd with baseline 25-hy-droxyvitamin d levels lower than 50 nmol/L (i.e., 30 ng/mL).37

According to findings mentioned above, our preliminary results on 45 cOPd patients with vitamin D deficiency, supplemented with vitamin d 1000 Ui daily, suggest a decrease in acute exacerbation and hospital admission for cOPd after 1 year of vitamin d replenish-ment.38

There are two double-blind, randomized pla-cebo-controlled trials which are currently still ongoing. One is the PrecOvid multi-center intervention study that enrolled 240 cOPd patients aged 40 and above, after an exacer-bation, and randomized them in a 1:1 ratio to receive vitamin d3 16800 iU or placebo orally once a week during 1 year.39 The other one is LungviTaL study, taking place in the United States among over 20,000 participants aged 50 years or older, including a subgroup of cOPd patients, to evaluate the influences of vitamin d and marine omega-3 fatty acid supplementa-tion, on pneumonia risk, respiratory exacerba-tion episodes and lung function.40

Immunological effects of vitamin D on asthma

as showed in a recent review of the litera-ture,41 vitamin D may influence the pathogen-esis of asthma, in addition to the above men-tioned immunological effects.

during life in utero, vitamin d regulates lung growth,42 and a maternal vitamin D defi-ciency was associated, in male children, with asthma at the age of 6.43

1,25-dihydroxy vitamin d acts on adaptive immune system by inhibiting the proliferation, differentiation and production of immuno-globulins of B lymphocytes, suppressing the secretion of pro-inflammatory cytokines by cd4+ T cells, inhibiting the development and function of multiple T-helper (Th) cells, such

These results were probably due to the fact that some patients in the study were already tak-ing vitamin d supplementation at baseline for osteopenia or osteoporosis. Hence, of course, once supplemented, vitamin d levels no lon-ger reflected the underlying COPD severity. in a second analysis of a study by Kunisaki et al.28 excluding those patients taking supple-ments, Heulens et al.33 demonstrated that pa-tients 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 fre-quent disease exacerbations and hospital ad-mission for acute exacerbation of the disease independently of patients’ characteristics and comorbidities.

recently, Zhang et al. published a meta-analysis of case-control study analyzing the re-lationship of vitamin d on asthma and cOPd. It showed that vitamin D insufficiency at base-line is not associated with increased odds ra-tio 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 exacer-bations in cOPd patients. Lehouck et al. ran-domized 182 patients with moderate to very severe cOPd with history of recent exacerba-tions to receive 100,000 iU of vitamin d sup-plementation 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, hospi-talization, quality of life, and death. However, a post hoc analysis in 30 participants with se-vere vitamin D deficiency at baseline (serum vitamin D levels <10 ng/mL) showed a signifi-cant reduction in exacerbations in the vitamin d add on group.36 Similar results were found in vidico Trial: 240 cOPd patients, enrolled by 60 general practices and four acute na-tional Health Service Trust clinics in London, were randomly allocated to vitamin d3 add-on group (receiving a 2-monthly oral dose of



response and may attenuate steroid resistance. The administration of vitamin d3 to healthy in-dividuals and steroid resistance asthmatic pa-tients enhanced subsequent responsiveness to dexamethasone for induction of iL-10 by cd4 +T cells.47 in another research performed on an experimental model of steroid resistance in which dexamethasone alone did not inhibit T cell proliferation, addition of vitamin d result-ed in significant dose-manner suppression of cell proliferation, due to the increase of MaPK 1 and iL10 mrna.48

vitamin d can act in synergy with steroids, decreasing responsiveness to self and external allergens by inducing a tolerogenic dentric cell phenotype.44

Vitamin D status, lung function and exacerbation in asthma

The effect of vitamin d on asthma was analyzed by many more studies than those on cOPd. recently, a review that examined all of these studies was published.49 in this review 25 case control studies were analyzed, evalu-ating 2568 asthmatic cases and 4376 controls, that examined vitamin d intake, status as well as correlations with respiratory and atopic pa-rameters in asthma cases compared to controls; 36 cross sectional studies, involving 386,584 subjects. The results of these studies suggest that low 25-hydroxy vitamin d serum level is associated with poor control, increased exac-erbation, reduced lung function an increased medication use in asthmatics.

Lately, Zhang et al.35 published a meta-anal-ysis of case-control study analyzing the rela-tionship of vitamin d to asthma and cOPd. it showed that vitamin D insufficiency at base-line is associated with increased odds ratio of severe asthma exacerbation, and children with insufficient vitamin D levels have a slightly lower mean Fev1 compared with children with sufficient levels.

These results are interesting, but they cannot demonstrate whether the vitamin D deficiency influences asthma pathogenesis, severity and control or vice versa.

More robust information is provided by in-

as Th1,Th9, Th17, upgrading the development of regulatory t cells and promoting tolerogenic phenotype of dentric cells.44

Up today, the role of vitamin d is not es-tablished on Th2 cells: there are many stud-ies with contradictory results; research with human cord blood cells has demonstrated in-hibition of both Th1 and Th2 differentiation with 1,25–dyhidroxy-vitamin d,44 whereas in another study 45 1,25-dyhidroxy-vitamin d has decreased Th1 cytokines and has increased Th2 cytokines in stimulated peripheral blood mononuclear cells in subjects with inflamma-tory bowel disease.46

another important feature of vitamin d is the correlation with iL 10 expression. active vitamin d response elements have been iden-tified in the IL-10 gene and 1,25-dyhydroxy vitamin d serum level is associated with in-creased iL10 gene expression in the T cells of patients with steroids refractory asthma. iL-10 inhibits activation and effector function of T cells, monocytes, and macrophages. in addi-tion to these activities, iL-10 regulates growth and differentiation of B cells, nK cells, mast cells, granulocytes, dendritic cells, keratino-cytes, and endothelial cells. iL-10 plays a key role in differentiation and function of Tregs and regulates response both of T-helper 1 (Th1)-type and Th2-type. These data suggest that vitamin d serum levels may be important for asthma control.44

vitamin d has been linked to reduced risk of viral respiratory illness due to direct influence on chemokine synthesis and the alteration of growth and differentiation of airway epithelial cells. This effect takes place because vitamin d supplementation increases the secretion of cXcL8 and cXcL10 that induce thickening of the cell layers and proliferation of cytokera-tin-5-expressing cells.44

Vitamin D may also influence airway re-modeling: it suppresses bronchial airway mus-cle cells proliferation and has direct inhibitory effects on passively sensitized human airway smooth muscle cells in vitro, including inhi-bition of cell proliferation and expression of MMP-9 and adaM33.44

vitamin d is also associated with steroid



sponse but also with increased airway hyper responsiveness.53

Gupta et al.54 found that 25-hydroxy vita-min D levels were significantly lower in severe asthma than either mild asthmatics or controls, bronchodilator response and ige and inverse-ly related with airway smooth muscle mass in children with severe asthma; further low 25-hydroxy vitamin d was related with asthma exacerbation and medication usage.

at the end, there is an increasing interest in association of higher vitamin d serum level and reduction of inhaled steroids dosages, es-pecially in children.48, 55-58

Conclusions

Studies on vitamin d suggest that it has an important role in lung diseases, especially in asthma and cOPd, depending on its immuno-modulatory function. Most of clinical studies demonstrated that dietary or pharmacological supplementation should reduce exacerbations and remodeling. nutritional lack and low sun exposure in large parts of word population seem to underline the need of attention on this yet controversial topic. More studies are need-ed to confirm these findings.

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