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EDITORIAL
Non-invasive markers of pulmonary hypertension in interstitial lung disease: Is cardiopulmonary exercise testing the Holy Grail? Key words: cardiopulmonary exercise test, interstitial lung disease, pulmonary hypertension, ventilatory inefficiency.
Interstitial lung diseases (ILD) comprise a heterogeneous group of pathologic conditions that are characterized by diffuse parenchymal infiltrates primarily involving the pulmonary interstitium, which share common physiological, clinical and imaging characteristics. Cough and exercise-induced dyspnoea are usually the first symptoms of ILD, while restrictive defect and impaired gas exchange are the most common physiological findings. However, prognosis is highly variable ranging from the imminently treatable infectious ILD to untreatable chronic entities, such as idiopathic pulmonary fibrosis.1,2 Pulmonary hypertension (PH), which may complicate the course of several ILD, has important implications regarding clinical manifestation, functional capacity and prognosis of ILD patients.2,3 Its specific prevalence varies widely according to the nature and severity of the underlying disorder, and the gold standard for its diagnosis is right heart catheterization (RHC).4 Although multifactorial in nature, progressive pulmonary fibrosis, worsening hypoxaemia and pulmonary vascular remodelling with fibrotic destruction and distortion of vessels seem to be common mechanisms of PH establishment in most of ILD.2 Several studies have investigated the potential association between PH and various markers of disease severity, but results are not validated in all ILD entities. The most useful resting physiological measurement seems to be diffusion capacity for carbon monoxide (DLCO); the presence of PH is inversely correlated with DLCO values, but this association has been mainly established in idiopathic pulmonary fibrosis and systemic sclerosis.5–7 The concomitant presence of low DLCO and resting hypoxaemia increases the probability of detecting PH in IPF.7 Interestingly, lung volumes measurements are not associated with PH presence in most ILD,2,3 although the severity of respiratory restriction is classified based on forced vital capacity and total lung capacity values. Exercise limitation is one of the hallmarks of PH; thus there is a strong rationale in evaluating the impact of PH on exercise parameters, instead of resting ones. The 6-min walking test (6MWT) is a cheap and easy-to-perform test in everyday clinical practice, and it has been traditionally used to evaluate outcomes of interest among patients with PH and lung parenchymal disease.8 Mean distance walked, nadir oxygen saturation and need of oxygen supplementation during the test are the parameters most © 2014 Asian Pacific Society of Respirology
often associated with PH.7,8 However, this is not always the case; the role and validity of 6MWT in detecting PH has been questioned in several ILD entities, including IPF and systemic sclerosis,9,10 that is in two disorders where the prevalence of PH could be particularly high. Cardiopulmonary exercise testing (CPET) provides an objective and quantitative assessment of metabolic, pulmonary and cardiovascular responses during exercise. Modern CPET devices record several functional parameters, including breath-by-breath measures of oxygen uptake, carbon dioxide production and ventilation, thus allowing an overall evaluation of the functional capacity of patients with heart and lung diseases.11,12 Therefore, a joint statement of American Thoracic Society/American College of Chest Physicians has recommended the use of CPET for the assessment of patients with PH.13 In this issue of Respirology, Armstrong et al.14 present a study that advances our knowledge regarding the association between PH and exercise