CORRESPONDENCE Jean-Philippe Baguet, M.D., Ph.D.* INSERM U1039 Grenoble, France and Mutualiste Hospital Group Grenoble, France
17. McDonald ML, Cho MH, Sørheim IC, Lutz SM, Castaldi PJ, Lomas DA, Coxson HO, Edwards LD, MacNee W, Vestbo J, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints and COPDGene Investigators. Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2014;51:678–687.
* These two authors share the responsibility of senior authorship.
Copyright © 2015 by the American Thoracic Society
References 1. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82–93. 2. Mart´ınez-Garc´ıa MA, Capote F, Campos-Rodr´ıguez F, Lloberes P, D´ıaz de Atauri MJ, Somoza M, Masa JF, Gonzalez ´ M, Sacristan ´ L, Barbe´ F, et al.; Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013; 310:2407–2415. 3. Baguet JP, Barone-Rochette G, Tamisier R, Levy P, Pepin ´ JL. Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol 2012;9:679–688. 4. Stowhas ¨ AC, Namdar M, Biaggi P, Russi EW, Bloch KE, Stradling JR, Kohler M. The effect of simulated obstructive apnea and hypopnea on aortic diameter and BP. Chest 2011;140:675–680. 5. Erbel R, Eggebrecht H. Aortic dimensions and the risk of dissection. Heart 2006;92:137–142. 6. Sampol G, Romero O, Salas A, Tovar JL, Lloberes P, Sagales ´ T, Evangelista A. Obstructive sleep apnea and thoracic aorta dissection. Am J Respir Crit Care Med 2003;168:1528–1531. 7. Lefebvre B, Pepin ´ JL, Baguet JP, Tamisier R, Roustit M, Riedweg K, Bessard G, Levy ´ P, Stanke-Labesque F. Leukotriene B4: early mediator of atherosclerosis in obstructive sleep apnoea? Eur Respir J 2008;32:113–120. 8. Baguet JP, Minville C, Tamisier R, Roche F, Barone-Rochette G, Ormezzano O, Levy P, Pepin JL. Increased aortic root size is associated with nocturnal hypoxia and diastolic blood pressure in obstructive sleep apnea. Sleep 2011;34:1605–1607. 9. Dematteis M, Julien C, Guillermet C, Sturm N, Lantuejoul S, Mallaret M, Levy ´ P, Gozal E. Intermittent hypoxia induces early functional cardiovascular remodeling in mice. Am J Respir Crit Care Med 2008; 177:227–235. 10. Parati G, Lombardi C, Hedner J, Bonsignore MR, Grote L, Tkacova R, Levy ´ P, Riha R, Bassetti C, Narkiewicz K, et al.; EU COST Action B26 members. Recommendations for the management of patients with obstructive sleep apnoea and hypertension. Eur Respir J 2013;41: 523–538. 11. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D’Agostino RB, Newman AB, Lebowitz MD, Pickering TG. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 2000;283:1829–1836. 12. Kimoff RJ, Cheong TH, Olha AE, Charbonneau M, Levy RD, Cosio MG, Gottfried SB. Mechanisms of apnea termination in obstructive sleep apnea: role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994;149:707–714. 13. Clarenbach CF, Camen G, Sievi NA, Wyss C, Stradling JR, Kohler M. Effect of simulated obstructive hypopnea and apnea on thoracic aortic wall transmural pressures. J Appl Physiol (1985) 2013;115: 613–617. 14. Cistulli PA, Sullivan CE. Sleep-disordered breathing in Marfan’s syndrome. Am Rev Respir Dis 1993;147:645–648. 15. Kohler M, Blair E, Risby P, Nickol AH, Wordsworth P, Forfar C, Stradling JR. The prevalence of obstructive sleep apnoea and its association with aortic dilatation in Marfan’s syndrome. Thorax 2009; 64:162–166. 16. Kohler M, Pitcher A, Blair E, Risby P, Senn O, Forfar C, Wordsworth P, Stradling JR. The impact of obstructive sleep apnea on aortic disease in Marfan’s syndrome. Respiration 2013;86:39–44.
