Value of lung diffusing capacity for nitric oxide in systemic sclerosis

Giovanni Barisione, Alessandro Garlaschi, Mariaelena Occhipinti, Michele Baroffio, Massimo Pistolesi, Vito Brusasco, Giovanni Barisione, Alessandro Garlaschi, Mariaelena Occhipinti, Michele Baroffio, Massimo Pistolesi, Vito Brusasco

Abstract

A decreased lung diffusing capacity for carbon monoxide (DLCO ) in systemic sclerosis (SSc) is considered to reflect losses of alveolar membrane diffusive conductance for CO (DMCO ), due to interstitial lung disease, and/or pulmonary capillary blood volume (VC ), due to vasculopathy. However, standard DLCO does not allow separate DMCO from VC . Lung diffusing capacity for nitric oxide (DLNO ) is considered to be more sensitive to decrement of alveolar membrane diffusive conductance than DLCO . Standard DLCO and DLNO were compared in 96 SSc subjects with or without lung restriction. Data showed that DLNO was reduced in 22% of subjects with normal lung volumes and DLCO , whereas DLCO was normal in 30% of those with decreased DLNO . In 30 subjects with available computed tomography of the chest, both DLCO and DLNO were negatively correlated with the extent of pulmonary fibrosis. However, DLNO but not DLCO was always reduced in subjects with ≥ 5% fibrosis, and also decreased in some subjects with < 5% fibrosis. DMCO and VC partitioning and Doppler ultrasound-determined systolic pulmonary artery pressure could not explain individual differences in DLCO and DLNO . DLNO may be of clinical value in SSc because it is more sensitive to DMCO loss than standard DLCO , even in nonrestricted subjects without fibrosis, whereas DLCO partitioning into its subcomponents does not provide information on whether diffusion limitation is primarily due to vascular or interstitial lung disease in individual subjects. Moreover, decreased DLCO in the absence of lung restriction does not allow to suspect pulmonary arterial hypertension without fibrosis.

Trial registration: ClinicalTrials.gov NCT03601520.

Keywords: Interstitial lung disease; lung diffusing capacity for carbon monoxide; lung diffusing capacity for nitric oxide; systemic sclerosis.

Conflict of interest statement

G.B., A.G., M.B. and M.P. have no financial/nonfinancial interests to disclose; M.O. received personal fees from Imbio LLC for consultancies and a grant for Ph.D. course from Menarini Foundation; V.B. received personal fees and nonfinancial support for consultancy, given lecture, and travel reimbursement from ndd Medizintechnik.

© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Figures

Figure 1
Figure 1
Relationships between the z‐scores of lung diffusing capacity for nitric oxide (DLNO) (y‐axis) and standard (9–11 sec breath‐hold time) lung diffusing capacity for carbon monoxide (DLCO) (x‐axis) in healthy controls (asterisks) and SSc subjects. Symbols indicate subjects with spirometry and total lung capacity (TLC) > LLN5 (white), DLCO < LLN5 (light grey), and TLC < LLN5 (dark grey). Triangles indicate subjects with systolic pulmonary artery pressure (sPap) > 36 mmHg. The dashed lines indicate the LLN5 (z‐score < −1.645). The absolute values indicate the number of the total 96 test results for DLNO that fall into each quadrant (Q1–Q4).
Figure 2
Figure 2
Relationships between the z‐scores of alveolar membrane diffusive conductance for CO (DMCO) (y‐axis) and pulmonary capillary blood volume (VC) (x‐axis) in mild hyperoxia (left panel) and normoxia (right panel) in healthy controls (asterisks) and SSc subjects. Symbols indicate subjects with spirometry and total lung capacity (TLC) > LLN5 (white), DLCO < LLN5 (light grey), and TLC < LLN5 (dark grey). Triangles indicate subjects with systolic pulmonary artery pressure (sPap) > 36 mmHg. The dashed lines indicate the LLN5 (z‐score < −1.645). The absolute values indicate the number of the total 96 test results for DMCO that fall into each quadrant (Q1–Q4).
Figure 3
Figure 3
Correlations between mean lung density (g·mL−1) or fibrosis extent (% CT volume) and z‐scores of (A) forced vital capacity (FVC) and (B) TLC. Symbols indicate SSc subjects with spirometry and TLC > LLN5 (white), DLCO < LLN5 (light grey), and TLC < LLN5 (dark grey) with (n = 11) or without (n = 3) DLCO < LLN5. Triangles indicate subjects with sPap > 36 mmHg. CI95% of the best‐fit regression line is marked by dotted lines whereas horizontal dashed line indicates the 5th percentile of reference values (−1.645 z‐score).
Figure 4
Figure 4
Correlations between mean lung density (g·mL−1) or fibrosis extent (% CT volume) and z‐scores of (A) standard DLCO and (B) DLNO. Symbols indicate SSc subjects with spirometry and TLC > LLN5 (white), DLCO < LLN5 (light grey), and TLC < LLN5 (dark grey) with (n = 11) or without (n = 3) DLCO < LLN5. Triangles indicate subjects with sPap > 36 mmHg. CI95% of the best‐fit regression line is marked by dotted lines whereas horizontal dashed line indicates the 5th percentile of reference values (−1.645 z‐score).
Figure 5
Figure 5
Bland‐Altman plot of the difference between absolute values of lung diffusing capacity for CO measured in mild hyperoxia (DLCO,dual) and normoxia (DLCO,stand) (y‐axis) vs. mean DLCO value (x‐axis) in healthy controls (white circles) and SSc subjects (grey circles). The standard deviation (SD) of mean difference is bounded by the shaded area included between the horizontal dashed lines indicating 95% confidence interval (CI95%). It is noteworthy the scattered fluctuations of data around the mean value and the limits of agreement exceeding CI95% in four cases.
Figure 6
Figure 6
Bland‐Altman plots of the difference between absolute values of alveolar membrane diffusive conductance for CO (DMCO) (left panel) and pulmonary capillary blood volume (VC) (right panel) both derived in mild hyperoxia and normoxia versus their respective mean value (x‐axis) in healthy controls (white circles) and SSc subjects (grey circles). The SD of mean differences is bounded by the shaded areas included between the horizontal dashed lines indicating CI95%. It is noteworthy the scattered fluctuations of data around the mean value of the relevant parameter and the limits of agreement exceeding CI95% in six and seven cases for DMCO and VC, respectively.

