Ultra-Small Lung Cysts Impair Diffusion Without Obstructing Air Flow in Lymphangioleiomyomatosis

Abstract

BackgroundLymphangioleiomyomatosis (LAM) is a rare lung disease found primarily in women of childbearing age, characterized by the formation of air-filled cysts, which may be associated with reductions in lung function. An experimental, regional ultra-high resolution CT scan identified an additional volume of cysts relative to standard chest CT imaging, which consisted primarily of ultra-small cysts.Research QuestionWhat is the impact of these ultra-small cysts on the pulmonary function of patients with LAM?Study Design and MethodsA group of 103 patients with LAM received pulmonary function tests and a CT examination in the same visit. Cyst score, the percentage lung volume occupied by cysts, was measured by using commercial software approved by the US Food and Drug Administration. The association between cyst scores and pulmonary function tests of diffusing capacity of the lungs for carbon monoxide (Dlco) (% predicted), FEV1 (% predicted), and FEV1/FVC (% predicted) was assessed with statistical analysis adjusted for demographic variables. The distributions of average cyst size and ultra-small cyst fraction among the patients were evaluated.ResultsThe additional cyst volume identified by the experimental, higher resolution scan consisted of cysts of 2.2 ± 0.8 mm diameter on average and are thus labeled the “ultra-small cyst fraction.” It accounted for 27.9 ± 19.0% of the total cyst volume among the patients. The resulting adjusted, whole-lung cyst scores better explained the variance of Dlco (P < .001 adjusted for multiple comparisons) but not FEV1 and FEV1/FVC (P = 1.00). The ultra-small cyst fraction contributed to the reduction in Dlco (P < .001) but not to FEV1 and FEV1/FVC (P = .760 and .575, respectively). The ultra-small cyst fraction and average cyst size were correlated with cyst burden, FEV1, and FEV1/FVC but less with Dlco.InterpretationThe ultra-small cysts primarily contributed to the reduction in Dlco, with minimal effects on FEV1 and FEV1/FVC. Patients with lower cyst burden and better FEV1 and FEV1/FVC tended to have smaller average cyst size and higher ultra-small cyst fraction.Clinical Trial RegistrationClinicalTrials.gov; No.: NCT00001465; URL: www.clinicaltrials.gov Lymphangioleiomyomatosis (LAM) is a rare lung disease found primarily in women of childbearing age, characterized by the formation of air-filled cysts, which may be associated with reductions in lung function. An experimental, regional ultra-high resolution CT scan identified an additional volume of cysts relative to standard chest CT imaging, which consisted primarily of ultra-small cysts. What is the impact of these ultra-small cysts on the pulmonary function of patients with LAM? A group of 103 patients with LAM received pulmonary function tests and a CT examination in the same visit. Cyst score, the percentage lung volume occupied by cysts, was measured by using commercial software approved by the US Food and Drug Administration. The association between cyst scores and pulmonary function tests of diffusing capacity of the lungs for carbon monoxide (Dlco) (% predicted), FEV1 (% predicted), and FEV1/FVC (% predicted) was assessed with statistical analysis adjusted for demographic variables. The distributions of average cyst size and ultra-small cyst fraction among the patients were evaluated. The additional cyst volume identified by the experimental, higher resolution scan consisted of cysts of 2.2 ± 0.8 mm diameter on average and are thus labeled the “ultra-small cyst fraction.” It accounted for 27.9 ± 19.0% of the total cyst volume among the patients. The resulting adjusted, whole-lung cyst scores better explained the variance of Dlco (P < .001 adjusted for multiple comparisons) but not FEV1 and FEV1/FVC (P = 1.00). The ultra-small cyst fraction contributed to the reduction in Dlco (P < .001) but not to FEV1 and FEV1/FVC (P = .760 and .575, respectively). The ultra-small cyst fraction and average cyst size were correlated with cyst burden, FEV1, and FEV1/FVC but less with Dlco. The ultra-small cysts primarily contributed to the reduction in Dlco, with minimal effects on FEV1 and FEV1/FVC. Patients with lower cyst burden and better FEV1 and FEV1/FVC tended to have smaller average cyst size and higher ultra-small cyst fraction. ClinicalTrials.gov; No.: NCT00001465; URL: www.clinicaltrials.gov Lymphangioleiomyomatosis (LAM), a rare, progressive, cystic lung disease found predominately in premenopausal women, is caused by the proliferation of abnormal-appearing, smooth muscle-like cells that leads to the formation of air-filled cysts in the lungs, loss of pulmonary function, and, in some cases, respiratory failure. The disease presents itself in two forms: sporadic LAM and in association with the autosomal-dominant, neurocutaneous disorder tuberous sclerosis complex (TSC-LAM). Sporadic LAM occurs in a randomized, nonhereditary fashion and is estimated to affect 3.3 to 7.4 per million women worldwide.1Hohman D.W. Noghrehkar D. Ratnayake S. Lymphangioleiomyomatosis: a review.Eur J Intern Med. 2008; 19: 319-324Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 2Taveira-DaSilva A.M. Steagall W.K. Moss J. Lymphangioleiomyomatosis.Atlas Genet Cytogenet Oncol Haematol. 2009; 13: 751-757PubMed Google Scholar, 3Harknett E.C. Chang W.Y.C. Byrnes S. et al.Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis.QJM Int J Med. 2011; 104: 971-979Crossref PubMed Scopus (82) Google Scholar, 4Gupta N. Vassallo R. Wikenheiser-Brokamp K.A. McCormack F.X. Diffuse cystic lung disease. Part I.Am J Respir Crit Care Med. 2015; 191: 1354-1366Crossref PubMed Scopus (98) Google Scholar, 5Taveira-DaSilva A.M. Moss J. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis.Clin Epidemiol. 2015; 7: 249-257Crossref PubMed Scopus (64) Google Scholar It is characterized by lung (eg, cysts, pneumothoraces, hemoptysis), lymphatic (eg, chylous effusions, lymphangioleiomyomas), and renal (eg, angiomyolipomas) manifestations.1Hohman D.W. Noghrehkar D. Ratnayake S. Lymphangioleiomyomatosis: a review.Eur J Intern Med. 2008; 19: 319-324Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,4Gupta N. Vassallo R. Wikenheiser-Brokamp K.A. McCormack F.X. Diffuse cystic lung disease. Part I.Am J Respir Crit Care Med. 2015; 191: 1354-1366Crossref PubMed Scopus (98) Google Scholar, 5Taveira-DaSilva A.M. Moss J. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis.Clin Epidemiol. 2015; 7: 249-257Crossref PubMed Scopus (64) Google Scholar, 6Tobino K. Johkoh T. Fujimoto K. et al.Computed tomographic features of lymphangioleiomyomatosis: evaluation in 138 patients.Eur J Radiol. 2015; 84: 534-541Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 7Moir L.M. Lymphangioleiomyomatosis: current understanding and potential treatments.Pharmacol Ther. 2016; 158: 114-124Crossref PubMed Scopus (20) Google Scholar TSC-LAM is associated with brain, skin, and cardiac manifestations, in addition to findings characteristic of sporadic LAM.1Hohman D.W. Noghrehkar D. Ratnayake S. Lymphangioleiomyomatosis: a review.Eur J Intern Med. 2008; 19: 319-324Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,4Gupta N. Vassallo R. Wikenheiser-Brokamp K.A. McCormack F.X. Diffuse cystic lung disease. Part I.Am J Respir Crit Care Med. 2015; 191: 1354-1366Crossref PubMed Scopus (98) Google Scholar,5Taveira-DaSilva A.M. Moss J. Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis.Clin Epidemiol. 2015; 7: 249-257Crossref PubMed Scopus (64) Google Scholar The cystic manifestations of LAM can develop, in an age-dependent manner, in up to 80% of women with TSC.8Seibert D. Hong C.H. Takeuchi F. et al.Recognition of tuberous sclerosis in adult women: delayed presentation with life-threatening consequences.Ann Intern Med. 2011; 154: 806Crossref PubMed Scopus (46) Google Scholar Clinically significant lung disease occurs only in a small percentage of women with TSC. Because LAM is a rare pulmonary disease, diagnosing the condition can be challenging, especially in the absence of extrapulmonary manifestations.9Xu K.F. Lo B.H. Lymphangioleiomyomatosis: differential diagnosis and optimal management.Ther Clin Risk Manag. 2014; 10: 691-700Crossref PubMed Scopus (19) Google Scholar Fortunately, CT scans provide a noninvasive, high-resolution view of the lungs that reveals round LAM cysts with distinct walls, which aids in the diagnosis. The extent of lung involvement with cysts (called “cyst score” herein) correlates with lung function and is a measure of disease severity.10Aberle D.R. Hansell D.M. Brown K. Tashkin D.P. Lymphangiomyomatosis—CT, chest radiographic, and functional correlations.Radiology. 