measurements. In a cohort of ILD patients being evaluated for lung transplantation, a direct comparison of 6MWT, CPET and pulmonary function testing variables in terms of correlation to mean pulmonary artery pressure (mPAP) values is conducted for the first time in literature. The authors reported that patients with PH presented with lower maximum exercise capacity, lower 6MWT and lower DLCO% predicted, confirming the results of previous reports. The intriguing finding of the current study is that CPET measurements of ventilatory inefficiency, as established by peak minute ventilation to rate of carbon dioxide produced (VE/VCO2) and even more by peak partial pressure of end-tidal carbon dioxide (PETCO2) were the parameters best correlated to mPAP values. Moreover, both VE/VCO2 and PETCO2 correlated with the severity of disease, establishing an incremental elevation as mPAP increased from mild and moderate to severe. The direct comparison of PETCO2, 6MWT and DLCO indicated that PETCO2 is by far the most accurate predictor of PH presence. Loss of pulmonary vasculature, increased metabolic demands, a shallow metabolic pattern, hypoxaemia and acidaemia15 may all result to increased ventilatory responses during exercise; high peak VE/VCO2 and low peak PETCO2 are the non-invasive markers of this ventilation-perfusion mismatching seen in patients with ILD and PH. Previous studies have indicated this strong correlation between parameters of ventilatory inefficiency and PH in patients with pulmonary fibrosis.15,16 However, the Respirology (2014) 19, 621–622 doi: 10.1111/resp.12321
622
Editorial
study of Armstrong et al. is novel with regard to three aspects: patients with ILD of various aetiology were studied, RHC was utilized to diagnose PH in all patients and a direct comparison between physiologic measurements in rest, submaximal and maximal exercising state were conducted, thus confirming that CPET is the most accurate functional method of detecting PH among patients with parenchymal lung disease. The establishment of a non-invasive functional marker of PH presence among patients with ILD is of great significance. Given the adverse impact of PH on the course of the disease,9 the early detection of signs of PH development with CPET may have important implications on disease progression and treatment. What needs to be clarified is whether CPET utilization is more informative regarding the presence of PH in specific ILD entities. The number of patients in Armstrong et al.’s study was relatively small, and separate analysis could not be conducted for each ILD entity, so this is a hypothesis that needs to be investigated with large prospective studies in the future. Moreover, we need to explore further whether the markers of PH presence detected by CPET carry any therapeutic implication for ILD patients. Treatment options for PH associated with ILD are limited, whereas the recent published experience with specific PH therapies was disappointing. In the light of these data, CPET offers a useful non-invasive tool that enables the discrimination of ILD patients with predominant circulatory exercise limitation. The design of clinical trials focused on this specific subgroup that would probably benefit more from PH-targeted therapies represents a major challenge for the future. Afroditi K. Boutou, MD, MSc, PhD, Georgia G. Pitsiou, MD, PhD and Paraskevi Argyropoulou, MD, PhD Respiratory Failure Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
REFERENCES 1 Chetta A, Marangio E, Olivieri D. Pulmonary function testing in interstitial lung diseases. Respiration 2004; 71: 209–13. 2 Nathan SD. Pulmonary hypertension in interstitial lung disease. Int. J. Clin. Pract. 2008; 62: 21–8. 3 Pitsiou G, Papakosta D, Bouros D. Pulmonary hypertension in idiopathic pulmonary fibrosis: a review. Respiration 2011; 82: 294–304.