References

    1. Aaron, S. D. , Dales R. E., and Cardinal P.. 1999. How accurate is spirometry at predicting restrictive impairment. Chest 115:869–873.
    1. Abramson, M. J. , Barnett A. J., Littlejohn G. O., Smith M. M., and Hall S.. 1991. Lung function abnormalities and decline of spirometry in scleroderma: an overrated danger? Postgrad. Med. J. 67:632–637.
    1. Asadi, A. K. , Sá R. C., Kim N. H., Theilmann R. J., Hopkins S. R., Buxton R. B., et al. 2015. Inhaled nitric oxide alters the distribution of blood flow in the healthy human lung, suggesting active hypoxic pulmonary vasoconstriction in normoxia. J. Appl. Physiol. 118:331–343.
    1. Asano, Y. , and Sato S.. 2015. Vasculopathy in scleroderma. Semin. Immunopathol. 37:489–500.
    1. Baldwin Ede, F. , Cournand A., and Richards D. W. Jr. 1949. Pulmonary insufficiency; a study of 39 cases of pulmonary fibrosis. Medicine (Baltimore) 28:1–25.
    1. Barisione, G. , Bacigalupo A., Brusasco C., Scanarotti C., Penco S., Bassi A. M., et al. 2014. Mechanisms for reduced pulmonary diffusing capacity in haematopoietic stem cell transplantation recipients. Respir. Physiol. Neurobiol. 194:54–61.
    1. Barisione, G. , Brusasco C., Garlaschi A., Baroffio M., and Brusasco V.. 2016. Lung diffusing capacity for nitric oxide as a marker of fibrotic changes in idiopathic interstitial pneumonias. J. Appl. Physiol. 120:1029–1038.
    1. Bohr, C. 1909. Über die spezifische Tätigkeit der Lungen bei der respiratorischen Gasaufnahme und ihr Verhalten zu der durch die Alveolarwand stattfindenden Gasdiffusion. Skandinavisches Archiv. für Physiologie 22:221–280.
    1. Borland, C. D. , and Cox Y.. 1991. Effect of varying alveolar oxygen partial pressure on diffusing capacity for nitric oxide and carbon monoxide, membrane diffusing capacity and lung capillary blood volume. Clin. Sci. 81:759–765.
    1. Borland, C. D. , and Higenbottam T. W.. 1989. A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide. Eur. Respir. J. 2:56–63.
    1. Borland, C. , Bottrill F., Jones A., Sparkes C., and Vuylsteke A.. 2014. The significant blood resistance to lung nitric oxide transfer lies within the red cell. J. Appl. Physiol. 116:32–41.
    1. Carlsen, E. , and Comroe J. H. Jr. 1958. The rate of uptake of carbon monoxide and of nitric oxide by normal human erythrocytes and experimentally produced spherocytes. J. Gen. Physiol. 42:83–107.
    1. Colombi, D. , Dinkel J., Weinheimer O., Obermayer B., Buzan T., Nabers D., et al. 2015. Visual vs fully automatic histogram‐based assessment of idiopathic pulmonary fibrosis (IPF) progression using sequential multidetector computed tomography (MDCT). PLoSOne 10:e0130653.
    1. Cotes, J. E. , Dabbs J. M., Elwood P. C., Hall A. M., McDonald A., and Saunders M. J.. 1972. Iron‐deficiency anaemia: its effect on transfer factor for the lung (diffusing capacity) and ventilation and cardiac frequency during sub‐maximal exercise. Clin. Sci. 42:325–335.
    1. Cotton, D. J. , Graham B. L., and Mink J. T.. 1990. Pulmonary diffusing capacity in adult cystic fibrosis: reduced positional changes are partially reversed by hyperoxia. Clin. Invest. Med. 13:82–91.
    1. Crapo, R. O. , Kanner R. E., Jensen R. L., and Elliott C. G.. 1988. Variability of the single‐breath carbon monoxide transfer factor as a function of inspired oxygen pressure. Eur. Respir. J. 1:573–574.
    1. Degano, B. , Soumagne T., Delaye T., Berger P., Perez T., Guillien A., et al. 2017. Combined measurement of carbon monoxide and nitric oxide lung transfer does not improve the identification of pulmonary hypertension in systemic sclerosis. Eur. Respir. J. 50:1701008 10.1183/13993003.01008-2017.
    1. Farha, S. , Laskowski D., George D., Park M. M., Tang W. H., Dweik R. A., et al. 2013. Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension. Respir. Res. 14:6 10.1186/1465-9921-14-6.
    1. Forster, R. E . 1987. Diffusion of gases across the alveolar membrane. In: Handbook of Physiology. The Respiratory System. Gas exchange. Bethesda, MD: Am. Physiol. Soc., 3, 71‐88.
    1. Galiè, N. , Hoeper M. M., Humbert M., Torbicki A., Vachiery J. L., Barbera J. A., et al. 2009. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur. Heart J. 30:2493–2537.
    1. Gattinoni, L. , Chiumello D., and Cressoni M.. 2005. Pulmonary computed tomography and adult respiratory distress syndrome. Swiss Med. Wkly 35:169–174.
