Cardiopulmonary exercise testing complements both spirometry and nuclear imaging for assessing sarcoidosis stage and for monitoring disease activity

Main Article Content

Chiara Torregiani https://orcid.org/0000-0001-9110-3029
Matia Reale
Marco Confalonieri https://orcid.org/0000-0002-4791-768X
Franca Dore
Carmelo Crisafulli https://orcid.org/0000-0002-1766-3033
Elisa Baratella https://orcid.org/0000-0002-1061-9507
Francesco Salton https://orcid.org/0000-0002-0864-9766
Paola Confalonieri
Barbara Ruaro https://orcid.org/0000-0001-8990-859X
Guido Maiello https://orcid.org/0000-0001-6625-2583

Keywords

Sarcoidosis, Cardiopulmonary Exercise Test, Spirometry, Scintigraphy, Positron Emission Tomography Imaging

Abstract

Background: Pulmonary sarcoidosis is a systemic disease that can confound established follow-up tools. Pulmonary function tests (PFTs) are recommended in initial and follow-up patient evaluations yet are imperfect predictors of disease progression. The cardiopulmonary exercise test (CPET) is another potentially useful monitoring tool, although previous studies report conflicting findings regarding which variables are altered by the disease. Nuclear imaging tests are also employed to assess inflammatory activity and may be predictive of functional deterioration. Aim: We asked whether PFTs or CPET are more diagnostic of disease stage, which subsets of functional variables are impacted by the disease, and how these relate to nuclear imaging signs of active inflammation. Study design and methods: We collected retrospective data (spirometry, CPET, Gallium-67 scintigraphy, 18F-FDG PET/CT) from 48 patients and 10 controls. Disease severity was assessed following Scadding classification. First, we correlated individual PFTs and CPET parameters to Scadding stage and nuclear imaging data. Next, we performed Principal Component Analysis (PCA) on PFTs and CPET parameters, separated into respiratory, cardiovascular and metabolic subsets. Finally, we constructed multiple regression models to determine which variable subsets were the best predictors of Scadding stage and disease activity. Results: The majority of PFTs and CPET single parameters were significantly correlated with patient stage, while only few correlated with disease activity. Nevertheless, multiple regression models were able to significantly relate PFTs and CPET to both disease stage and activity. Additionally, these analyses highlighted CPET cardiovascular parameters as the best overall predictors of disease stage and activity. Conclusions: Our results display how CPET and spirometry data complement each other for sarcoidosis disease staging, and how these tests are able to detect disease activity. Our findings suggest that CPET, a repeatable and non-invasive functional test, should be more routinely performed and taken into account in sarcoidosis patient follow-up.


 