114
Relationship between Change in Lung Density and Long-Term Progression of Lung Function To the Editor: For more than 20 years, the presence of pulmonary emphysema has been assessed qualitatively by a radiologist using computed tomography (CT) of the lungs. With the development of dedicated software for analysis of the distribution of lung densities in CT images, it became possible to quantify the extent of emphysema and measure its progression over a relatively short period of time; that is, 1–2 years (1). This approach facilitated testing the efficacy of new drugs for emphysema over a shorter period of time and with fewer study patients than would be necessary using spirometry or gas transfer as the primary outcome parameter. Depending on the expected effect size of a new drug, application of lung densitometry, for example, can reduce trial duration by 3 years and require 300 fewer study participants diagnosed with emphysema related to type ZZ a1antitrypsin deficiency (2). A clinical trial using lung densitometry as an outcome parameter has shown that intravenous augmentation therapy with human a1-antitrypsin significantly reduced emphysema progression, measured by the 15th percentile density point (PD15), in severely deficient subjects (3). No statistically significant effect of the treatment was seen on FEV1 or gas transfer over a study period of 2–3 years. Therefore, the implications of a change in lung density during a short period with respect to the more conventional long-term changes in physiology remains unknown. To address this, we studied long-term change in postbronchodilator spirometry and gas transfer in a1antitrypsin–deficient patients who participated in the Retinoid Treatment of Emphysema in Patients on the a(1)-Antitrypsin International Registry (REPAIR) study (4). We analyzed data from the Netherlands, the United Kingdom, and Sweden who had participated in the trial and received placebo treatment for a period of 12 months and had CT scans at baseline and at months 6 and 12 for assessment of the PD15 progression. After the trial was finished, we determined whether FEV1 and diffusing capacity of the lung for carbon monoxide (DLCO)/VA (KCO) were measured at least 6 years after the last visit for the REPAIR study. The difference from baseline was divided by the years between measurements to obtain a measure of the annual decline. We calculated in this subgroup the correlation between the short-term change in PD15 (during a 1-yr period), corrected for lung volume, and a long-term change in FEV1 and DLCO/VA (KCO) over a mean (SD) period of 8 (1.5) years. The data were analyzed in SPSS, version 15.0 (SPSS Inc., Chicago, IL). Statistical significance within groups was calculated with Student’s t test, and significance of Pearson correlation for annual decline between parameters was calculated by analysis of variance.
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
CORRESPONDENCE Table 1. Patient Characteristics Age, yr Sex, F/M, % of total Subjects who stopped smoking more than 1 yr, % Smoking, pack-years Concomitant medications LABA 1 ICS 1 LAMA LABA 1 ICS SGRQ total score FEV1 after 400 mg salbutamol, % predicted KCO, % predicted
53.9 6 6.3 27/73 85 19.0 6 12.3 58% 23% 44 6 16 46.8 6 16.7 41.7 6 10.8
Definition of abbreviations: ICS = inhaled corticosteroids; LABA = long-acting b-agonist; LAMA = long-acting muscarinic antagonist; SGRQ = Saint George Respiratory Questionnaire. Data are mean values 6 SD unless otherwise indicated.