Respirology (2014) 19, 621–622
4 Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC), European Respiratory Society (ERS), International Society of Heart and Lung Transplantation (ISHLT), Galiè N, Hoeper MM, Humbert M, Torbicki J-L, Vachiery A, Barbera JA, Beghetti M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Respir. J. 2009; 34: 1219–63. 5 Handa T, Nagai S, Miki S, Ueda S, Yukawa N, Fushimi Y, Ohta K, Mimori T, Mishima M, Izumi T. Incidence of pulmonary hypertension and its clinical relevance in patients with interstitial pneumonias: comparison between idiopathic and collagen vascular disease associated interstitial pneumonias. Intern. Med. 2007; 46: 831–7. 6 Launay D, Mouthon L, Hachulla E, Pagnoux C, de Groote P, Remy-Jardin M, Matran R, Lambert M, Queyrel V, Morell-Dubois S et al. Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J. Rheumatol. 2007; 34: 1005–11. 7 Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129: 746–52. 8 Ruiz-Cano MJ, Escribano P, Alonso R, Delgado J, Carreira P, Velazquez T, Sanchez MAG, Sáenz de la Calzada C. Comparison of baseline characteristics and survival between patients with idiopathic and connective tissue disease-related pulmonary arterial hypertension. J. Heart Lung Transplant. 2009; 28: 621–7. 9 Caminati A, Cassandro R, Harari S. Pulmonary hypertension in chronic interstitial lung diseases. Eur. Respir. Rev. 2013; 22: 292–301. 10 Impens AJ, Wangkaew S, Seibold JR. The 6-minute walk test in scleroderma—how measuring everything measures nothing. Rheumatology (Oxford) 2008; 47: v68–9. 11 Arena R, Sietsema KE. Cardiopulmonary exercise testing in the clinical evaluation of patients with heart and lung disease. Circulation 2011; 123: 668–80. 12 Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M et al. Clinician’s guide to cardiopulmonary exercise testing in adults a scientific statement from the american heart association. Circulation 2010; 122: 191–225. 13 American Thoracic Society, American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am. J. Respir. Crit. Care Med. 2003; 167: 211–77. 14 Armstrong HF, Christian Schulze P, Bacchetta M, Thirapatarapong W, Bartels MN. The impact of pulmonary hypertension on exercise performance in patients with interstitial lung disease undergoing evaluation for lung transplantation. Respirology 2014; 19: 675–82. 15 Boutou AK, Pitsiou GG, Trigonis I, Papakosta D, Kontou PK, Chavouzis N, Nakou C, Argyropoulou P, Wasserman K, Stanopoulos I. Exercise capacity in idiopathic pulmonary fibrosis: the effect of pulmonary hypertension. Respirology 2011; 16: 451–8. 16 Gläser S, Noga O, Koch B, Opitz CF, Schmidt B, Temmesfeld B, Dörr M, Ewert R, Schäperet C. Impact of pulmonary hypertension on gas exchange and exercise capacity in patients with pulmonary fibrosis. Respir. Med. 2009; 103: 317–24.
© 2014 Asian Pacific Society of Respirology
EDITORIAL
Non-invasive markers of pulmonary hypertension in interstitial lung disease: Is cardiopulmonary exercise testing the Holy Grail? Key words: cardiopulmonary exercise test, interstitial lung disease, pulmonary hypertension, ventilatory inefficiency.
Interstitial lung diseases (ILD) comprise a heterogeneous group of pathologic conditions that are characterized by diffuse parenchymal infiltrates primarily involving the pulmonary interstitium, which share common physiological, clinical and imaging characteristics. Cough and exercise-induced dyspnoea are usually the first symptoms of ILD, while restrictive defect and impaired gas exchange are the most common physiological findings. However, prognosis is highly variable ranging from the imminently treatable infectious ILD to untreatable chronic entities, such as idiopathic pulmonary fibrosis.1,2 Pulmonary hypertension (PH), which may complicate the course of several ILD, has important implications regarding clinical manifestation, functional capacity and prognosis of ILD patients.2,3 Its specific prevalence varies widely according to the nature and severity of the underlying disorder, and the gold standard for its diagnosis is right heart catheterization (RHC).4 Although multifactorial in nature, progressive pulmonary fibrosis, worsening hypoxaemia and pulmonary vascular remodelling with fibrotic destruction and distortion of vessels seem to be common mechanisms of PH establishment in most of ILD.2 Several studies have investigated the potential association between PH and various markers of disease severity, but results are not validated in all ILD entities. The most useful resting physiological measurement seems to be diffusion capacity for carbon monoxide (DLCO); the presence of PH is inversely correlated with DLCO values, but this association has been mainly established in idiopathic pulmonary fibrosis and systemic sclerosis.5–7 The concomitant presence of low DLCO and resting hypoxaemia increases the probability of detecting PH in IPF.7 Interestingly, lung volumes measurements are not associated with PH presence in most ILD,2,3 although the severity of respiratory restriction is classified based on forced vital capacity and total lung capacity values. Exercise limitation is one of the hallmarks of PH; thus there is a strong rationale in evaluating the impact of PH on exercise parameters, instead of resting ones. The 6-min walking test (6MWT) is a cheap and easy-to-perform test in everyday clinical practice, and it has been traditionally used to evaluate outcomes of interest among patients with PH and lung parenchymal disease.8 Mean distance walked, nadir oxygen saturation and need of oxygen supplementation during the test are the parameters most © 2014 Asian Pacific Society of Respirology