1990; 176: 381-387Crossref PubMed Scopus (104) Google Scholar, 11Crausman R.S. Lynch D.A. Mortenson R.L. et al.Quantitative CT predicts the severity of physiologic dysfunction in patients with lymphangioleiomyomatosis.Chest. 1996; 109: 131-137Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 12Avila N.A. Kelly J.A. Dwyer A.J. Johnson D.L. Jones E.C. Moss J. Lymphangioleiomyomatosis: correlation of qualitative and quantitative thin-section CT with pulmonary function tests and assessment of dependence on pleurodesis.Radiology. 2002; 223: 189-197Crossref PubMed Scopus (57) Google Scholar Pulmonary function tests (PFTs) are used to determine disease severity and progression in LAM. Although PFTs measure the functional manifestation of pathologic changes in the lungs, chest CT examinations provide a direct visual representation of such changes. CT evaluation was initially a subjective determination of the percentage of lung that was abnormal. This subjective CT evaluation was shown to correlate with PFTs of FEV1 % predicted and diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted.10Aberle D.R. Hansell D.M. Brown K. Tashkin D.P. Lymphangiomyomatosis—CT, chest radiographic, and functional correlations.Radiology. 1990; 176: 381-387Crossref PubMed Scopus (104) Google Scholar,12Avila N.A. Kelly J.A. Dwyer A.J. Johnson D.L. Jones E.C. Moss J. Lymphangioleiomyomatosis: correlation of qualitative and quantitative thin-section CT with pulmonary function tests and assessment of dependence on pleurodesis.Radiology. 2002; 223: 189-197Crossref PubMed Scopus (57) Google Scholar Subsequently, an index describing the percent volume of the parenchyma occupied by cysts, or cyst score, was introduced together with automated segmentation software for its measurement,11Crausman R.S. Lynch D.A. Mortenson R.L. et al.Quantitative CT predicts the severity of physiologic dysfunction in patients with lymphangioleiomyomatosis.Chest. 1996; 109: 131-137Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar removing some subjective in the evaluation of CT The cyst shown to correlate with FEV1, and Dlco in of R.S. Lynch D.A. Mortenson R.L. et al.Quantitative CT predicts the severity of physiologic dysfunction in patients with lymphangioleiomyomatosis.Chest. 1996; 109: 131-137Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 12Avila N.A. Kelly J.A. Dwyer A.J. Johnson D.L. Jones E.C. Moss J. Lymphangioleiomyomatosis: correlation of qualitative and quantitative thin-section CT with pulmonary function tests and assessment of dependence on pleurodesis.Radiology. 2002; 223: 189-197Crossref PubMed Scopus (57) Google Scholar, et for the extent of cystic on chest in J 2009; PubMed Scopus Google Scholar, A.M. Moss J. in lung function in patients with with or Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. Moss J. Med. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. Johkoh T. et of the progression of pulmonary cysts assessed by among and PubMed Scopus Google Scholar, J. Steagall W.K. et al.Use of CT to progression and to in lymphangioleiomyomatosis.Chest. Full Text Full Text PDF PubMed Scopus Google Scholar The current standard for the of cyst is the chest CT which used the standard to CT scans of et using CT with and J 2016; PubMed Scopus Google Scholar, S. S. et on CT using percentage of volume and size of lung effects of reduction using J Radiol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, et of and CT for of J PubMed Scopus Google Scholar, et al.Quantitative and qualitative of lung and pulmonary functional loss thin-section CT in pulmonary Radiol. Full Text Full Text PDF PubMed Scopus Google Scholar, et using chest of reduction and PubMed Scopus Google Scholar, S. et CT scan of a and chest a of in lymphangioleiomyomatosis.Chest. Full Text Full Text PDF PubMed Scopus Google Scholar a found that small cysts may not be identified to the of resolution of standard chest CT A.M. et CT of the percentage volume occupied by cysts in patients with lymphangioleiomyomatosis.Clin Full Text Full Text PDF PubMed Scopus Google Scholar an regional ultra-high resolution CT the smaller cysts can be A.M. et CT of the percentage volume occupied by cysts in patients with lymphangioleiomyomatosis.Clin Full Text Full Text PDF PubMed Scopus Google Moss J. of a scan for lung in a CT Clin 19: PubMed Scopus Google Scholar The scan the a of the a view of the lung The of the current was to the distributions of average cyst size and ultra-small cyst fraction in an and, in with the impact of the ultra-small cyst fraction on pulmonary function in these patients. 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of 103 patients with an scan identified an additional volume of cysts primarily of ultra-small cysts. Dlco but not FEV1 or FEV1/FVC. The resulting adjusted whole-lung cyst better explained the variance in Dlco among the but not FEV1 or FEV1/FVC. The distributions of average cyst size and ultra-small cyst fraction were and among the patients. Patients with lower cyst burden, smaller average cyst and higher ultra-small cyst fraction better FEV1 and FEV1/FVC. D.R. Hansell D.M. Brown K. Tashkin D.P. Lymphangiomyomatosis—CT, chest radiographic, and functional correlations.Radiology. 1990; 176: 381-387Crossref PubMed Scopus (104) Google Scholar, 11Crausman R.S. Lynch D.A. Mortenson R.L. et al.Quantitative CT predicts the severity of physiologic dysfunction in patients with lymphangioleiomyomatosis.Chest. 1996; 109: 131-137Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 12Avila N.A. Kelly J.A. Dwyer A.J. Johnson D.L. Jones E.C. Moss J. Lymphangioleiomyomatosis: correlation of qualitative and quantitative thin-section CT with pulmonary function tests and assessment of dependence on pleurodesis.Radiology. 2002; 223: 189-197Crossref PubMed Scopus (57) Google Scholar, et for the extent of cystic on chest in J 2009; PubMed Scopus Google Scholar in patients with LAM that the cyst correlated better with FEV1 with Dlco. et et for the extent of cystic on chest in J 2009; PubMed Scopus Google Scholar found in patients with LAM that percent cyst volume a correlation with FEV1 Dlco = < et N.A. Kelly J.A. Dwyer A.J. Johnson D.L. Jones E.C. Moss J. Lymphangioleiomyomatosis: correlation of qualitative and quantitative thin-section CT with pulmonary function tests and assessment of dependence on pleurodesis.Radiology. 2002; 223: 189-197Crossref PubMed Scopus (57) Google Scholar in patients a higher correlation of percent lung volume to FEV1 = < .001) to Dlco = < by et D.R. Hansell D.M. Brown K. Tashkin D.P. Lymphangiomyomatosis—CT, chest radiographic, and functional correlations.Radiology. 1990; 176: 381-387Crossref PubMed Scopus (104) Google Scholar found in patients with LAM a correlation between cyst scores standard chest CT scans and FEV1 = < Dlco = < the of et R.S. Lynch D.A. Mortenson R.L. et al.Quantitative CT predicts the severity of physiologic dysfunction in patients with lymphangioleiomyomatosis.Chest. 1996; 109: 131-137Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar found that the of cystic parenchyma in the lung to CT scan was better correlated with FEV1 = < Dlco = < in of the additional cyst volume by the experimental, ultra-high resolution the association between the cyst and Dlco was to a better of Dlco FEV1 or FEV1/FVC. of these findings is that the ultra-small cysts may not by FEV1 and associated the capacity for to a by et R.L. McCormack capacity is an of in pulmonary associated with 158: Full Text Full Text PDF PubMed Scopus Google Scholar in patients with and pulmonary found that to be in in the and Dlco is an of disease that by or by CT of et capacity of carbon monoxide in assessment of Full Text Full Text PDF PubMed Scopus Google Scholar the of ultra-small cysts on in the the by et Lo et quantitative tomographic analysis in 2016; 13: PubMed Scopus (19) Google Scholar in patients with LAM CT and found of in cysts by the of size to by et et and disease in PubMed Scopus Google Scholar that cyst is among cysts. A by et K. K. T. R. analysis of cystic lung by of and of the extent of and evaluation of PubMed Scopus Google Scholar in pulmonary LAM CT ultra-small cysts not with or were small to have a cysts may be associated with burden of LAM cells that and the respiratory Pulmonary in Respir PubMed Google Scholar, A.M. et proliferation of smooth and of of in J Respir Crit Care Med. 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Moss J. in lung function in patients with with or Full Text Full Text PDF PubMed Scopus Google Scholar in a a of Dlco FEV1 in the of the disease. Although the current is the association is with the that patients an of the disease, with lower cyst burden and better may have smaller cysts and higher ultra-small cyst which to affect Dlco FEV1 and FEV1/FVC. 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