A total of 51 subjects were analyzed (see Table 1 for patient characteristics). Five patients did not have a baseline gas transfer measurement, so the change could only be determined in the remaining 46 patients with data both at baseline and after 6 or more years. The change in lung function was annualized by dividing the total change by the number of years between baseline and final measurement. The mean annual decline in FEV1 was 66 6 60.9 ml (P , 0.0001) and in KCO was 27.5 6 25.9 mmol/kPa/L/min (P , 0.001). In the REPAIR study, the annual decline in PD15 was 2.15 6 3.27 g/L (P , 0.001). The annual decline in lung density PD15 correlated significantly with the annual decline in FEV1 (r = 0.41; P = 0.003), but not with KCO (r = 0.18; P = 0.185) (Figure 1). Interestingly, there was no correlation between the annual changes of FEV1 and KCO (r = 0.21; P = 0.165). Here we show, for the first time, that a statistically significant and clinically meaningful mean annual decline in FEV1 of 66 ml in 8 years is preceded by a statistically significant decline in lung density over only 1 year in subjects with emphysema related to PiZZ a1-antitrypsin deficiency. It is known that PD15 lung density is a sensitive parameter to detect changes in lung structure in emphysema (1). In at least three different clinical trials, placebo-treated patients had an annual decline in PD15 between 2 and 3 g/L (3, 4). Depending on the baseline patient characteristics of subjects with PiZZ a1-antitrypsin
A –15
Author disclosures are available with the text of this letter at www.atsjournals.org. Jan Stolk, M.D. Leiden University Medical Center Leiden, the Netherlands Robert A. Stockley, M.D. Queen Elizabeth Hospital Birmingham Birmingham, United Kingdom Eeva Piitulainen, M.D. Skane ˚ University Hospital Malmo, ¨ Sweden Berend C. Stoel, Ph.D. Leiden University Medical Center Leiden, the Netherlands
References 1. Stolk J, Putter H, Bakker EM, Shaker SB, Parr DG, Piitulainen E, Russi EW, Grebski E, Dirksen A, Stockley RA, et al. Progression parameters for emphysema: a clinical investigation. Respir Med 2007;101:1924–1930. 2. Schluchter MD, Stoller JK, Barker AF, Buist AS, Crystal RG, Donohue JF, Fallat RJ, Turino GM, Vreim CE, Wu MC; The Alpha 1-Antitrypsin Deficiency Registry Study Group. Feasibility of a clinical trial of
B
PD15 (gr/L) –10
deficiency and pulmonary emphysema, a significant decline in PD15 can be measured in 1–3 years, which is not possible for measures of airflow obstruction nor gas transfer (1). It is worth noting that in our study population, change in FEV1 was not correlated with a change in gas transfer over a mean period of 8 years, despite the statistically significant decline over that period of time. This suggests that the two parameters measure different anatomic consequences of emphysematous tissue destruction, a finding consistent with crosssectional studies reported by others (5). The current data suggest that in our patients with emphysema, a decline in lung density in 1 year is an early predictor of a decline in lung function occurring 8 years later. In conclusion, CT scan–derived short-term lung density PD15 annual decline is related to a future decline in FEV1, the diseasedefining biomarker of chronic obstructive pulmonary disease/ emphysema phenotype in severe a1-antitrypsin deficiency. Future studies may show similar results for patients with emphysema without the inherited deficiency. n
–5
5
–100
–50
50
–200
FEV1 (ml)
–300
FEV1 (ml)
–200
Kco (mmol/kg/L/min)
–300
Figure 1. (A) Relation between change in lung density (PD15) in grams per liter in 1 year and annual change in FEV1 in milliliters during a mean period of 8 years. The Pearson correlation is 0.41 (P = 0.003). (B) Relation between annual change in FEV1 in milliliters during a mean period of 8 years and annual change in gas transfer KCO (mmol/kPa/L/min) over the same period of time. The Pearson correlation is 0.21 (P = 0.165).
Correspondence
115
CORRESPONDENCE augmentation therapy for a1-antitrypsin deficiency. Am J Respir Crit Care Med 2000;161:796–801. 3. Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A. Therapeutic efficacy of a-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res 2010;11:136. 4. Stolk J, Stockley RA, Stoel BC, Cooper BG, Piitulainen E, Seersholm N, Chapman KR, Burdon JG, Decramer M, Abboud RT, et al. Randomised controlled trial for emphysema with a selective agonist of the g-type retinoic acid receptor. Eur Respir J 2012;40:306–312. 5. Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. Am J Respir Crit Care Med 2004;170:1172–1178.