often associated with PH.7,8 However, this is not always the case; the role and validity of 6MWT in detecting PH has been questioned in several ILD entities, including IPF and systemic sclerosis,9,10 that is in two disorders where the prevalence of PH could be particularly high. Cardiopulmonary exercise testing (CPET) provides an objective and quantitative assessment of metabolic, pulmonary and cardiovascular responses during exercise. Modern CPET devices record several functional parameters, including breath-by-breath measures of oxygen uptake, carbon dioxide production and ventilation, thus allowing an overall evaluation of the functional capacity of patients with heart and lung diseases.11,12 Therefore, a joint statement of American Thoracic Society/American College of Chest Physicians has recommended the use of CPET for the assessment of patients with PH.13 In this issue of Respirology, Armstrong et al.14 present a study that advances our knowledge regarding the association between PH and exercise measurements. In a cohort of ILD patients being evaluated for lung transplantation, a direct comparison of 6MWT, CPET and pulmonary function testing variables in terms of correlation to mean pulmonary artery pressure (mPAP) values is conducted for the first time in literature. The authors reported that patients with PH presented with lower maximum exercise capacity, lower 6MWT and lower DLCO% predicted, confirming the results of previous reports. The intriguing finding of the current study is that CPET measurements of ventilatory inefficiency, as established by peak minute ventilation to rate of carbon dioxide produced (VE/VCO2) and even more by peak partial pressure of end-tidal carbon dioxide (PETCO2) were the parameters best correlated to mPAP values. Moreover, both VE/VCO2 and PETCO2 correlated with the severity of disease, establishing an incremental elevation as mPAP increased from mild and moderate to severe. The direct comparison of PETCO2, 6MWT and DLCO indicated that PETCO2 is by far the most accurate predictor of PH presence. Loss of pulmonary vasculature, increased metabolic demands, a shallow metabolic pattern, hypoxaemia and acidaemia15 may all result to increased ventilatory responses during exercise; high peak VE/VCO2 and low peak PETCO2 are the non-invasive markers of this ventilation-perfusion mismatching seen in patients with ILD and PH. Previous studies have indicated this strong correlation between parameters of ventilatory inefficiency and PH in patients with pulmonary fibrosis.15,16 However, the Respirology (2014) 19, 621–622 doi: 10.1111/resp.12321
622
Editorial
study of Armstrong et al. is novel with regard to three aspects: patients with ILD of various aetiology were studied, RHC was utilized to diagnose PH in all patients and a direct comparison between physiologic measurements in rest, submaximal and maximal exercising state were conducted, thus confirming that CPET is the most accurate functional method of detecting PH among patients with parenchymal lung disease. The establishment of a non-invasive functional marker of PH presence among patients with ILD is of great significance. Given the adverse impact of PH on the course of the disease,9 the early detection of signs of PH development with CPET may have important implications on disease progression and treatment. What needs to be clarified is whether CPET utilization is more informative regarding the presence of PH in specific ILD entities. The number of patients in Armstrong et al.’s study was relatively small, and separate analysis could not be conducted for each ILD entity, so this is a hypothesis that needs to be investigated with large prospective studies in the future. Moreover, we need to explore further whether the markers of PH presence detected by CPET carry any therapeutic implication for ILD patients. Treatment options for PH associated with ILD are limited, whereas the recent published experience with specific PH therapies was disappointing. In the light of these data, CPET offers a useful non-invasive tool that enables the discrimination of ILD patients with predominant circulatory exercise limitation. The design of clinical trials focused on this specific subgroup that would probably benefit more from PH-targeted therapies represents a major challenge for the future. Afroditi K. Boutou, MD, MSc, PhD, Georgia G. Pitsiou, MD, PhD and Paraskevi Argyropoulou, MD, PhD Respiratory Failure Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
REFERENCES 1 Chetta A, Marangio E, Olivieri D. Pulmonary function testing in interstitial lung diseases. Respiration 2004; 71: 209–13. 2 Nathan SD. Pulmonary hypertension in interstitial lung disease. Int. J. Clin. Pract. 2008; 62: 21–8. 3 Pitsiou G, Papakosta D, Bouros D. Pulmonary hypertension in idiopathic pulmonary fibrosis: a review. Respiration 2011; 82: 294–304.
