CORRESPONDENCE A potential concern is the effect of exogenous flow on endogenous cardiac output. Assessment of this relationship is complex (12); however, it is unlikely that native cardiac output would perfectly adjust (increasing or decreasing) to match the induced ECMO flow _ O2, we would expect to see variations. Thus, if V_ O2 was dependent on D some correlating fluctuation. This conclusion is reinforced by the fact that the pattern of D_ O2 versus V_ O2 in the full cohort was identical to that in two patients without endogenous cardiac output (Figure 1). Finally, although O2 supply dependency has traditionally been proposed in patients with sepsis (1), careful delineation of _ O2–V_ O2 relationships in individual patients reveals no differences D between patients with proven sepsis versus those without sepsis (6); patients in the current had elevated inflammatory markers (e.g., CRP . 50 mg/L in most), suggesting important systemic inflammation (see Table E6). _ O2–V_ O2 relationships in In summary, we studied the D hemodynamically resuscitated critically ill patients with evidence of systemic inflammation receiving VA ECMO and found V_ O2 to be independent of D_ O2 in the ranges studied. Clinical trial registered with www.clinicaltrials.gov (NCT 01521195). n Author disclosures are available with the text of this letter at www.atsjournals.org. Acknowledgment: The authors thank the studied patients and their families and the intensive care unit team that provided their care. The authors also acknowledge the statistical expertise of Dr. Tim Grant of StatisticaMedica Ltd. Alvise Tosoni, M.D. Hospital for Sick Children Toronto, Ontario, Canada Gustavo La Rotta, M.D. University of Toronto Toronto, Ontario, Canada Cormac Breatnach, M.B. Vijay Anand, M.D. Celeste Foreman Leanne Davidson Hospital for Sick Children Toronto, Ontario, Canada Andrew N. Redington, M.D. University of Toronto Toronto, Ontario, Canada Brian P. Kavanagh, M.B. Hospital for Sick Children Toronto, Ontario, Canada and University of Toronto Toronto, Ontario, Canada
References 1. Friedman G, De Backer D, Shahla M, Vincent JL. Oxygen supply dependency can characterize septic shock. Intensive Care Med 1998; 24:118–123. 2. Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med 1987;13:223–229. 3. Phang PT, Cunningham KF, Ronco JJ, Wiggs BR, Russell JA. Mathematical coupling explains dependence of oxygen consumption on oxygen delivery in ARDS. Am J Respir Crit Care Med 1994;150:318–323.
Correspondence
4. Russell JA, Phang PT. The oxygen delivery/consumption controversy: approaches to management of the critically ill. Am J Respir Crit Care Med 1994;149:533–537. 5. Schumacker PT. Oxygen supply dependency in critical illness: an evolving understanding. Intensive Care Med 1998;24:97–99. 6. Ronco JJ, Fenwick JC, Tweeddale MG, Wiggs BR, Phang PT, Cooper DJ, Cunningham KF, Russell JA, Walley KR. Identification of the critical oxygen delivery for anaerobic metabolism in critically ill septic and nonseptic humans. JAMA 1993;270:1724–1730. 7. La Rotta G, Breatnach C, Tosoni A, Anand V, Foreman C, Davidson L, Redington A, Kavanagh BP. Unravelling oxygen transport relationships in critically ill children [abstract]. Acta Anestesiologica Scandinavica 2013;57:9.7. 8. Anand V, Tosoni A, La Rotta G, Breatnach C, Foreman C, Davidson L, Reddington AN, Kavanagh BP. Changing oxygen delivery does not alter oxygen consumption in critically ill children [abstract]. Am J Respir Crit Care Med 2014;189:A2599. 9. Li J, Zhang G, Benson L, Holtby H, Cai S, Humpl T, Van Arsdell GS, Redington AN, Caldarone CA. Comparison of the profiles of postoperative systemic hemodynamics and oxygen transport in neonates after the hybrid or the Norwood procedure: a pilot study. Circulation 2007;116:I179–I187. 10. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717–1722. 11. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R. A trial of goal-oriented hemodynamic therapy in critically ill patients: SvO2 Collaborative Group. N Engl J Med 1995;333:1025–1032. 12. Shen I, Levy FH, Vocelka CR, O’Rourke PP, Duncan BW, Thomas R, Verrier ED. Effect of extracorporeal membrane oxygenation on left ventricular function of swine. Ann Thorac Surg 2001;71:862–867.
Copyright © 2015 by the American Thoracic Society
Further Progress in Understanding Fibrosing Mediastinitis To the Editor: Fibrosing mediastinitis (FM) is a poorly understood disorder with unknown pathogenic mechanisms that typically affects otherwise healthy young adults. In the United States, it is most commonly a result of prior histoplasmosis (1–3). A typical presentation is functional autoamputation of one lung (vessels, airways, or both); however, FM can be life threatening for the 20% of patients in whom both lungs are affected. Therefore, medical therapy represents a tremendous unmet need. After many decades without such therapy, it is very encouraging that Westerly and Peikert are successfully targeting novel therapies to patients with FM (4). Peikert and colleagues also formerly reported that up to one-third of patients with FM demonstrate histologic features of IgG4-related disease according to established criteria for the pathology of IgG4-related disease (5, 6). On the basis of those This study was supported by Vanderbilt Clinical and Translational Science Award UL1 RR024975 from the National Center for Research Resources/ National Institutes of Health. Author Contributions: S.B.S. participated in the design and coordination of the study and drafted the letter. W.M. acquired all patient samples. J.E.L. participated in the design and coordination of the study and helped draft the letter. All authors read and approved the final manuscript. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
767
CORRESPONDENCE pathologic findings, the authors propose that measurement of serum IgG4 may be useful in patients with FM. We write to report a study of serum IgG4 levels in 40 serial patients with FM diagnosed by established clinical and radiographic criteria (1–3, 7). We tested serum IgG subclasses (IgG1, IgG2, IgG3, IgG4) using quantitative nephelometry at ARUP Laboratories (Salt Lake City, UT). IgG subsets were normal in all 40 patients with FM (mean IgG4, 32.3 mg/dl; SD, 24.7 mg/dl; median IgG4, 23.5 mg/dl; interquartile range, 32.3 mg/dl). None had a serum IgG4 above 140 mg/dl, a level recently described to have 96% negative predictive value (8). Our cohort included a broad severity of FM, from unilateral disease with minimal symptoms to bilateral disease with life-threatening complications, and we found no correlation of disease severity with IgG4 levels. More information is needed to understand the discordance between FM tissue and serum IgG4, but it seems possible that for a focal process such as FM, the burden of IgG4-producing plasma cells is not sufficient to increase the level in sera. n
(FM) (2). It is not surprising to find elevated IgG4 levels in a small subgroup of patients with FM. IgG4-RD likely only represents a small subgroup of FM (20%), and serum IgG4 levels are known to be normal in 20% of patients with IgG4-RD (2, 3). Normal IgG4 levels can be found in the presence of characteristic tissue changes, as pointed out by Dr. Strock and colleagues. In our clinical practice, we have not yet identified a patient presenting with FM and an elevated IgG4 level, despite measuring IgG4 levels regularly. In contrast, we have encountered patients with a clinical and histological diagnosis of IgG4-RD and normal IgG4 levels. All patients in our rituximab-treated series of FM had normal IgG4 levels (1). In summary, we agree with Dr. Strock and colleagues that routine measurements of serum IgG4 may add little to the diagnostic workup of patients with FM and that more data regarding the relationship between and FM and IgG4-RD is needed, particularly as rituximab has also been shown to be effective in IgG4-RD (4). n
Author disclosures are available with the text of this letter at www.atsjournals.org.
Author disclosures are available with the text of this letter at www.atsjournals.org. Tobias Peikert, M.D. Blair Westerly, M.D. Ulrich Specks, M.D. Mayo Clinic Rochester, Minnesota
Stephen B. Strock, M.D. Wendi Mason, C.R.N.P. James E. Loyd, M.D. Vanderbilt University Nashville, Tennessee
References
References 1. Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore) 1981;60:231–266. 2. Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine (Baltimore) 1988;67:295–310. 3. Sherrick AD, Brown LR, Harms GF, Myers JL. The radiographic findings of fibrosing mediastinitis. Chest 1994;106:484–489. 4. Westerly BD, Johnson GB, Maldonado F, Utz JP, Specks U, Peikert T. Targeting B lymphocytes in progressive fibrosing mediastinitis [letter]. Am J Respir Crit Care Med 2014;190:1069–1071. 5. Peikert T, Shrestha B, Aubry MC, Colby TV, Ryu JH, Sekiguchi H, Smyrk TC, Specks U, Yi ES. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. Int J Rheumatol 2012;2012:207056. 6. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Kloppel ¨ G, Heathcote JG, Khosroshahi A, Ferry JA, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181–1192. 7. Peikert T, Colby TV, Midthun DE, Pairolero PC, Edell ES, Schroeder DR, Specks U. Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, and adaptive immune response. Medicine (Baltimore) 2011;90:412–423. 8. Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis 2015;74:14–18.
Copyright © 2015 by the American Thoracic Society
Reply From the Authors: We thank Dr. Strock and colleagues for their interest in our research letter (1). We agree that IgG4-related disease (IgG4-RD) should be considered in the differential diagnosis of fibrosing mediastinitis 768
1. Westerly BD, Johnson GB, Maldonado F, Utz JP, Specks U, Peikert T. Targeting B lymphocytes in progressive fibrosing mediastinitis [letter]. Am J Respir Crit Care Med 2014;190:1069–1071. 2. Peikert T, Shrestha B, Aubry MC, Colby TV, Ryu JH, Sekiguchi H, Smyrk TC, Specks U, Yi ES. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. Int J Rheumatol 2012;2012:207056. 3. Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet 2015;385:1460–1471. 4. Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, Deshpande V, Smyrk TC, Chari S, Stone JH. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis 2015;74:1171–1177.
Copyright © 2015 by the American Thoracic Society
The Worldwide End-of-Life Practice for Patients in Intensive Care Units Study: Adding Africa To the Editor: We are impressed by the enormous effort by the investigators in the Worldwide End-of-Life Practice for Patients in Intensive Care Units (WELPICUS) Project (1) to develop worldwide consensus on the important topic of end-of-life care in the critically ill. Although we appreciate the difficult task of reaching critical care professionals throughout the world, we were disappointed that only 11 of the 1,366 survey responses were from Africa, and all those were from one country: South Africa (1). As physicians working in Kenya, we would like to highlight the growing field of critical care medicine in Africa and advocate for the whole of sub-Saharan Africa to be appropriately represented in these
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 6 | September 15 2015
References 1. Friedman G, De Backer D, Shahla M, Vincent JL. Oxygen supply dependency can characterize septic shock. Intensive Care Med 1998; 24:118–123. 2. Schumacker PT, Cain SM. The concept of a critical oxygen delivery. Intensive Care Med 1987;13:223–229. 3. Phang PT, Cunningham KF, Ronco JJ, Wiggs BR, Russell JA. Mathematical coupling explains dependence of oxygen consumption on oxygen delivery in ARDS. Am J Respir Crit Care Med 1994;150:318–323.
Correspondence
4. Russell JA, Phang PT. The oxygen delivery/consumption controversy: approaches to management of the critically ill. Am J Respir Crit Care Med 1994;149:533–537. 5. Schumacker PT. Oxygen supply dependency in critical illness: an evolving understanding. Intensive Care Med 1998;24:97–99. 6. Ronco JJ, Fenwick JC, Tweeddale MG, Wiggs BR, Phang PT, Cooper DJ, Cunningham KF, Russell JA, Walley KR. Identification of the critical oxygen delivery for anaerobic metabolism in critically ill septic and nonseptic humans. JAMA 1993;270:1724–1730. 7. La Rotta G, Breatnach C, Tosoni A, Anand V, Foreman C, Davidson L, Redington A, Kavanagh BP. Unravelling oxygen transport relationships in critically ill children [abstract]. Acta Anestesiologica Scandinavica 2013;57:9.7. 8. Anand V, Tosoni A, La Rotta G, Breatnach C, Foreman C, Davidson L, Reddington AN, Kavanagh BP. Changing oxygen delivery does not alter oxygen consumption in critically ill children [abstract]. Am J Respir Crit Care Med 2014;189:A2599. 9. Li J, Zhang G, Benson L, Holtby H, Cai S, Humpl T, Van Arsdell GS, Redington AN, Caldarone CA. Comparison of the profiles of postoperative systemic hemodynamics and oxygen transport in neonates after the hybrid or the Norwood procedure: a pilot study. Circulation 2007;116:I179–I187. 10. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717–1722. 11. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R. A trial of goal-oriented hemodynamic therapy in critically ill patients: SvO2 Collaborative Group. N Engl J Med 1995;333:1025–1032. 12. Shen I, Levy FH, Vocelka CR, O’Rourke PP, Duncan BW, Thomas R, Verrier ED. Effect of extracorporeal membrane oxygenation on left ventricular function of swine. Ann Thorac Surg 2001;71:862–867.
Copyright © 2015 by the American Thoracic Society
Further Progress in Understanding Fibrosing Mediastinitis To the Editor: Fibrosing mediastinitis (FM) is a poorly understood disorder with unknown pathogenic mechanisms that typically affects otherwise healthy young adults. In the United States, it is most commonly a result of prior histoplasmosis (1–3). A typical presentation is functional autoamputation of one lung (vessels, airways, or both); however, FM can be life threatening for the 20% of patients in whom both lungs are affected. Therefore, medical therapy represents a tremendous unmet need. After many decades without such therapy, it is very encouraging that Westerly and Peikert are successfully targeting novel therapies to patients with FM (4). Peikert and colleagues also formerly reported that up to one-third of patients with FM demonstrate histologic features of IgG4-related disease according to established criteria for the pathology of IgG4-related disease (5, 6). On the basis of those This study was supported by Vanderbilt Clinical and Translational Science Award UL1 RR024975 from the National Center for Research Resources/ National Institutes of Health. Author Contributions: S.B.S. participated in the design and coordination of the study and drafted the letter. W.M. acquired all patient samples. J.E.L. participated in the design and coordination of the study and helped draft the letter. All authors read and approved the final manuscript. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
767
CORRESPONDENCE pathologic findings, the authors propose that measurement of serum IgG4 may be useful in patients with FM. We write to report a study of serum IgG4 levels in 40 serial patients with FM diagnosed by established clinical and radiographic criteria (1–3, 7). We tested serum IgG subclasses (IgG1, IgG2, IgG3, IgG4) using quantitative nephelometry at ARUP Laboratories (Salt Lake City, UT). IgG subsets were normal in all 40 patients with FM (mean IgG4, 32.3 mg/dl; SD, 24.7 mg/dl; median IgG4, 23.5 mg/dl; interquartile range, 32.3 mg/dl). None had a serum IgG4 above 140 mg/dl, a level recently described to have 96% negative predictive value (8). Our cohort included a broad severity of FM, from unilateral disease with minimal symptoms to bilateral disease with life-threatening complications, and we found no correlation of disease severity with IgG4 levels. More information is needed to understand the discordance between FM tissue and serum IgG4, but it seems possible that for a focal process such as FM, the burden of IgG4-producing plasma cells is not sufficient to increase the level in sera. n
(FM) (2). It is not surprising to find elevated IgG4 levels in a small subgroup of patients with FM. IgG4-RD likely only represents a small subgroup of FM (20%), and serum IgG4 levels are known to be normal in 20% of patients with IgG4-RD (2, 3). Normal IgG4 levels can be found in the presence of characteristic tissue changes, as pointed out by Dr. Strock and colleagues. In our clinical practice, we have not yet identified a patient presenting with FM and an elevated IgG4 level, despite measuring IgG4 levels regularly. In contrast, we have encountered patients with a clinical and histological diagnosis of IgG4-RD and normal IgG4 levels. All patients in our rituximab-treated series of FM had normal IgG4 levels (1). In summary, we agree with Dr. Strock and colleagues that routine measurements of serum IgG4 may add little to the diagnostic workup of patients with FM and that more data regarding the relationship between and FM and IgG4-RD is needed, particularly as rituximab has also been shown to be effective in IgG4-RD (4). n
Author disclosures are available with the text of this letter at www.atsjournals.org.
Author disclosures are available with the text of this letter at www.atsjournals.org. Tobias Peikert, M.D. Blair Westerly, M.D. Ulrich Specks, M.D. Mayo Clinic Rochester, Minnesota
Stephen B. Strock, M.D. Wendi Mason, C.R.N.P. James E. Loyd, M.D. Vanderbilt University Nashville, Tennessee
References
References 1. Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore) 1981;60:231–266. 2. Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine (Baltimore) 1988;67:295–310. 3. Sherrick AD, Brown LR, Harms GF, Myers JL. The radiographic findings of fibrosing mediastinitis. Chest 1994;106:484–489. 4. Westerly BD, Johnson GB, Maldonado F, Utz JP, Specks U, Peikert T. Targeting B lymphocytes in progressive fibrosing mediastinitis [letter]. Am J Respir Crit Care Med 2014;190:1069–1071. 5. Peikert T, Shrestha B, Aubry MC, Colby TV, Ryu JH, Sekiguchi H, Smyrk TC, Specks U, Yi ES. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. Int J Rheumatol 2012;2012:207056. 6. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Kloppel ¨ G, Heathcote JG, Khosroshahi A, Ferry JA, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181–1192. 7. Peikert T, Colby TV, Midthun DE, Pairolero PC, Edell ES, Schroeder DR, Specks U. Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, and adaptive immune response. Medicine (Baltimore) 2011;90:412–423. 8. Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis 2015;74:14–18.
Copyright © 2015 by the American Thoracic Society
Reply From the Authors: We thank Dr. Strock and colleagues for their interest in our research letter (1). We agree that IgG4-related disease (IgG4-RD) should be considered in the differential diagnosis of fibrosing mediastinitis 768
1. Westerly BD, Johnson GB, Maldonado F, Utz JP, Specks U, Peikert T. Targeting B lymphocytes in progressive fibrosing mediastinitis [letter]. Am J Respir Crit Care Med 2014;190:1069–1071. 2. Peikert T, Shrestha B, Aubry MC, Colby TV, Ryu JH, Sekiguchi H, Smyrk TC, Specks U, Yi ES. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. Int J Rheumatol 2012;2012:207056. 3. Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet 2015;385:1460–1471. 4. Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, Deshpande V, Smyrk TC, Chari S, Stone JH. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis 2015;74:1171–1177.
Copyright © 2015 by the American Thoracic Society
The Worldwide End-of-Life Practice for Patients in Intensive Care Units Study: Adding Africa To the Editor: We are impressed by the enormous effort by the investigators in the Worldwide End-of-Life Practice for Patients in Intensive Care Units (WELPICUS) Project (1) to develop worldwide consensus on the important topic of end-of-life care in the critically ill. Although we appreciate the difficult task of reaching critical care professionals throughout the world, we were disappointed that only 11 of the 1,366 survey responses were from Africa, and all those were from one country: South Africa (1). As physicians working in Kenya, we would like to highlight the growing field of critical care medicine in Africa and advocate for the whole of sub-Saharan Africa to be appropriately represented in these
American Journal of Respiratory and Critical Care Medicine Volume 192 Number 6 | September 15 2015
