- Email: [email protected]
Quantifying Latent TB Infection
6. Svanberg L. Influence of posture on the lung volumes, ventilation and circulation in normals; a spirometric-bronchospirometric investigation. Scand J Clin Lab Invest. 1957;9(suppl 25):1-195.
Increased Morning Cortisol Level Effect of Sleep Fragmentation or Stress Response to the Last Annoying Stimulus? To the Editor: Fragmented sleep has great effects on daily life, including sleepiness, impaired cognitive function, decreased mood, and elevated BP.1-3 In an excellent study in a recent issue of CHEST (January 2010), Stamatakis and Punjabi4 show that two nights of nonspecific sleep fragmentation in healthy volunteers led to decreased insulin sensitivity and glucose effectiveness despite normal sleep duration. This study helps to elucidate the influence of sleep fragmentation per se on glucose metabolism without the confounding effect of sleep duration or hypoxic insult, as seen in the case of obstructive sleep apnea. The authors concluded that increased sympathetic activity and adrenocortical activity likely mediate the adverse effects of poor sleep quality, based on the finding of increased morning cortisol levels and increased sympathetic activity. They used auditory and mechanical stimuli to elicit EEG microarousals with a frequency of 30 events/h. If the stimuli failed, the subsequent stimulus got larger by increasing the tone volume of auditory stimuli or combining the two kinds of stimulus. In this study, most of the stimuli were effective, including the last one at the end of the sleep period, which was probably the largest stimulus in intensity. When a human is exposed to noxious or potentially noxious stimuli, there is an increased secretion of corticotropin and, consequently, a rise in the circulating cortisol. Approximately 90% to 95% of the cortisol in the plasma binds to plasma proteins, which slows the elimination of cortisol from the plasma. Therefore, cortisol has a relatively long half-life of 60 to 90 min and thus a lasting action.5 An increased morning cortisol level (measured at 8:00 am in this study) may be the consequence of the last effective stimulus, elicited 1 or 2 h prior to measurement, rather than that of sleep fragmentation. As the authors stated, elevations of cortisol, even within the normal physiologic range, can decrease insulin sensitivity, enhance hepatic gluconeogenesis, and inhibit insulin secretion.6 To settle this dispute, one additional night of nonfragmented sleep following the two nights of fragmented sleep is needed as a sleep-recovery period, as stated in some sleep deprivation studies.7-9 In addition, one single stimulus is given near the end of the night, which is of the same intensity and timing as the last stimulus in the previous night of sleep fragmentation. If an elevated cortisol level is still observed in the coming morning (day 5), the disturbed glucose metabolism may not be attributed to the effect of sleep fragmentation. Besides, evening cortisol concentration following sleep deprivation was raised in sleep deprivation studies, reflecting an impairment of negative feedback control of the hypothalamopituitary-adrenal axis.8,10 This finding was not observed in this study, suggestive of a different mechanism underlying sleep deprivation and sleep fragmentation, or just an unequal stress in intensity, which deserves further exploring. Kun-Ta Chou, MD Guang-Ming Shiao, MD, FCCP Taipei, Taiwan
Affiliations: From the Chest Department (Drs Chou and Shiao), Taipei Veterans General Hospital; and Faculty of Medicine, School of Medicine, National Yang-Ming University (Dr Shiao). Financialnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesorganizations whose products or services may be discussed in this article. Correspondence to: Kun-Ta Chou, MD, Chest Department, Taipei Veterans General Hospital, No. 201, Section 2 Shih-Pei Rd, Taipei 112, Taiwan; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org sitemiscreprints.xhtml). DOI: 10.1378/chest.10-0433
References 1. Kingshott RN, Cosway RJ, Deary IJ, Douglas NJ. The effect of sleep fragmentation on cognitive processing using computerized topographic brain mapping. J Sleep Res. 2000;9(4): 353-357. 2. Morrell MJ, Finn L, Kim H, Peppard PE, Badr MS, Young T. Sleep fragmentation, awake blood pressure, and sleepdisordered breathing in a population-based study. Am J Respir Crit Care Med. 2000;162(6):2091-2096. 3. Stepanski EJ. The effect of sleep fragmentation on daytime function. Sleep. 2002;25(3):268-276. 4. Stamatakis KA, Punjabi NM. Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest. 2010; 137(1):95-101. 5. Guyton AC, Hall JE. Guyton & Hall Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Saunders; 2006:947. 6. Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond). 1999; 96(5):513-523. 7. Follenius M, Brandenberger G, Bandesapt JJ, Libert JP, Ehrhart J. Nocturnal cortisol release in relation to sleep structure. Sleep. 1992;15(1):21-27. 8. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999; 354(9188):1435-1439. 9. Akerstedt T, Palmblad J, de la Torre B, Marana R, Gillberg M. Adrenocortical and gonadal steroids during sleep deprivation. Sleep. 1980;3(1):23-30. 10. Leproult R, Copinschi G, Buxton O, Van Cauter E. Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 1997;20(10):865-870.
Quantifying Latent TB Infection The Dilemma Continues To the Editor: The study in the May 2010 issue of CHEST by Gallant et al,1 whereby they simultaneously compared the quantitative results of in vivo and in vitro assays for TB infection generates a lot of interest. There are a couple of issues that need to be addressed in this study. The authors have used Bacillus Calmette-Guérin (BCG), purified protein derivative (PPD), and early-secreted antigenic target-6 (ESAT-6) as the triggers for the release of interferon (IFN)-g in the in vitro assays. The authors have justified the use of PPD in both the in vitro and in vivo assays because it may avoid the antigen specificity as the confounding factor, but the use of BCG as an in vitro trigger remains questionable because the BCG status of the population in question is not known.
460
Correspondence
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on August 3, 2010 © 2010 American College of Chest Physicians
ESAT-6 and complement fixation protein-10 (CFP-10) have been suggested as standard triggers for IFN-g release from lymphocytes,2 but the employment of BCG and PPD for this purpose warrants further research. The higher specificity of ESAT-6 and CFP-10 (ESAT-6 in this study) as compared with other triggers is reflected in the authors’ observation that among the 100 patients with tuberculin skin test induration of , 5 mm, only 7% showed IFN-g production in response to ESAT-6. On the other hand, 74% of the BCG subgroup and 65% of the PPD subgroup had positive IFN-g production. This rather highlights the redundant nature of in vitro and in vivo assays, provided the antigens used are only ESAT-6 and CFP-10, although the higher specificity of these IFN-g release assays is well proven.2 Latent TB infection has been a gray area for decades now because of the heterogenous prevalence of the disease and infection around the globe. We need further studies to reach definite conclusions. Alkesh Kumar Khurana, MD, DNB, FCCP Ujjawal Khurana, MD, DNB Chandigarh, India Affiliations: From the Department of Pulmonary Medicine (Dr A. K. Khurana) and the Department of Pathology (Dr U. Khurana), Government Medical College and Hospital. Financialnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesorganizations whose products or services may be discussed in this article. Correspondence to: Alkesh Kumar Khurana, MD, DNB, FCCP, Department of Pulmonary Medicine, Government Medical College and Hospital, Section 32, Chandigarh, 160030 India; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org sitemiscreprints.xhtml). DOI: 10.1378/chest.10-0473
References 1. Gallant CJ, Cobat A, Simkin L, et al. Tuberculin skin test and in vitro assays provide complementary measures of antimycobacterial immunity in children and adolescents. Chest. 2010;137(5):1071-1077. 2. Brodie D, Lederer DJ, Gallardo JS, Trivedi SH, Burzynski JN, Schluger NW. Use of an interferon-g release assay to diagnose latent tuberculosis infection in foreign-born patients. Chest. 2008;133(4):869-874.
Response
Caroline J. Gallant, PhD Montreal, QC, Canada Aurelie Cobat, MD Paris, France Eileen G. Hoal, PhD Tygerberg, South Africa Erwin Schurr, PhD Montreal, QC, Canada Affiliations: From the McGill Centre for the Study of Host Resistance and the Departments of Human Genetics and Medicine (Drs Gallant and Schurr), McGill University; the Faculté de Médecine Necker (Dr Cobat), Université de Paris Descartes; and the Department of Molecular Biology and Human Genetics (Dr Hoal), Medical Research Council Centre for Molecular and Cellular Biology, Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University. Financialnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesorganizations whose products or services may be discussed in this article. Correspondence to: Erwin Schurr, PhD, Montreal General Hospital Research Institute, 1650 Cedar Ave, Room L11-521, Montreal, QC, H3G 1A4, Canada; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org sitemiscreprints.xhtml). DOI: 10.1378/chest.10-1000
References 1. Gallant CJ, Cobat A, Simkin L, et al. Tuberculin skin test and in vitro assays provide complementary measures of antimycobacterial immunity in children and adolescents. Chest. 2010;137(5):1071-1077. 2. Cobat A, Gallant CJ, Simkin L, et al. High heritability of antimycobacterial immunity in an area of hyperendemicity for tuberculosis disease. J Infect Dis. 2010;201(1):15-19. 3. Corrigall J, Coetzee D, Cameron N. Is the Western Cape at risk of an outbreak of preventable childhood diseases? Lessons from an evaluation of routine immunisation coverage. S Afr Med J. 2008;98(1):41-45.
Is Pulmonary Arterial Hypertension Really a Late Complication of Systemic Sclerosis?
To the Editor: Two interesting points are raised by Drs Khurana and Khurana about our study in CHEST (May 2010).1 As correctly pointed out, we did not attempt to verify the Bacillus Calmette-Guérin (BCG) vaccination status of our study subjects. However, BCG vaccination at birth has been mandatory in the study area since 1975,2 and vaccine coverage in the Western Cape is very high at 99% (95% CI, 99%-99.5%).3 Hence, we can safely assume that the majority of our study subjects were BCG vaccinated. The other point concerns redundancy of in vivo and in vitro assays. Our study was not designed to evaluate the possible redundancy of cutoff points and positive vs negative responses. Rather, we focused on the correlation in the extent of responsiveness between assays and detected low correlation between assay readouts. From this, we inferred biologic nonredundancy of the different assays. We agree that further studies into the mycobacterial www.chestpubs.org
host responses, including the immune assays currently used for diagnosis of latent TB infection, are needed.
To the Editor: We read with great interest the report by Hachulla et al in CHEST (May 2009)1 regarding the time of presentation of pulmonary arterial hypertension (PAH) during the course of scleroderma disease (SSc). In their cohort of 78 patients with SScassociated PAH (PAH-SSc), the authors found the following: (1) 55% of the patients had early-onset PAH (ie, within the first 5 years of SSc-related non-Raynaud symptoms); (2) These patients were older at the time of SSc diagnosis and presented with more severe hemodynamics, although functional class (FC) and mortality outcomes were similar to those of patients with lateonset PAH; (3) Diffusing capacity of the lung for carbon monoxide (Dlco) , 35% and FC class 4 were the only predictors for survival CHEST / 138 / 2 / AUGUST, 2010
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on August 3, 2010 © 2010 American College of Chest Physicians
461
Increased Morning Cortisol Level Effect of Sleep Fragmentation or Stress Response to the Last Annoying Stimulus? To the Editor: Fragmented sleep has great effects on daily life, including sleepiness, impaired cognitive function, decreased mood, and elevated BP.1-3 In an excellent study in a recent issue of CHEST (January 2010), Stamatakis and Punjabi4 show that two nights of nonspecific sleep fragmentation in healthy volunteers led to decreased insulin sensitivity and glucose effectiveness despite normal sleep duration. This study helps to elucidate the influence of sleep fragmentation per se on glucose metabolism without the confounding effect of sleep duration or hypoxic insult, as seen in the case of obstructive sleep apnea. The authors concluded that increased sympathetic activity and adrenocortical activity likely mediate the adverse effects of poor sleep quality, based on the finding of increased morning cortisol levels and increased sympathetic activity. They used auditory and mechanical stimuli to elicit EEG microarousals with a frequency of 30 events/h. If the stimuli failed, the subsequent stimulus got larger by increasing the tone volume of auditory stimuli or combining the two kinds of stimulus. In this study, most of the stimuli were effective, including the last one at the end of the sleep period, which was probably the largest stimulus in intensity. When a human is exposed to noxious or potentially noxious stimuli, there is an increased secretion of corticotropin and, consequently, a rise in the circulating cortisol. Approximately 90% to 95% of the cortisol in the plasma binds to plasma proteins, which slows the elimination of cortisol from the plasma. Therefore, cortisol has a relatively long half-life of 60 to 90 min and thus a lasting action.5 An increased morning cortisol level (measured at 8:00 am in this study) may be the consequence of the last effective stimulus, elicited 1 or 2 h prior to measurement, rather than that of sleep fragmentation. As the authors stated, elevations of cortisol, even within the normal physiologic range, can decrease insulin sensitivity, enhance hepatic gluconeogenesis, and inhibit insulin secretion.6 To settle this dispute, one additional night of nonfragmented sleep following the two nights of fragmented sleep is needed as a sleep-recovery period, as stated in some sleep deprivation studies.7-9 In addition, one single stimulus is given near the end of the night, which is of the same intensity and timing as the last stimulus in the previous night of sleep fragmentation. If an elevated cortisol level is still observed in the coming morning (day 5), the disturbed glucose metabolism may not be attributed to the effect of sleep fragmentation. Besides, evening cortisol concentration following sleep deprivation was raised in sleep deprivation studies, reflecting an impairment of negative feedback control of the hypothalamopituitary-adrenal axis.8,10 This finding was not observed in this study, suggestive of a different mechanism underlying sleep deprivation and sleep fragmentation, or just an unequal stress in intensity, which deserves further exploring. Kun-Ta Chou, MD Guang-Ming Shiao, MD, FCCP Taipei, Taiwan