Copyright © 2015 by the American Thoracic Society
The Role of Immunohistochemistry in Diagnosis of Pulmonary Tumor Thrombotic Microangiopathy To the Editor: We read with interest the case report of progressive right ventricular dysfunction by Buser and colleagues (1). It is important to clarify that tumor emboli and pulmonary tumor thrombotic microangiopathy (PTTM) are overlapping clinical entities and can only be differentiated by histology and immunohistochemistry. The presence of vascular endothelial growth factor (VEGF) and tissue factor (TF) are important features that allow one to distinguish between the two entities (2, 3), but those findings were not reported in this case. Much remains to be elucidated about the pathophysiology of these disorders. We recently took care of a similar case of acute right ventricular dysfunction, which progressed rapidly to death (4). We diagnosed PTTM without fibrocellular intimal proliferation because the immunohistochemistry was VEGF- and TF-positive. We note that Buser and colleagues’ patient had breast cancer, which is most commonly associated with tumor emboli rather than PTTM. It is possible that some previously reported cases of tumor emboli were, in fact, PTTM, as intimal proliferation was described in many cases, but no VEGF and TF stains were reported (5). n Author disclosures are available with the text of this letter at www.atsjournals.org. Pedro Salinas, M.D. Harold Manning, M.D. Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire
References 1. Buser M, Felizeter-Kessler M, Lenggenhager D, Maeder MT. Rapidly progressive pulmonary hypertension in a patient with pulmonary tumor thrombotic microangiopathy. Am J Respir Crit Care Med 2015; 191:711–712. 2. Chinen K, Tokuda Y, Fujiwara M, Fujioka Y. Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: an analysis of 6 autopsy cases and review of the literature. Pathol Res Pract 2010;206: 682–689. 3. Uruga H, Fujii T, Kurosaki A, Hanada S, Takaya H, Miyamoto A, Morokawa N, Homma S, Kishi K. Pulmonary tumor thrombotic microangiopathy: a clinical analysis of 30 autopsy cases. Intern Med 2013;52:1317–1323. 4. Salinas PD, Toth LN, Manning HL. A rare cause of postoperative hypotension. Chest 2015;147:e175–e180.
116
5. Roberts KE, Hamele-Bena D, Saqi A, Stein CA, Cole RP. Pulmonary tumor embolism: a review of the literature. Am J Med 2003;115: 228–232.
Copyright © 2015 by the American Thoracic Society
Reply From the Authors: We thank Drs. Salinas and Manning for their interest in our case (1). We agree that a positive immunohistochemistry for vascular endothelial growth factor and tissue factor would have further strengthened the diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM) (2), as this would have been an additional indicator of a proliferative process rather than pure embolization of tumor cells. However, we feel that a number of other features favored a diagnosis of PTTM. For example, light microscopy clearly revealed fibrocellular intimal proliferation of pulmonary arterioles, as shown in the figure. In this context, we are somewhat surprised about the authors’ reference to a case of PTTM without fibrocellular intimal proliferation, the latter being a hallmark of the condition (3). The hemodynamic features were also consistent with PTTM; that is, the presence of a significantly increased pulmonary vascular resistance, and even obstruction of small vessels (3). For the readers’ interest, we highlight in more detail the hemodynamic constellation: There was a high mean pulmonary artery pressure (mPAP; 51 mm Hg), a discordance between left ventricular end-diastolic pressure (8 mm Hg) and mean pulmonary artery occlusion pressure (mPAOP; 34 mm Hg) with a spuriously small transpulmonary gradient (i.e., the difference between mPAP and mPAOP; 17 mm Hg), and V waves of the PAOP trace occurring early relative to the T wave of the ECG. The latter phenomenon may be explained by a backward transmission of the pulmonary arterial pressure signal from the obstructed and remodelled arterioles, which are anatomically closer to the balloon catheter than the left atrium, which is usually responsible for the generation of the true V waves that typically are seen simultaneously to the T wave; that is, later than in the present case (4). In addition, the presence of breast cancer does not exclude PTTM, as several cases of PTTM in the context of breast cancer have been described (2, 4, 5). n Author disclosures are available with the text of this letter at www.atsjournals.org. Micha T. Maeder, M.D. Marc Buser, M.D. Monika Felizeter-Kessler, M.D. Daniela Lenggenhager, M.D. Kantonsspital St. Gallen St. Gallen, Switzerland
References 1. Buser M, Felizeter-Kessler M, Lenggenhager D, Maeder MT. Rapidly progressive pulmonary hypertension in a patient with pulmonary tumor thrombotic microangiopathy. Am J Respir Crit Care Med 2015; 191:711–712. 2. Uruga H, Fujii T, Kurosaki A, Hanada S, Takaya H, Miyamoto A, Morokawa N, Homma S, Kishi K. Pulmonary tumor thrombotic
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
17. McDonald ML, Cho MH, Sørheim IC, Lutz SM, Castaldi PJ, Lomas DA, Coxson HO, Edwards LD, MacNee W, Vestbo J, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints and COPDGene Investigators. Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2014;51:678–687.
