- Email: [email protected]
Clinical Applications of Induced Sputum
itors are developed and tested will patients with sleep complaints be best served with the use of such devices. Nancy A. Collop, MD, FCCP Johns Hopkins University Baltimore, MD The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Nancy A. Collop, MD, FCCP, Johns Hopkins University, Division of Pulmonary/CCM, Johns Hopkins University DOM, 1830 East Monument St, Room 555, Baltimore, MD 21205; e-mail: [email protected] DOI: 10.1378/chest.130.5.1625a
Sputum Induction for Diagnosis of Pulmonary Tuberculosis Ready for Prime Time?
The authors have no financial or other potential conflicts of interest. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Donald C. Vinh, MD, Section of Infectious Diseases, University of Manitoba, 543–730 William Ave, Winnipeg, MB, Canada, R3E 0W3; e-mail: [email protected] DOI: 10.1378/chest.130.5.1626
References 1 Brightling CE. Clinical applications of induced sputum. Chest 2006; 129:1344 –1348 2 Anderson C, Inhaber N, Menzies D. Comparison of sputum induction with fiber-optic bronchoscopy in the diagnosis of tuberculosis. Am J Respir Crit Care Med 1995; 152:1570 –1574 3 Conde MB, Soares SL, Mello FC, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis. Am J Respir Crit Care Med 2000; 162:2238 –2240 4 Al Zahrani K, Al Jahdali H, Poirier L, et al. Yield of smear, culture and amplification tests from repeated sputum induction for the diagnosis of pulmonary tuberculosis. Int J Tuberc Lung Dis 2001; 5:855– 860 5 McWilliams T, Wells AU, Harrison AC, et al. Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis. Thorax 2002; 57:1010 –1014
To the Editor: In his review of the clinical applications of induced sputum, Dr. Brightling1 states that “sputum induction provides a real alternative to bronchoscopy and BAL in the diagnosis of pulmonary tuberculosis.” However, it is the clinical utility of serial sputum induction as a primary diagnostic modality for pulmonary tuberculosis (TB) that should be emphasized. In the diagnosis of pulmonary TB, sputum induction has been shown to have a better diagnostic yield than spontaneous sputum and gastric aspirates. Sputum induction fell into disuse, though, with the advent of fiberoptic bronchoscopy, which has become the primary method in many institutions. However, several studies2,3 have demonstrated that the diagnostic yield of one induced sputum is at least equivalent to that of one bronchoscopy with BAL, both in terms of acid-fast smear and mycobacterial culture. The diagnostic yield of induced sputa is further increased when multiple (three or more) specimens are obtained, with reported detection rates by smear of 91 to 98% and by culture of 99 to 100%,4 significantly higher than with bronchoscopy alone.5 Induced sputum is a very well-tolerated procedure, with extremely low rates of adverse events (most commonly, headache, and bronchospasm/cough). Bronchoscopy has the inherent risks of an invasive procedure requiring a sedative. Both procedures must be performed in an airborne infection isolation room with respiratory protective equipment to minimize the risk of nosocomial transmission. Cost analysis studies2,5 also favor sputum induction over bronchoscopy. Sputum induction can also be used effectively to diagnose other infections, such as Pneumocystis jiroveci pneumonia, and for assessment of other pulmonary conditions, including malignancy, interstitial lung diseases, and granulomatous diseases (eg, sarcoidosis). Thus, the rationale of performing bronchoscopy with BAL because of the perceived improved diagnostic yield in noninfectious pulmonary conditions may not always be valid. Rather than an “alternative” test, as described by Dr. Brightling, serial induced sputa should be considered as an inexpensive, and safe, primary diagnostic modality. Donald C. Vinh, MD Winnipeg, MB, Canada Dick Menzies, MD Montreal, QC, Canada 1626
Clinical Applications of Induced Sputum To the Editor: I would like to thank Drs. Vinh and Menzies for their comments on the recent review in CHEST (May 2006)1 of the clinical applications of induced sputum testing. The review was focused on the added value that sputum induction provides the clinician when managing patients with airways disease; in particular, that the presence of a sputum eosinophilia is important in the diagnosis of nonasthmatic chronic cough2,3 and is beneficial in guiding corticosteroid therapy in asthma patients.4 The value of sputum induction in the setting of other respiratory diseases such as the diagnosis of pulmonary tuberculosis (TB) and lung cancer, and its potential role in interstitial lung disease were highlighted but were given less prominence in the review. Drs. Vinh and Menzies championed the role of induced sputum in the diagnosis of pulmonary TB. I agree that, compared to bronchoscopy, repeated induced sputum testing offers many advantages in terms of safety and cost with at least comparable if not greater diagnostic yield.5 Induced sputum testing in the diagnosis of pulmonary TB carries a risk of nosocomial TB; therefore, it is important to reiterate that it needs to be performed under conditions of respiratory isolation. Therefore, induced sputum testing has a role in the management of several respiratory conditions and should be a technique that is widely available to respiratory physicians. Christopher E. Brightling, PhD, FCCP Glenfield Hospital Leicester, UK
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence
Correspondence to: Christopher Brightling, PhD, FCCP, Institute for Lung Health, University of Leicester, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, UK; e-mail: [email protected] DOI: 10.1378/chest.130.5.1626a
References 1 Brightling CE. Clinical applications of induced sputum. Chest 2006; 129:1344 –1348 2 Brightling CE. Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines. Chest 2006; 129(suppl):116S–121S 3 Melvin R. Pratter MR, Brightling CE, et al. An empiric integrative approach to the management of cough: ACCP evidence-based clinical practice guidelines. Chest 2006; 129(suppl):222S–231S 4 Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360:1715–1721 5 McWilliams T, Wells AU, Harrison AC, et al. Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis. Thorax 2002; 57:1010 –1014
The Role of NT-proBNP as a Prognostic Marker in Pulmonary Hypertension To the Editor: In an article recently published in CHEST (May 2006), Fijalkowska et al1 provided important information on the value of N-terminal pro-type B natriuretic peptide (NT-proBNP) as a prognostic marker in patients with pulmonary hypertension (PH). There is growing interest in the role of natriuretic peptides in understanding the natural history of PH.2,3 The authors demonstrated that NT-proBNP is correlated with echocardiographic variables of right ventricular function and confirmed previous findings about the correlation of NT-proBNP with invasive hemodynamic variables. Unfortunately, the prognostic utility of NT-proBNP is limited by several factors that were not acknowledged in their article. First, they did not present 95% confidence intervals around the estimates of sensitivity and specificity for predicting death. Since there were only 16 deaths in this cohort, the confidence intervals were quite wide, making the utility of the proposed NT-proBNP cutoff problematic. Although the sensitivity of this test was reported as 88%, the lower bound of the 95% confidence interval was 63%. The specificity of this test was reported as 53%, but the lower bound of the 95% confidence interval was 38%. Second, the authors used stepwise regression to build their survival model and screened several variables for inclusion. Multivariate models built using stepwise regression techniques are unreliable when there are ⬍ 10 outcomes per screened variable.4 Finally, once the presented model is prognostic rather than explanatory it is important to use appropriate statistical shrinkage techniques to account for the fact that the authors used the same data set to derive and validate this model, and to avoid overfitting.5 The study adds further details about the role of natriuretic peptides in the evaluation of PH patients, but its provocative findings about the prognostic value of NT-proBNP remain to be confirmed. Roge´rio Souza, MD, PhD Carlos Jardim, MD, PhD Carlos Carvalho, MD, PhD University of Sa˜o Paulo Medical School Sa˜o Paulo, Brazil Gordon Rubenfeld, MS, MD University of Washington Seattle, WA www.chestjournal.org
None of the authors presents any conflict of interest with this letter. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Roge´rio Souza, MD, PhD, Pulmonary Department, University of Sa˜o Paulo Medical School, R. Afonso de Freitas 451, No. 112, Sa˜o Paulo, Brazil 04006-052; e-mail: [email protected] DOI: 10.1378/chest.130.5.1627
References 1 Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum Nterminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006; 129: 1313–1321 2 Souza R, Bogossian HB, Humbert M, et al. N-terminal-probrain natriuretic peptide as a haemodynamic marker in idiopathic pulmonary arterial hypertension. Eur Respir J 2005; 25:509 –513 3 Leuchte HH, Holzapfel M, Baumgartner RA, et al. Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension. Chest 2005; 128:2368 – 2374 4 Diamond GA. Stepwise transgression. Am J Cardiol 1990; 65:1047 5 Steyerberg EW, Eijkemans MJ, Harrell FE Jr, et al. Prognostic modeling with logistic regression analysis: in search of a sensible strategy in small data sets. Med Decis Making 2001; 21:45–56 To the Editor: We thank very much Dr. Souza et al for their interest in our article (May 2006)1 on the potential clinical role of N-terminalpro-brain natriuretic peptide (NT-proBNP) estimation in patients with pulmonary arterial hypertension (PAH). We also agree with their concerns regarding the universal validity of the prognostic cutoff values that were reported in our article. Clearly, with a study group of slightly ⬎ 50 patients we would not impose or recommend such values for universal prognostic use. Furthermore, we do not believe that even the most sophisticated statistical analysis could extract more objective truth from such a database. On the other hand, by looking at the receiving operating characteristic analysis and trying to identify prognostic thresholds we wanted to avoid the common practice of reporting the prognostic significance of median values. While highly dependent on the initial characteristics of the study group of the index trial, such median values later often become surprisingly “magic numbers” and are extrapolated to other populations with even less evidence. This was the case both for a 6-min walk test distance of 332 m or an NT-proBNP concentration of 150 pg/L as a result of the reports of Nagaya et al2 and Miyamoto et al.3 Therefore, rather than defending our 1,400 and 3,400 pg/L thresholds, even though they were derived from a receiving operating characteristic analysis, we would reply by issuing a call for pulling together data on PAH patients whose baseline clinical characteristics and NT-proBNP concentrations were tested with a method similar to the one used in our study. This may be true, for instance, for the study population of a trial recently published by Souza et al.4 We have recently witnessed a great step forward in the understanding of the efficacy of the new drugs developed for the treatment of PAH thanks to global collaboration between expert centers. It is time to try to start building networks of collaboration to learn more about prognostic indexes and clinical end points. We would be available for this type of collaboration. Regarding other, technical remarks, the 95% confidence intervals were not given for prognostic thresholds in order to make the presentation of the results clearer. However, all data needed for the calculation of those intervals were available in the published CHEST / 130 / 5 / NOVEMBER, 2006
1627
Sputum Induction for Diagnosis of Pulmonary Tuberculosis Ready for Prime Time?
The authors have no financial or other potential conflicts of interest. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Donald C. Vinh, MD, Section of Infectious Diseases, University of Manitoba, 543–730 William Ave, Winnipeg, MB, Canada, R3E 0W3; e-mail: [email protected] DOI: 10.1378/chest.130.5.1626
References 1 Brightling CE. Clinical applications of induced sputum. Chest 2006; 129:1344 –1348 2 Anderson C, Inhaber N, Menzies D. Comparison of sputum induction with fiber-optic bronchoscopy in the diagnosis of tuberculosis. Am J Respir Crit Care Med 1995; 152:1570 –1574 3 Conde MB, Soares SL, Mello FC, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis. Am J Respir Crit Care Med 2000; 162:2238 –2240 4 Al Zahrani K, Al Jahdali H, Poirier L, et al. Yield of smear, culture and amplification tests from repeated sputum induction for the diagnosis of pulmonary tuberculosis. Int J Tuberc Lung Dis 2001; 5:855– 860 5 McWilliams T, Wells AU, Harrison AC, et al. Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis. Thorax 2002; 57:1010 –1014
To the Editor: In his review of the clinical applications of induced sputum, Dr. Brightling1 states that “sputum induction provides a real alternative to bronchoscopy and BAL in the diagnosis of pulmonary tuberculosis.” However, it is the clinical utility of serial sputum induction as a primary diagnostic modality for pulmonary tuberculosis (TB) that should be emphasized. In the diagnosis of pulmonary TB, sputum induction has been shown to have a better diagnostic yield than spontaneous sputum and gastric aspirates. Sputum induction fell into disuse, though, with the advent of fiberoptic bronchoscopy, which has become the primary method in many institutions. However, several studies2,3 have demonstrated that the diagnostic yield of one induced sputum is at least equivalent to that of one bronchoscopy with BAL, both in terms of acid-fast smear and mycobacterial culture. The diagnostic yield of induced sputa is further increased when multiple (three or more) specimens are obtained, with reported detection rates by smear of 91 to 98% and by culture of 99 to 100%,4 significantly higher than with bronchoscopy alone.5 Induced sputum is a very well-tolerated procedure, with extremely low rates of adverse events (most commonly, headache, and bronchospasm/cough). Bronchoscopy has the inherent risks of an invasive procedure requiring a sedative. Both procedures must be performed in an airborne infection isolation room with respiratory protective equipment to minimize the risk of nosocomial transmission. Cost analysis studies2,5 also favor sputum induction over bronchoscopy. Sputum induction can also be used effectively to diagnose other infections, such as Pneumocystis jiroveci pneumonia, and for assessment of other pulmonary conditions, including malignancy, interstitial lung diseases, and granulomatous diseases (eg, sarcoidosis). Thus, the rationale of performing bronchoscopy with BAL because of the perceived improved diagnostic yield in noninfectious pulmonary conditions may not always be valid. Rather than an “alternative” test, as described by Dr. Brightling, serial induced sputa should be considered as an inexpensive, and safe, primary diagnostic modality. Donald C. Vinh, MD Winnipeg, MB, Canada Dick Menzies, MD Montreal, QC, Canada 1626
Clinical Applications of Induced Sputum To the Editor: I would like to thank Drs. Vinh and Menzies for their comments on the recent review in CHEST (May 2006)1 of the clinical applications of induced sputum testing. The review was focused on the added value that sputum induction provides the clinician when managing patients with airways disease; in particular, that the presence of a sputum eosinophilia is important in the diagnosis of nonasthmatic chronic cough2,3 and is beneficial in guiding corticosteroid therapy in asthma patients.4 The value of sputum induction in the setting of other respiratory diseases such as the diagnosis of pulmonary tuberculosis (TB) and lung cancer, and its potential role in interstitial lung disease were highlighted but were given less prominence in the review. Drs. Vinh and Menzies championed the role of induced sputum in the diagnosis of pulmonary TB. I agree that, compared to bronchoscopy, repeated induced sputum testing offers many advantages in terms of safety and cost with at least comparable if not greater diagnostic yield.5 Induced sputum testing in the diagnosis of pulmonary TB carries a risk of nosocomial TB; therefore, it is important to reiterate that it needs to be performed under conditions of respiratory isolation. Therefore, induced sputum testing has a role in the management of several respiratory conditions and should be a technique that is widely available to respiratory physicians. Christopher E. Brightling, PhD, FCCP Glenfield Hospital Leicester, UK
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence
Correspondence to: Christopher Brightling, PhD, FCCP, Institute for Lung Health, University of Leicester, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, UK; e-mail: [email protected] DOI: 10.1378/chest.130.5.1626a
References 1 Brightling CE. Clinical applications of induced sputum. Chest 2006; 129:1344 –1348 2 Brightling CE. Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines. Chest 2006; 129(suppl):116S–121S 3 Melvin R. Pratter MR, Brightling CE, et al. An empiric integrative approach to the management of cough: ACCP evidence-based clinical practice guidelines. Chest 2006; 129(suppl):222S–231S 4 Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360:1715–1721 5 McWilliams T, Wells AU, Harrison AC, et al. Induced sputum and bronchoscopy in the diagnosis of pulmonary tuberculosis. Thorax 2002; 57:1010 –1014
The Role of NT-proBNP as a Prognostic Marker in Pulmonary Hypertension To the Editor: In an article recently published in CHEST (May 2006), Fijalkowska et al1 provided important information on the value of N-terminal pro-type B natriuretic peptide (NT-proBNP) as a prognostic marker in patients with pulmonary hypertension (PH). There is growing interest in the role of natriuretic peptides in understanding the natural history of PH.2,3 The authors demonstrated that NT-proBNP is correlated with echocardiographic variables of right ventricular function and confirmed previous findings about the correlation of NT-proBNP with invasive hemodynamic variables. Unfortunately, the prognostic utility of NT-proBNP is limited by several factors that were not acknowledged in their article. First, they did not present 95% confidence intervals around the estimates of sensitivity and specificity for predicting death. Since there were only 16 deaths in this cohort, the confidence intervals were quite wide, making the utility of the proposed NT-proBNP cutoff problematic. Although the sensitivity of this test was reported as 88%, the lower bound of the 95% confidence interval was 63%. The specificity of this test was reported as 53%, but the lower bound of the 95% confidence interval was 38%. Second, the authors used stepwise regression to build their survival model and screened several variables for inclusion. Multivariate models built using stepwise regression techniques are unreliable when there are ⬍ 10 outcomes per screened variable.4 Finally, once the presented model is prognostic rather than explanatory it is important to use appropriate statistical shrinkage techniques to account for the fact that the authors used the same data set to derive and validate this model, and to avoid overfitting.5 The study adds further details about the role of natriuretic peptides in the evaluation of PH patients, but its provocative findings about the prognostic value of NT-proBNP remain to be confirmed. Roge´rio Souza, MD, PhD Carlos Jardim, MD, PhD Carlos Carvalho, MD, PhD University of Sa˜o Paulo Medical School Sa˜o Paulo, Brazil Gordon Rubenfeld, MS, MD University of Washington Seattle, WA www.chestjournal.org
None of the authors presents any conflict of interest with this letter. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Roge´rio Souza, MD, PhD, Pulmonary Department, University of Sa˜o Paulo Medical School, R. Afonso de Freitas 451, No. 112, Sa˜o Paulo, Brazil 04006-052; e-mail: [email protected] DOI: 10.1378/chest.130.5.1627
References 1 Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum Nterminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006; 129: 1313–1321 2 Souza R, Bogossian HB, Humbert M, et al. N-terminal-probrain natriuretic peptide as a haemodynamic marker in idiopathic pulmonary arterial hypertension. Eur Respir J 2005; 25:509 –513 3 Leuchte HH, Holzapfel M, Baumgartner RA, et al. Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension. Chest 2005; 128:2368 – 2374 4 Diamond GA. Stepwise transgression. Am J Cardiol 1990; 65:1047 5 Steyerberg EW, Eijkemans MJ, Harrell FE Jr, et al. Prognostic modeling with logistic regression analysis: in search of a sensible strategy in small data sets. Med Decis Making 2001; 21:45–56 To the Editor: We thank very much Dr. Souza et al for their interest in our article (May 2006)1 on the potential clinical role of N-terminalpro-brain natriuretic peptide (NT-proBNP) estimation in patients with pulmonary arterial hypertension (PAH). We also agree with their concerns regarding the universal validity of the prognostic cutoff values that were reported in our article. Clearly, with a study group of slightly ⬎ 50 patients we would not impose or recommend such values for universal prognostic use. Furthermore, we do not believe that even the most sophisticated statistical analysis could extract more objective truth from such a database. On the other hand, by looking at the receiving operating characteristic analysis and trying to identify prognostic thresholds we wanted to avoid the common practice of reporting the prognostic significance of median values. While highly dependent on the initial characteristics of the study group of the index trial, such median values later often become surprisingly “magic numbers” and are extrapolated to other populations with even less evidence. This was the case both for a 6-min walk test distance of 332 m or an NT-proBNP concentration of 150 pg/L as a result of the reports of Nagaya et al2 and Miyamoto et al.3 Therefore, rather than defending our 1,400 and 3,400 pg/L thresholds, even though they were derived from a receiving operating characteristic analysis, we would reply by issuing a call for pulling together data on PAH patients whose baseline clinical characteristics and NT-proBNP concentrations were tested with a method similar to the one used in our study. This may be true, for instance, for the study population of a trial recently published by Souza et al.4 We have recently witnessed a great step forward in the understanding of the efficacy of the new drugs developed for the treatment of PAH thanks to global collaboration between expert centers. It is time to try to start building networks of collaboration to learn more about prognostic indexes and clinical end points. We would be available for this type of collaboration. Regarding other, technical remarks, the 95% confidence intervals were not given for prognostic thresholds in order to make the presentation of the results clearer. However, all data needed for the calculation of those intervals were available in the published CHEST / 130 / 5 / NOVEMBER, 2006
1627