Abstract 286 | PDF Downloads 264

References

1. Statement on Sarcoidosis. Am J Respir Crit Care Med. 1999 Aug 1;160(2):736–55.
2. Costabel U, Hunninghake GW. On behalf of the Sarcoidosis Statement Committee. ATS/ERS/WASOG statement on sarcoidosis. Eur Respir J. 1999 Oct;14(4):735.
3. Pereira CAC, Dornfeld MC, Baughman R, Judson MA. Clinical phenotypes in sarcoidosis. Current Opinion in Pulmonary Medicine. 2014 Sep;20(5):496–502.
4. Culver DA, Baughman RP. It’s time to evolve from Scadding: phenotyping sarcoidosis. Eur Respir J. 2018 Jan;51(1):1800050.
5. Judson MA. The treatment of pulmonary sarcoidosis. Respiratory Medicine. 2012 Oct;106(10):1351–61.
6. Ruaro B, Confalonieri P, Santagiuliana M, et al. Correlation between Potential Risk Factors and Pulmonary Embolism in Sarcoidosis Patients Timely Treated. JCM. 2021 Jun 2;10(11):2462.
7. Cifaldi R, Salton F, Confalonieri P, et al. Pulmonary Sarcoidosis and Immune Dysregulation: A Pilot Study on Possible Correlation. Diagnostics. 2023 Sep 11;13(18):2899.
8. Klech H, Köhn H, Huppmann M, Pohl W. Thoracic imaging with gallium-67. Eur J Nucl Med. 1987 Jun;13(S1):S24–36.
9. Keijsers RG, Verzijlbergen EJ, van den Bosch JM, et al. 18F-FDG PET as a predictor of pulmonary function in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2011 Oct;28(2):123–9.
10. Drent M, Jacobs JA, de Vries J, Lamers RJS, Liem IH, Wouters EFM. Does the cellular bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis? Eur Respir J. 1999 Jun 1;13(6):1338–44.
11. Prabhakar HB, Rabinowitz CB, Gibbons FK, O’Donnell WJ, Shepard JAO, Aquino SL. Imaging Features of Sarcoidosis on MDCT, FDG PET, and PET/CT. American Journal of Roentgenology. 2008 Mar;190(3_supplement):S1–6.
12. Keijsers RGM, van den Heuvel DAF, Grutters JC. Imaging the inflammatory activity of sarcoidosis. Eur Respir J. 2013 Mar;41(3):743–51.
13. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2020 Apr 15;201(8):e26–51.
14. Israel HL, Albertine KH, Park CH, Patrick H. Whole-body Gallium 67 Scans: Role in Diagnosis of Sarcoidosis. Am Rev Respir Dis. 1991 Nov;144(5):1182–6.
15. Sulavik SB, Spencer RP, Weed DA, Shapiro HR, Shiue ST, Castriotta RJ. Recognition of distinctive patterns of gallium-67 distribution in sarcoidosis. J Nucl Med. 1990 Dec;31(12):1909–14.
16. Sulavik SB, Spencer RP, Palestro CJ, Swyer AJ, Teirstein AS, Goldsmith SJ. Specificity and Sensitivity of Distinctive Chest Radiographic and/or 67Ga Images in the Noninvasive Diagnosis of Sarcoidosis. Chest. 1993 Feb;103(2):403–9.
17. Lopes AJ, Menezes SLS, Dias CM, Oliveira JF, Mainenti MRM, Guimarães FS. Cardiopulmonary exercise testing variables as predictors of long-term outcome in thoracic sarcoidosis. Braz J Med Biol Res. 2012 Mar;45(3):256–63.
18. Marcellis RGJ, Lenssen AF, de Vries GJ, et al. Is There an Added Value of Cardiopulmonary Exercise Testing in Sarcoidosis Patients? Lung. 2013 Feb;191(1):43–52.
19. Mezzani A. Cardiopulmonary Exercise Testing: Basics of Methodology and Measurements. Annals ATS. 2017 Jul;14(Supplement_1):S3–11.
20. Kallianos A, Zarogoulidis P, Ampatzoglou F, et al. Reduction of exercise capacity in sarcoidosis in relation to disease severity. Patient Prefer Adherence. 2015;9:1179–88.
21. Medinger AE, Khouri S, Rohatgi PK. Sarcoidosis: The Value of Exercise Testing. Chest. 2001 Jul;120(1):93–101.
22. Miller A, Brown LK, Sloane MF, Bhuptani A, Teirstein AS. Cardiorespiratory Responses to Incremental Exercise in Sarcoidosis Patients With Normal Spirometry. Chest. 1995 Feb;107(2):323–9.
23. Barros WGP, Neder JA, Pereira CAC, Nery LE. Clinical. Radiographic and Functional Predictors of Pulmonary Gas Exchange Impairment at Moderate Exercise in Patients with Sarcoidosis. Respiration. 2004;71(4):367–73.
24. Kiani A, Eslaminejad A, Shafeipour M, et al. Spirometry, cardiopulmonary exercise testing and the six-minute walk test results in sarcoidosis patients. Sarcoidosis vasculitis and diffuse lung disease. 2019 Sep 16;36(3):185–94.
25. Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Journal of Clinical Epidemiology. 2008 Apr;61(4):344–9.
26. Scadding JG. Prognosis of Intrathoracic Sarcoidosis in England. BMJ. 1961 Nov 4;2(5261):1165–72.
27. Miller MR. Standardisation of spirometry. European Respiratory Journal. 2005 Aug 1;26(2):319–38.
28. Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005 Sep;26(3):511–22.
29. Tailor V, Bossi M, Bunce C, Greenwood JA, Dahlmann-Noor A. Binocular versus standard occlusion or blurring treatment for unilateral amblyopia in children aged three to eight years. In: Cochrane Database of Systematic Reviews [Internet]. John Wiley & Sons, Ltd; 2015 [cited 2017 Dec 31]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011347.pub2/abstract
30. Casali M, Lauri C, Altini C, et al. State of the art of 18F-FDG PET/CT application in inflammation and infection: a guide for image acquisition and interpretation. Clin Transl Imaging. 2021 Aug;9(4):299–339.
31. Seabold JE, Palestro CJ, Brown ML, et al. Procedure guideline for gallium scintigraphy in inflammation. Society of Nuclear Medicine. J Nucl Med. 1997 Jun;38(6):994–7.
32. Mostard RLM, Verschakelen JA, van Kroonenburgh MJPG, et al. Severity of pulmonary involvement and 18F-FDG PET activity in sarcoidosis. Respiratory Medicine. 2013 Mar;107(3):439–47.
33. Zappala CJ, Desai SR, Copley SJ, et al. Optimal scoring of serial change on chest radiography in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2011 Oct;28(2):130–8.
34. Winterbauer RH, Hutchinson JF. Use of Pulmonary Function Tests in the Management of Sarcoidosis. Chest. 1980 Oct;78(4):640–7.
35. Wallaert B, Talleu C, Wemeau-Stervinou L, Duhamel A, Robin S, Aguilaniu B. Reduction of Maximal Oxygen Uptake in Sarcoidosis: Relationship with Disease Severity. Respiration. 2011;82(6):501–8.
36. Delobbe A, Perrault H, Maitre J, et al. Impaired exercise response in sarcoid patients with normal pulmonary functio. Sarcoidosis Vasc Diffuse Lung Dis. 2002 Jun;19(2):148–53.
37. Matthews JI, Hooper RG. Exercise Testing in Pulmonary Sarcoidosis. Chest. 1983 Jan;83(1):75–81.
38. Kollert F, Geck B, Suchy R, et al. The impact of gas exchange measurement during exercise in pulmonary sarcoidosis. Respiratory Medicine. 2011 Jan;105(1):122–9.
39. Keijsers RGM, Grutters JC. In Which Patients with Sarcoidosis Is FDG PET/CT Indicated? JCM. 2020 Mar 24;9(3):890.
40. Huang B, Law MWM, Khong PL. Whole-Body PET/CT Scanning: Estimation of Radiation Dose and Cancer Risk. Radiology. 2009 Apr;251(1):166–74.
41. Demirkok SS, Basaranoglu M, Akinci ED, Karayel T. Analysis of 275 patients with sarcoidosis over a 38 year period; a single-institution experience. Respiratory Medicine. 2007 Jun;101(6):1147–54.
42. Lynch J, Ma Y, Koss M, White E. Pulmonary Sarcoidosis. Semin Respir Crit Care Med. 2007 Feb;28(1):053–74.
43. Castro MDC, Pereira CA de C, Soares MR. Prognostic features of sarcoidosis course in a Brazilian cohort. J Bras Pneumol. 2022;48(1):e20210366.
44. Vagts C, Ascoli C, Fraidenburg DR, et al. Unsupervised Clustering Reveals Sarcoidosis Phenotypes Marked by a Reduction in Lymphocytes Relate to Increased Inflammatory Activity on 18FDG-PET/CT. Front Med. 2021 Feb 24;8:595077.