    1. Gibson, Q. H. , and Roughton F. J.. 1957. The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J. Physiol. 136:507–524.
    1. Glenny, R. W. , and Robertson H. T.. 2011. Spatial distribution of ventilation and perfusion: mechanisms and regulation. Compr. Physiol. 1:375–395.
    1. Graham, B. L. , Mink J. T., and Cotton D. J.. 1985. Effect of breath‐hold time on DLCO(SB) in patients with airway obstruction. J. Appl. Physiol. 58:1319–1325.
    1. Graham, B. L. , Mink J. T., and Cotton D. J.. 2002. Effects of increasing carboxyhemoglobin on the single breath carbon monoxide diffusing capacity. Am. J. Respir. Crit. Care Med. 165:1504–1510.
    1. Greiner, S. , Jud A., Aurich M., Hess A., Hilbel T., Hardt S., et al. 2014. Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population. J. Am. Heart Assoc. 3:e001103 10.1161/jaha.114.001103.
    1. Guarnieri, G. , Zanatta E., Mason P., Scarpa M. C., Pigatto E., Maestrelli P., et al. 2015. Determinants of impairment in lung diffusing capacity in patients with systemic sclerosis. Clin. Exp. Rheumatol. 33(Suppl 91):S80–S86.
    1. Guénard, H. , Varène N., and Vaida P.. 1987. Determination of lung capillary blood volume and membrane diffusing capacity by measurement of NO and CO transfer. Respir. Physiol. 70:113–120.
    1. Guénard, H. J. , Martinot J.‐B., Martin S., Maury B., Lalande S., and Kays C.. 2016. In vivo estimates of NO and CO conductance for haemoglobin and for lung transfer in humans. Respir. Physiol. Neurobiol. 228:1–8.
    1. Hatle, L. , Angelsen B. A., and Tromsdal A.. 1981. Non‐invasive estimation of pulmonary artery systolic pressure with Doppler ultrasound. Br. Heart. J. 45:157–165.
    1. van den Hoogen, F. , Khanna D., Fransen J., Johnson S. R., Baron M., Tyndall A., et al. 2013. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 65:2737–2747.
    1. Hsia, C. C. , Chuong C. J., and Johnson R. L. Jr. 1997. Red cell distortion and conceptual basis of diffusing capacity estimates: finite element analysis. J. Appl. Physiol. 83:1397–1404.
    1. Hsia, C. C. , Wagner P. D., Dane D. M., Wagner H. E., and Johnson R. L. Jr. 2008. Predicting diffusive alveolar oxygen transfer from carbon monoxide‐diffusing capacity in exercising foxhounds. J. Appl. Physiol. 105:1441–1447.
    1. Jacobsen, S. , Halberg P., Ullman S., Høier‐Madsen M., Petersen J., Mortensen J. A., et al. 1997. A longitudinal study of pulmonary function in Danish patients with systemic sclerosis. Clin. Rheumatol. 16:384–390.
    1. Jones, R. S. , and Meade F.. 1961. A theoretical and experimental analysis of anomalies in the estimation of pulmonary diffusing capacity by the single breath method. Q. J. Exp. Physiol. Cogn. Med. Sci. 46:131–143.
    1. Kang, M. Y. , and Sapoval B.. 2016. Time‐based understanding of DLCO and DLNO. Respir. Physiol. Neurobiol. 225:48–59.
    1. Khanna, D. , Gladue H., Channick R., Chung L., Distler O., Furst D. E., et al. 2013. Recommendations for screening and detection of connective tissue disease‐associated pulmonary arterial hypertension. Arthritis Rheum. 65:3194–3201.
    1. van der Lee, I. , Zanen P., Biesma D. H., and van den Bosch J. M.. 2005. The effect of red cell transfusion on nitric oxide diffusing capacity. Respiration 72:512–516.
    1. Macintyre, N. , Crapo R. O., Viegi G., Johnson D. C., van der Grinten C. P., Brusasco V., et al. 2005. Standardisation of the single breath determination of carbon monoxide uptake in the lung. Eur. Respir. J. 26:720–735.
    1. Miller, M. R. , Hankinson J., Brusasco V., Burgos F., Casaburi R., Coates A., et al. 2005. Standardisation of spirometry. Eur. Respir. J. 26:319–338.
    1. Mukerjee, D. , St George D., Knight C., Davar J., Wells A. U., Du Bois R. M., et al. 2004. Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Rheumatology (Oxford) 43:461–466.
    1. Munkholm, M. , Marott J. L., Bjerre‐Kristensen L., Madsen F., Pedersen O. F., Lange P., et al. 2018. Reference equations for pulmonary diffusing capacity of carbon monoxide and nitric oxide in adult Caucasians. Eur. Respir. J. 19:1500677 10.1183/13993003.00677-2015
    1. O'Leary, J. M. , Assad T. R., Xu M., Farber‐Eger E., Wells Q. S., Hemnes A. R., et al. 2018. Lack of a tricuspid regurgitation Doppler signal and pulmonary hypertension by invasive measurement. J. Am. Heart Assoc. 7:e009362 10.1161/jaha.118.009362