Respirology (2014) 19, 621–622
4 Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC), European Respiratory Society (ERS), International Society of Heart and Lung Transplantation (ISHLT), Galiè N, Hoeper MM, Humbert M, Torbicki J-L, Vachiery A, Barbera JA, Beghetti M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Respir. J. 2009; 34: 1219–63. 5 Handa T, Nagai S, Miki S, Ueda S, Yukawa N, Fushimi Y, Ohta K, Mimori T, Mishima M, Izumi T. Incidence of pulmonary hypertension and its clinical relevance in patients with interstitial pneumonias: comparison between idiopathic and collagen vascular disease associated interstitial pneumonias. Intern. Med. 2007; 46: 831–7. 6 Launay D, Mouthon L, Hachulla E, Pagnoux C, de Groote P, Remy-Jardin M, Matran R, Lambert M, Queyrel V, Morell-Dubois S et al. Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J. Rheumatol. 2007; 34: 1005–11. 7 Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129: 746–52. 8 Ruiz-Cano MJ, Escribano P, Alonso R, Delgado J, Carreira P, Velazquez T, Sanchez MAG, Sáenz de la Calzada C. Comparison of baseline characteristics and survival between patients with idiopathic and connective tissue disease-related pulmonary arterial hypertension. J. Heart Lung Transplant. 2009; 28: 621–7. 9 Caminati A, Cassandro R, Harari S. Pulmonary hypertension in chronic interstitial lung diseases. Eur. Respir. Rev. 2013; 22: 292–301. 10 Impens AJ, Wangkaew S, Seibold JR. The 6-minute walk test in scleroderma—how measuring everything measures nothing. Rheumatology (Oxford) 2008; 47: v68–9. 11 Arena R, Sietsema KE. Cardiopulmonary exercise testing in the clinical evaluation of patients with heart and lung disease. Circulation 2011; 123: 668–80. 12 Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M et al. Clinician’s guide to cardiopulmonary exercise testing in adults a scientific statement from the american heart association. Circulation 2010; 122: 191–225. 13 American Thoracic Society, American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am. J. Respir. Crit. Care Med. 2003; 167: 211–77. 14 Armstrong HF, Christian Schulze P, Bacchetta M, Thirapatarapong W, Bartels MN. The impact of pulmonary hypertension on exercise performance in patients with interstitial lung disease undergoing evaluation for lung transplantation. Respirology 2014; 19: 675–82. 15 Boutou AK, Pitsiou GG, Trigonis I, Papakosta D, Kontou PK, Chavouzis N, Nakou C, Argyropoulou P, Wasserman K, Stanopoulos I. Exercise capacity in idiopathic pulmonary fibrosis: the effect of pulmonary hypertension. Respirology 2011; 16: 451–8. 16 Gläser S, Noga O, Koch B, Opitz CF, Schmidt B, Temmesfeld B, Dörr M, Ewert R, Schäperet C. Impact of pulmonary hypertension on gas exchange and exercise capacity in patients with pulmonary fibrosis. Respir. Med. 2009; 103: 317–24.
© 2014 Asian Pacific Society of Respirology