* These two authors share the responsibility of senior authorship.
Copyright © 2015 by the American Thoracic Society
References 1. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82–93. 2. Mart´ınez-Garc´ıa MA, Capote F, Campos-Rodr´ıguez F, Lloberes P, D´ıaz de Atauri MJ, Somoza M, Masa JF, Gonzalez ´ M, Sacristan ´ L, Barbe´ F, et al.; Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013; 310:2407–2415. 3. Baguet JP, Barone-Rochette G, Tamisier R, Levy P, Pepin ´ JL. Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol 2012;9:679–688. 4. Stowhas ¨ AC, Namdar M, Biaggi P, Russi EW, Bloch KE, Stradling JR, Kohler M. The effect of simulated obstructive apnea and hypopnea on aortic diameter and BP. Chest 2011;140:675–680. 5. Erbel R, Eggebrecht H. Aortic dimensions and the risk of dissection. Heart 2006;92:137–142. 6. Sampol G, Romero O, Salas A, Tovar JL, Lloberes P, Sagales ´ T, Evangelista A. Obstructive sleep apnea and thoracic aorta dissection. Am J Respir Crit Care Med 2003;168:1528–1531. 7. Lefebvre B, Pepin ´ JL, Baguet JP, Tamisier R, Roustit M, Riedweg K, Bessard G, Levy ´ P, Stanke-Labesque F. Leukotriene B4: early mediator of atherosclerosis in obstructive sleep apnoea? Eur Respir J 2008;32:113–120. 8. Baguet JP, Minville C, Tamisier R, Roche F, Barone-Rochette G, Ormezzano O, Levy P, Pepin JL. Increased aortic root size is associated with nocturnal hypoxia and diastolic blood pressure in obstructive sleep apnea. Sleep 2011;34:1605–1607. 9. Dematteis M, Julien C, Guillermet C, Sturm N, Lantuejoul S, Mallaret M, Levy ´ P, Gozal E. Intermittent hypoxia induces early functional cardiovascular remodeling in mice. Am J Respir Crit Care Med 2008; 177:227–235. 10. Parati G, Lombardi C, Hedner J, Bonsignore MR, Grote L, Tkacova R, Levy ´ P, Riha R, Bassetti C, Narkiewicz K, et al.; EU COST Action B26 members. Recommendations for the management of patients with obstructive sleep apnoea and hypertension. Eur Respir J 2013;41: 523–538. 11. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D’Agostino RB, Newman AB, Lebowitz MD, Pickering TG. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 2000;283:1829–1836. 12. Kimoff RJ, Cheong TH, Olha AE, Charbonneau M, Levy RD, Cosio MG, Gottfried SB. Mechanisms of apnea termination in obstructive sleep apnea: role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994;149:707–714. 13. Clarenbach CF, Camen G, Sievi NA, Wyss C, Stradling JR, Kohler M. Effect of simulated obstructive hypopnea and apnea on thoracic aortic wall transmural pressures. J Appl Physiol (1985) 2013;115: 613–617. 14. Cistulli PA, Sullivan CE. Sleep-disordered breathing in Marfan’s syndrome. Am Rev Respir Dis 1993;147:645–648. 15. Kohler M, Blair E, Risby P, Nickol AH, Wordsworth P, Forfar C, Stradling JR. The prevalence of obstructive sleep apnoea and its association with aortic dilatation in Marfan’s syndrome. Thorax 2009; 64:162–166. 16. Kohler M, Pitcher A, Blair E, Risby P, Senn O, Forfar C, Wordsworth P, Stradling JR. The impact of obstructive sleep apnea on aortic disease in Marfan’s syndrome. Respiration 2013;86:39–44.
114
Relationship between Change in Lung Density and Long-Term Progression of Lung Function To the Editor: For more than 20 years, the presence of pulmonary emphysema has been assessed qualitatively by a radiologist using computed tomography (CT) of the lungs. With the development of dedicated software for analysis of the distribution of lung densities in CT images, it became possible to quantify the extent of emphysema and measure its progression over a relatively short period of time; that is, 1–2 years (1). This approach facilitated testing the efficacy of new drugs for emphysema over a shorter period of time and with fewer study patients than would be necessary using spirometry or gas transfer as the primary outcome parameter. Depending on the expected effect size of a new drug, application of lung densitometry, for example, can reduce trial duration by 3 years and require 300 fewer study participants diagnosed with emphysema related to type ZZ a1antitrypsin deficiency (2). A clinical trial using lung densitometry as an outcome parameter has shown that intravenous augmentation therapy with human a1-antitrypsin significantly reduced emphysema progression, measured by the 15th percentile density point (PD15), in severely deficient subjects (3). No statistically significant effect of the treatment was seen on FEV1 or gas transfer over a study period of 2–3 years. Therefore, the implications of a change in lung density during a short period with respect to the more conventional long-term changes in physiology remains unknown. To address this, we studied long-term change in postbronchodilator spirometry and gas transfer in a1antitrypsin–deficient patients who participated in the Retinoid Treatment of Emphysema in Patients on the a(1)-Antitrypsin International Registry (REPAIR) study (4). We analyzed data from the Netherlands, the United Kingdom, and Sweden who had participated in the trial and received placebo treatment for a period of 12 months and had CT scans at baseline and at months 6 and 12 for assessment of the PD15 progression. After the trial was finished, we determined whether FEV1 and diffusing capacity of the lung for carbon monoxide (DLCO)/VA (KCO) were measured at least 6 years after the last visit for the REPAIR study. The difference from baseline was divided by the years between measurements to obtain a measure of the annual decline. We calculated in this subgroup the correlation between the short-term change in PD15 (during a 1-yr period), corrected for lung volume, and a long-term change in FEV1 and DLCO/VA (KCO) over a mean (SD) period of 8 (1.5) years. The data were analyzed in SPSS, version 15.0 (SPSS Inc., Chicago, IL). Statistical significance within groups was calculated with Student’s t test, and significance of Pearson correlation for annual decline between parameters was calculated by analysis of variance.
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
CORRESPONDENCE Table 1. Patient Characteristics Age, yr Sex, F/M, % of total Subjects who stopped smoking more than 1 yr, % Smoking, pack-years Concomitant medications LABA 1 ICS 1 LAMA LABA 1 ICS SGRQ total score FEV1 after 400 mg salbutamol, % predicted KCO, % predicted
53.9 6 6.3 27/73 85 19.0 6 12.3 58% 23% 44 6 16 46.8 6 16.7 41.7 6 10.8
Definition of abbreviations: ICS = inhaled corticosteroids; LABA = long-acting b-agonist; LAMA = long-acting muscarinic antagonist; SGRQ = Saint George Respiratory Questionnaire. Data are mean values 6 SD unless otherwise indicated.
A total of 51 subjects were analyzed (see Table 1 for patient characteristics). Five patients did not have a baseline gas transfer measurement, so the change could only be determined in the remaining 46 patients with data both at baseline and after 6 or more years. The change in lung function was annualized by dividing the total change by the number of years between baseline and final measurement. The mean annual decline in FEV1 was 66 6 60.9 ml (P , 0.0001) and in KCO was 27.5 6 25.9 mmol/kPa/L/min (P , 0.001). In the REPAIR study, the annual decline in PD15 was 2.15 6 3.27 g/L (P , 0.001). The annual decline in lung density PD15 correlated significantly with the annual decline in FEV1 (r = 0.41; P = 0.003), but not with KCO (r = 0.18; P = 0.185) (Figure 1). Interestingly, there was no correlation between the annual changes of FEV1 and KCO (r = 0.21; P = 0.165). Here we show, for the first time, that a statistically significant and clinically meaningful mean annual decline in FEV1 of 66 ml in 8 years is preceded by a statistically significant decline in lung density over only 1 year in subjects with emphysema related to PiZZ a1-antitrypsin deficiency. It is known that PD15 lung density is a sensitive parameter to detect changes in lung structure in emphysema (1). In at least three different clinical trials, placebo-treated patients had an annual decline in PD15 between 2 and 3 g/L (3, 4). Depending on the baseline patient characteristics of subjects with PiZZ a1-antitrypsin
A –15
Author disclosures are available with the text of this letter at www.atsjournals.org. Jan Stolk, M.D. Leiden University Medical Center Leiden, the Netherlands Robert A. Stockley, M.D. Queen Elizabeth Hospital Birmingham Birmingham, United Kingdom Eeva Piitulainen, M.D. Skane ˚ University Hospital Malmo, ¨ Sweden Berend C. Stoel, Ph.D. Leiden University Medical Center Leiden, the Netherlands
References 1. Stolk J, Putter H, Bakker EM, Shaker SB, Parr DG, Piitulainen E, Russi EW, Grebski E, Dirksen A, Stockley RA, et al. Progression parameters for emphysema: a clinical investigation. Respir Med 2007;101:1924–1930. 2. Schluchter MD, Stoller JK, Barker AF, Buist AS, Crystal RG, Donohue JF, Fallat RJ, Turino GM, Vreim CE, Wu MC; The Alpha 1-Antitrypsin Deficiency Registry Study Group. Feasibility of a clinical trial of
B
PD15 (gr/L) –10
deficiency and pulmonary emphysema, a significant decline in PD15 can be measured in 1–3 years, which is not possible for measures of airflow obstruction nor gas transfer (1). It is worth noting that in our study population, change in FEV1 was not correlated with a change in gas transfer over a mean period of 8 years, despite the statistically significant decline over that period of time. This suggests that the two parameters measure different anatomic consequences of emphysematous tissue destruction, a finding consistent with crosssectional studies reported by others (5). The current data suggest that in our patients with emphysema, a decline in lung density in 1 year is an early predictor of a decline in lung function occurring 8 years later. In conclusion, CT scan–derived short-term lung density PD15 annual decline is related to a future decline in FEV1, the diseasedefining biomarker of chronic obstructive pulmonary disease/ emphysema phenotype in severe a1-antitrypsin deficiency. Future studies may show similar results for patients with emphysema without the inherited deficiency. n
–5
5
–100
–50
50
–200
FEV1 (ml)
–300
FEV1 (ml)
–200
Kco (mmol/kg/L/min)
–300
Figure 1. (A) Relation between change in lung density (PD15) in grams per liter in 1 year and annual change in FEV1 in milliliters during a mean period of 8 years. The Pearson correlation is 0.41 (P = 0.003). (B) Relation between annual change in FEV1 in milliliters during a mean period of 8 years and annual change in gas transfer KCO (mmol/kPa/L/min) over the same period of time. The Pearson correlation is 0.21 (P = 0.165).
Correspondence
115
CORRESPONDENCE augmentation therapy for a1-antitrypsin deficiency. Am J Respir Crit Care Med 2000;161:796–801. 3. Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A. Therapeutic efficacy of a-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res 2010;11:136. 4. Stolk J, Stockley RA, Stoel BC, Cooper BG, Piitulainen E, Seersholm N, Chapman KR, Burdon JG, Decramer M, Abboud RT, et al. Randomised controlled trial for emphysema with a selective agonist of the g-type retinoic acid receptor. Eur Respir J 2012;40:306–312. 5. Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. Am J Respir Crit Care Med 2004;170:1172–1178.