    1. Oppenheimer, B. W. , Berger K. I., Hadjiangelis N. P., Norman R. G., Rapoport D. M., and Goldring R. M.. 2006. Membrane diffusion in diseases of the pulmonary vasculature. Respir. Med. 100:1247–1253.
    1. Overbeek, M. J. , Groepenhoff H., Voskuyl A. E., Smit E. F., Peeters J. W., Vonk‐Noordegraaf A., et al. 2008. Membrane diffusion‐ and capillary blood volume measurements are not useful as screening tools for pulmonary arterial hypertension in systemic sclerosis: a case control study. Respir. Res. 9:68 10.1186/1465-9921-9-68.
    1. Pande, J. N. , Gupta S. P., and Guleria J. S.. 1975. Clinical significance of the measurement of membrane diffusing capacity and pulmonary capillary blood volume. Respiration 32:317–324.
    1. Pellegrino, R. , Viegi G., Brusasco V., Crapo R. O., Burgos F., Casaburi R., et al. 2005. Interpretative strategies for lung function tests. Eur. Respir. J. 26:948–968.
    1. Pernot, J. , Puzenat E., Magy‐Bertrand N., Manzoni P., Gondouin A., Bourdin H., et al. 2012. Detection of interstitial lung disease in systemic sclerosis through partitioning of lung transfer for carbon monoxide. Respiration 84:461–468.
    1. Phansalkar, A. R. , Hanson C. M., Shakir A. R., Johnson R. L. Jr, and Hsia C. C.. 2004. Nitric oxide diffusing capacity and alveolar microvascular recruitment in sarcoidosis. Am. J. Respir. Crit. Care Med. 169:1034–1040.
    1. Quanjer, P. H. , Tammeling G. J., Cotes J. E., Pedersen O. F., Peslin R., and Yernault J. C.. 1993. Lung volumes and forced ventilatory flows. Report Working Party, Standardization of Lung Function Tests, European Community for Steel and Coal and European Respiratory Society. Eur. Respir. J. 6(Suppl 16):5–40.
    1. Quanjer, P. H. , Stanojevic S., Cole T. J., Baur X., Hall G. L., Culver B. H., et al. 2012. Multi‐ethnic reference values for spirometry for the 3‐95‐yr age range: the global lung function 2012 equations. Eur. Respir. J. 40:1324–1343.
    1. Roughton, F. J. , and Forster R. E.. 1957. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J. Appl. Physiol. 11:290–302.
    1. Schneider, P. D. , Wise R. A., Hochberg M. C., and Wigley F. M.. 1982. Serial pulmonary function in systemic sclerosis. Am. J. Med. 73:385–394.
    1. Schoenfeld, S. R. , and Castelino F. V.. 2015. Interstitial lung disease in scleroderma. Rheum. Dis. Clin. North Am. 41:237–248.
    1. Sivova, N. , Launay D., Wémeau‐Stervinou L., De Groote P., Remy‐Jardin M., Denis G., et al. 2013. Relevance of partitioning DLCO to detect pulmonary hypertension in systemic sclerosis. PLoS ONE 8:e78001.
    1. Spengler, M. I. , Svetaz M. J., Leroux M. B., Leiva M. L., and Bottai H. M.. 2004. Association between capillaroscopy, haemorheological variables and plasma proteins in patients bearing Raynaud's phenomenon. Clin. Hemorheol. Microcirc. 30:17–24.
    1. Stanojevic, S. , Graham B. L., Cooper B. G., Thompson B. R., Carter K. W., Francis R. W., et al. 2017. Official ERS technical standards: global Lung Function Initiative reference values for the carbon monoxide transfer factor for Caucasians. Eur. Respir. J. 50:1700010 10.1183/13993003.00010-2017
    1. Steen, V. D. , Graham G., Conte C., Owens G., and Medsger T. A. Jr. 1992. Isolated diffusing capacity reduction in systemic sclerosis. Arth. Rheumat. 35:765–770.
    1. Wanger, J. , Clausen J. L., Coates A., Pedersen O. F., Brusasco V., Burgos F., et al. 2005. Standardisation of the measurement of lung volumes. Eur. Respir. J. 26:511–522.
    1. Wilhelm, E. , Battino R., and Wilcock R. J.. 1977. Low‐pressure solubility of gases in liquid water. Chem. Rev. 77:219–262.
    1. Wilson, R. J. , Rodnan G. P., and Robin E. D.. 1964. An early pulmonary physiologic abnormality in progressive systemic sclerosis (diffuse scleroderma). Am. J. Med. 36:361–369.
    1. Yushkevich, P. A. , Piven J., Hazlett H. C., Smith R. G., Ho S., Gee J. C., et al. 2006. User‐guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. NeuroImage 31:1116–1128.
    1. Zavorsky, G. S. , and Murias J. M.. 2006. A small amount of inhaled nitric oxide does not increase lung diffusing capacity. Eur. Respir. J. 27:1251–1257.
    1. Zavorsky, G. S. , Hsia C. C., Hughes J. M., Borland C. D., Guénard H., van der Lee I., et al. 2017. Standardisation and application of the single‐breath determination of nitric oxide uptake in the lung. Eur. Respir. J. 49:1600962 10.1183/13993003.00962-2016

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe