Nitrogen leaching in multiple breathing and structural changes in the bronchopulmonary system in adult patients with cystic fibrosis

The aim of this work was to assess the functional and structural disorders of the bronchopulmonary system detected by high-resolution computed tomography (HRCT) in adult patients with cystic fibrosis (CF), and to determine the correlation between them.

Methods. A cross-sectional study included patients with CF (n = 54: 20 male and 34 female; median age 25 years) and healthy volunteers (n = 32: 12 male, 20 female; median age 25 years). A complex study of the pulmonary function test (PFT) was carried out; it included spirometry, bodyplethysmography and measurement of the diffusing lung capacity for carbon monoxide (DLCO), nitrogen leaching in multiple respiration (NLMR) and HRCT. Dyspnea was assessed using the Modified Research Council Scale (mMRC). NLMR measurements were performed using the Easy-One Pro module, MBW (NDD Medizintechnik AG, Switzerland). Analysis of HRCT data according to the Bhalla classification was performed by two independent, experienced radiologists.

Results. The mean value (± SD) of the forced expiratory volume for 1 second (FEV1) was 63 ± 26% of the proper value, forced vital capacity of the lungs (FVC) was 86 ± 20% of the proper value, the ratio of FEV1/FVC was 61 ± 15%; residual lung volume (RLV) was 220 ± 71% of the proper value, the ratio of RLV/ total lung capacity (TLC) was 48 ± 13%, intrathoracic gas volume was 150 ± 33% of the proper value, DLCO was 80 ± 16% of the proper value, lung clearance index (LCI) was 16.9 ± 5.0; moment ratio (MR2) was 54.7 ± 34.1. Bronchoectases with predominant lesions of > 9 segments and bronchial lesions from V generation and more distal were found in all patients. Peribronchial infiltration and mucoid plugs were also diagnosed in almost all patients (94 and 96%, respectively), while bronchogenic cysts or abscesses, atelectasis/consolidation, bullae or emphysema were rarely detected (in 30, 35, 20, and 17% of cases, respectively). The parameters of NLMR were statistically significantly correlated with both the PFT parameters and the HRTC data.

Conclusion. In adult patients with CF, there is a significant unevenness of pulmonary ventilation, progressing as structural damage to the bronchopulmonary system increases and the PFT worsens. With a statistically significant increase in MR, the involvement of not only the central, but also peripheral airways in the pathological process is emphasized. It has been established that in adult CF patients there is a strong correlation between LCI and the severity of structural changes, detected by HRCT, comparable in strength and significance to FEV1. 

1. Krasovskiy S.A., Chernyak A.V., Amelina E.L. et al. [Survival trends of cystic fibrosis patients in Moscow and Moscow region in 1992–2001 and 2002–2011]. Pul'monologiya. 2012; (3): 79–86. DOI: 10.18093/0869-0189-2012-0-3-79-86 (in Russian).

2. Kashirskaya N.Yu. Krasovskiy S.A., Chernyak A.V. et al. [Trends in life expectancy of cystic fibrosis patients in Moscow and their connection with the treatment received: retrospective analysis for 1993–2013]. Voprosy sovremennoy pediatrii. 2015; 14 (4): 503–508. DOI: 10.15690/vsp.v14.i4.1390 (in Russian).

3. Voronkova A.Yu., Amelina E.L., Kashirskaya N.Yu. et al. (eds.). [Register of cystic fibrosis patients in the Russian Federation. 2017]. Moscow: Medpraktika-M; 2019 (in Russian).

4. Tiddens H.A. Detecting early structural lung damage in cystic fibrosis. Pediatr. Pulmonol. 2002; 34 (3): 228–231. DOI: 10.1002/ppul.10134.

5. Brody A.S., Tiddens H.A., Castile R.G. et al. Computed tomography in the evaluation of cystic fibrosis lung disease. Am. J. Respir. Crit. Care Med. 2005; 172 (10): 1246–1252. DOI: 10.1164/rccm.200503-401PP.

6. Hulzebos E.H., Bomhof-Roordink H., van de Weert-van Leeuwen P.B. et al. Prediction of mortality in adolescents with cystic fibrosis. Med. Sci. Sports Exerc. 2014; 46 (11): 2047– 2052. DOI: 10.1249/MSS.0000000000000344.

7. Chernyak A.V., Krasovskiy S.A., Gorinova Yu.V. et al. [The relationship of the pulmonary function with nutritional and microbiological status in patients with cystic fibrosis]. Prakticheskaya pul'monologiya. 2018; (1): 43–50 (in Russian).

8. Gustafsson P.M., Aurora P., Lindblad A. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur. Respir. J. 2003; 22 (6): 972–979. DOI: 10.1183/09031936.03.00049502.

9. Becklake M.R. A new index of the intrapulmonary mixture of inspired air. Thorax. 1 952; 7: 111–116. DOI: 10.1136/thx.7.1.111.

10. Kraemer R., Blum A., Schibler A. et al. Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 2005; 171 (4): 371–378. DOI: 10.1164/rccm.200407-948OC.

11. Davis S.D., Fordham L.A., Brody A.S. et al. Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis. Am. J. Respir. Crit. Care Med. 2007; 175 (9): 943–950. DOI: 10.1164/rccm.200603-343OC.

12. Ramsey K.A., Rosenow T., Turkovic L. et al. Lung clearance index and structural lung disease on computed tomography in early cystic fibrosis. Am. J. Respir. Crit. Care Med. 2016; 193 (1): 60–67. DOI: 10.1164/rccm.201507-1409OC.

13. Sanders D.B., Li Z., Brody A.S. Chest computed tomography predicts the frequency of pulmonary exacerbations in children with cystic fibrosis. Ann. Am. Thorac. Soc. 2015; 12 (1): 64–69. DOI: 10.1513/AnnalsATS.201407-338OC.

14. Sanders D.B., Li Z., Parker-McGill K. et al. Quantitative chest computerized tomography and FEV1 equally identify pulmonary exacerbation risk in children with cystic fibrosis. Pediatr. Pulmonol. 2018; 53 (10): 1369–1377. DOI: 10.1002/ppul.24144.

15. Amelina E.L., Marchenkov Ya.V., Chernyak A.V., Krasovskiy S.A. [Quantitative estimation of results of high resolution computer tomography of chest organs in adult patients with cystic fibrosis]. Pul'monologiya. 2009; (1): 59–66 (in Russian).

16. Smyth A.R., Bell S.C., Bojcin S. et al. European Cystic Fibrosis Society standards of care: Best practice guidelines. J. Cyst. Fibros. 2014; 13 (Suppl. 1): S23–42. DOI: 10.1016/j.jcf.2014.03.010.

17. Miller M.R., Hankinson J., Brusasco V. et al. Standardisation of spirometry. Eur. Respir. J. 2005; 26 (2): 319–337. DOI: 10.1183/09031936.05.00034805.

18. Wanger J., Clausen J.L., Coates A. et al. Standardisation of the measurement of lung volumes. Eur. Respir. J. 2005; 26 (3): 511–522. DOI: 10.1183/09031936.05.00035005.

19. Macintyre N., Crapo R.O., Viegi G. et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur. Respir. J. 2005; 26 (4): 720–735. DOI: 10.1183/09031936.05.00034905.

20. Robinson P.D., Latzin Ph., Verbanck S. et al. Consensus statement for inert gas washout measurement using multiple- and single-breath tests. Eur. Respir. J. 2013; 41 (3): 507–522. DOI: 10.1183/09031936.00069712.

21. Quanjer P.H., Tammeling G.J., Cotes J.E. et al. [Lung volumes and forced ventilatory flows. Work Group on Standardization of Respiratory Function Tests. European Community for Coal and Steel. Official position of the European Respiratory Society]. Rev. Mal. Respir. 1994; 11 (Suppl. 3): 5–40 (in French).

22. Task Group on Surveillance for Respiratory Hazards in the Occupational Setting, Brooks S.M. (Chairman). Surveillance for respiratory hazards. ATS News. 1982; 8: 12–16.

23. Bhalla M., Turcios N., Aponte V. et al. Cystic fibrosis: scoring system with thin-section CT. Radiology. 1991; 179 (3): 783–788. DOI: 10.1148/radiology.179.3.2027992.

24. Robinson P.D., Goldman M.D., Gustafsson P.M. Inert gas washout: Theoretical background and clinical utility in respiratory disease. Respiration. 2009; 78 (3): 339–355. DOI: 10.1159/000225373.

25. Shaw M., Oppelaar M.C., Jensen R. et al. The utility of mo - ment ratios and abbreviated endpoints of the multiple breath washout test in preschool children with cystic fibrosis. Pediatr. Pulmonol. 2020; 55 (3): 649–653. DOI: 10.1002/ppul.24618.

26. Wielpütz M.O., Weinheimer O., Eichinger M. et al. Pulmo - nary emphysema in cystic fibrosis detected by densitometry on chest multidetector computed tomography. PLoS One. 2013; 8 (8): e73142. DOI: 10.1371/journal.pone.0073142.

27. Gustafsson P.M., De Jong P.A., Tiddens H.A., Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008; 63 (2): 129–134. DOI: 10.1136/thx.2007.077784.

28. Ellemunter H., Fuchs S.I., Unsinn K.M. et al. Sensitivity of lung clearance index and chest computed tomography in early CF lung disease. Respir. Med. 2010; 104 (12): 1834–1842. DOI: 10.1016/j.rmed.2010.06.010.

29. Owens C.M., Aurora P., Stanojevic S. et al. Lung clearance index and HRCT are complementary markers of lung abnormalities in young children with CF. Thorax. 2011; 66 (6): 481–488. DOI: 10.1136/thx.2010.150375.