Copyright © 2015 by the American Thoracic Society
The Role of Immunohistochemistry in Diagnosis of Pulmonary Tumor Thrombotic Microangiopathy To the Editor: We read with interest the case report of progressive right ventricular dysfunction by Buser and colleagues (1). It is important to clarify that tumor emboli and pulmonary tumor thrombotic microangiopathy (PTTM) are overlapping clinical entities and can only be differentiated by histology and immunohistochemistry. The presence of vascular endothelial growth factor (VEGF) and tissue factor (TF) are important features that allow one to distinguish between the two entities (2, 3), but those findings were not reported in this case. Much remains to be elucidated about the pathophysiology of these disorders. We recently took care of a similar case of acute right ventricular dysfunction, which progressed rapidly to death (4). We diagnosed PTTM without fibrocellular intimal proliferation because the immunohistochemistry was VEGF- and TF-positive. We note that Buser and colleagues’ patient had breast cancer, which is most commonly associated with tumor emboli rather than PTTM. It is possible that some previously reported cases of tumor emboli were, in fact, PTTM, as intimal proliferation was described in many cases, but no VEGF and TF stains were reported (5). n Author disclosures are available with the text of this letter at www.atsjournals.org. Pedro Salinas, M.D. Harold Manning, M.D. Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire
References 1. Buser M, Felizeter-Kessler M, Lenggenhager D, Maeder MT. Rapidly progressive pulmonary hypertension in a patient with pulmonary tumor thrombotic microangiopathy. Am J Respir Crit Care Med 2015; 191:711–712. 2. Chinen K, Tokuda Y, Fujiwara M, Fujioka Y. Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: an analysis of 6 autopsy cases and review of the literature. Pathol Res Pract 2010;206: 682–689. 3. Uruga H, Fujii T, Kurosaki A, Hanada S, Takaya H, Miyamoto A, Morokawa N, Homma S, Kishi K. Pulmonary tumor thrombotic microangiopathy: a clinical analysis of 30 autopsy cases. Intern Med 2013;52:1317–1323. 4. Salinas PD, Toth LN, Manning HL. A rare cause of postoperative hypotension. Chest 2015;147:e175–e180.
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5. Roberts KE, Hamele-Bena D, Saqi A, Stein CA, Cole RP. Pulmonary tumor embolism: a review of the literature. Am J Med 2003;115: 228–232.
Copyright © 2015 by the American Thoracic Society
Reply From the Authors: We thank Drs. Salinas and Manning for their interest in our case (1). We agree that a positive immunohistochemistry for vascular endothelial growth factor and tissue factor would have further strengthened the diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM) (2), as this would have been an additional indicator of a proliferative process rather than pure embolization of tumor cells. However, we feel that a number of other features favored a diagnosis of PTTM. For example, light microscopy clearly revealed fibrocellular intimal proliferation of pulmonary arterioles, as shown in the figure. In this context, we are somewhat surprised about the authors’ reference to a case of PTTM without fibrocellular intimal proliferation, the latter being a hallmark of the condition (3). The hemodynamic features were also consistent with PTTM; that is, the presence of a significantly increased pulmonary vascular resistance, and even obstruction of small vessels (3). For the readers’ interest, we highlight in more detail the hemodynamic constellation: There was a high mean pulmonary artery pressure (mPAP; 51 mm Hg), a discordance between left ventricular end-diastolic pressure (8 mm Hg) and mean pulmonary artery occlusion pressure (mPAOP; 34 mm Hg) with a spuriously small transpulmonary gradient (i.e., the difference between mPAP and mPAOP; 17 mm Hg), and V waves of the PAOP trace occurring early relative to the T wave of the ECG. The latter phenomenon may be explained by a backward transmission of the pulmonary arterial pressure signal from the obstructed and remodelled arterioles, which are anatomically closer to the balloon catheter than the left atrium, which is usually responsible for the generation of the true V waves that typically are seen simultaneously to the T wave; that is, later than in the present case (4). In addition, the presence of breast cancer does not exclude PTTM, as several cases of PTTM in the context of breast cancer have been described (2, 4, 5). n Author disclosures are available with the text of this letter at www.atsjournals.org. Micha T. Maeder, M.D. Marc Buser, M.D. Monika Felizeter-Kessler, M.D. Daniela Lenggenhager, M.D. Kantonsspital St. Gallen St. Gallen, Switzerland
References 1. Buser M, Felizeter-Kessler M, Lenggenhager D, Maeder MT. Rapidly progressive pulmonary hypertension in a patient with pulmonary tumor thrombotic microangiopathy. Am J Respir Crit Care Med 2015; 191:711–712. 2. Uruga H, Fujii T, Kurosaki A, Hanada S, Takaya H, Miyamoto A, Morokawa N, Homma S, Kishi K. Pulmonary tumor thrombotic
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 1 | July 1 2015