Affiliations: From the Chest Department (Drs Chou and Shiao), Taipei Veterans General Hospital; and Faculty of Medicine, School of Medicine, National Yang-Ming University (Dr Shiao). Financialnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesorganizations whose products or services may be discussed in this article. Correspondence to: Kun-Ta Chou, MD, Chest Department, Taipei Veterans General Hospital, No. 201, Section 2 Shih-Pei Rd, Taipei 112, Taiwan; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org sitemiscreprints.xhtml). DOI: 10.1378/chest.10-0433
References 1. Kingshott RN, Cosway RJ, Deary IJ, Douglas NJ. The effect of sleep fragmentation on cognitive processing using computerized topographic brain mapping. J Sleep Res. 2000;9(4): 353-357. 2. Morrell MJ, Finn L, Kim H, Peppard PE, Badr MS, Young T. Sleep fragmentation, awake blood pressure, and sleepdisordered breathing in a population-based study. Am J Respir Crit Care Med. 2000;162(6):2091-2096. 3. Stepanski EJ. The effect of sleep fragmentation on daytime function. Sleep. 2002;25(3):268-276. 4. Stamatakis KA, Punjabi NM. Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest. 2010; 137(1):95-101. 5. Guyton AC, Hall JE. Guyton & Hall Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Saunders; 2006:947. 6. Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond). 1999; 96(5):513-523. 7. Follenius M, Brandenberger G, Bandesapt JJ, Libert JP, Ehrhart J. Nocturnal cortisol release in relation to sleep structure. Sleep. 1992;15(1):21-27. 8. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999; 354(9188):1435-1439. 9. Akerstedt T, Palmblad J, de la Torre B, Marana R, Gillberg M. Adrenocortical and gonadal steroids during sleep deprivation. Sleep. 1980;3(1):23-30. 10. Leproult R, Copinschi G, Buxton O, Van Cauter E. Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 1997;20(10):865-870.
Quantifying Latent TB Infection The Dilemma Continues To the Editor: The study in the May 2010 issue of CHEST by Gallant et al,1 whereby they simultaneously compared the quantitative results of in vivo and in vitro assays for TB infection generates a lot of interest. There are a couple of issues that need to be addressed in this study. The authors have used Bacillus Calmette-Guérin (BCG), purified protein derivative (PPD), and early-secreted antigenic target-6 (ESAT-6) as the triggers for the release of interferon (IFN)-g in the in vitro assays. The authors have justified the use of PPD in both the in vitro and in vivo assays because it may avoid the antigen specificity as the confounding factor, but the use of BCG as an in vitro trigger remains questionable because the BCG status of the population in question is not known.
460
Correspondence
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on August 3, 2010 © 2010 American College of Chest Physicians
ESAT-6 and complement fixation protein-10 (CFP-10) have been suggested as standard triggers for IFN-g release from lymphocytes,2 but the employment of BCG and PPD for this purpose warrants further research. The higher specificity of ESAT-6 and CFP-10 (ESAT-6 in this study) as compared with other triggers is reflected in the authors’ observation that among the 100 patients with tuberculin skin test induration of , 5 mm, only 7% showed IFN-g production in response to ESAT-6. On the other hand, 74% of the BCG subgroup and 65% of the PPD subgroup had positive IFN-g production. This rather highlights the redundant nature of in vitro and in vivo assays, provided the antigens used are only ESAT-6 and CFP-10, although the higher specificity of these IFN-g release assays is well proven.2 Latent TB infection has been a gray area for decades now because of the heterogenous prevalence of the disease and infection around the globe. We need further studies to reach definite conclusions. Alkesh Kumar Khurana, MD, DNB, FCCP Ujjawal Khurana, MD, DNB Chandigarh, India Affiliations: From the Department of Pulmonary Medicine (Dr A. K. Khurana) and the Department of Pathology (Dr U. Khurana), Government Medical College and Hospital. Financialnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesorganizations whose products or services may be discussed in this article. Correspondence to: Alkesh Kumar Khurana, MD, DNB, FCCP, Department of Pulmonary Medicine, Government Medical College and Hospital, Section 32, Chandigarh, 160030 India; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org sitemiscreprints.xhtml). DOI: 10.1378/chest.10-0473
References 1. Gallant CJ, Cobat A, Simkin L, et al. Tuberculin skin test and in vitro assays provide complementary measures of antimycobacterial immunity in children and adolescents. Chest. 2010;137(5):1071-1077. 2. Brodie D, Lederer DJ, Gallardo JS, Trivedi SH, Burzynski JN, Schluger NW. Use of an interferon-g release assay to diagnose latent tuberculosis infection in foreign-born patients. Chest. 2008;133(4):869-874.
Response
Caroline J. Gallant, PhD Montreal, QC, Canada Aurelie Cobat, MD Paris, France Eileen G. Hoal, PhD Tygerberg, South Africa Erwin Schurr, PhD Montreal, QC, Canada Affiliations: From the McGill Centre for the Study of Host Resistance and the Departments of Human Genetics and Medicine (Drs Gallant and Schurr), McGill University; the Faculté de Médecine Necker (Dr Cobat), Université de Paris Descartes; and the Department of Molecular Biology and Human Genetics (Dr Hoal), Medical Research Council Centre for Molecular and Cellular Biology, Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University. Financialnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesorganizations whose products or services may be discussed in this article. Correspondence to: Erwin Schurr, PhD, Montreal General Hospital Research Institute, 1650 Cedar Ave, Room L11-521, Montreal, QC, H3G 1A4, Canada; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org sitemiscreprints.xhtml). DOI: 10.1378/chest.10-1000
References 1. Gallant CJ, Cobat A, Simkin L, et al. Tuberculin skin test and in vitro assays provide complementary measures of antimycobacterial immunity in children and adolescents. Chest. 2010;137(5):1071-1077. 2. Cobat A, Gallant CJ, Simkin L, et al. High heritability of antimycobacterial immunity in an area of hyperendemicity for tuberculosis disease. J Infect Dis. 2010;201(1):15-19. 3. Corrigall J, Coetzee D, Cameron N. Is the Western Cape at risk of an outbreak of preventable childhood diseases? Lessons from an evaluation of routine immunisation coverage. S Afr Med J. 2008;98(1):41-45.
Is Pulmonary Arterial Hypertension Really a Late Complication of Systemic Sclerosis?
To the Editor: Two interesting points are raised by Drs Khurana and Khurana about our study in CHEST (May 2010).1 As correctly pointed out, we did not attempt to verify the Bacillus Calmette-Guérin (BCG) vaccination status of our study subjects. However, BCG vaccination at birth has been mandatory in the study area since 1975,2 and vaccine coverage in the Western Cape is very high at 99% (95% CI, 99%-99.5%).3 Hence, we can safely assume that the majority of our study subjects were BCG vaccinated. The other point concerns redundancy of in vivo and in vitro assays. Our study was not designed to evaluate the possible redundancy of cutoff points and positive vs negative responses. Rather, we focused on the correlation in the extent of responsiveness between assays and detected low correlation between assay readouts. From this, we inferred biologic nonredundancy of the different assays. We agree that further studies into the mycobacterial www.chestpubs.org
host responses, including the immune assays currently used for diagnosis of latent TB infection, are needed.
To the Editor: We read with great interest the report by Hachulla et al in CHEST (May 2009)1 regarding the time of presentation of pulmonary arterial hypertension (PAH) during the course of scleroderma disease (SSc). In their cohort of 78 patients with SScassociated PAH (PAH-SSc), the authors found the following: (1) 55% of the patients had early-onset PAH (ie, within the first 5 years of SSc-related non-Raynaud symptoms); (2) These patients were older at the time of SSc diagnosis and presented with more severe hemodynamics, although functional class (FC) and mortality outcomes were similar to those of patients with lateonset PAH; (3) Diffusing capacity of the lung for carbon monoxide (Dlco) , 35% and FC class 4 were the only predictors for survival CHEST / 138 / 2 / AUGUST, 2010
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on August 3, 2010 © 2010 American College of Chest Physicians
461