EDITORIALS 6. Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol 2007;2:369–399. 7. MacKenzie AM, Peacock AJ. Medical therapies for the treatment of pulmonary arterial hypertension: how do we choose? Curr Hypertens Rep 2015;17:56. 8. Yung L-M, Nikolic I, Paskin-Flerlage SD, Pearsall RS, Kumar R, Yu PB. A selective transforming growth factor-b ligand trap attenuates pulmonary hypertension. Am J Respir Crit Care Med 2016;194:1140–1151. 9. Anderton MJ, Mellor HR, Bell A, Sadler C, Pass M, Powell S, Steele SJ, Roberts RR, Heier A. Induction of heart valve lesions by smallmolecule ALK5 inhibitors. Toxicol Pathol 2011;39:916–924. 10. Long L, Ormiston ML, Yang X, Southwood M, Graf ¨ S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 2015;21:777–785. 11. Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 2013;123:3600–3613. 12. Spiekerkoetter E, Sung YK, Sudheendra D, Bill M, Aldred MA, van de Veerdonk MC, Vonk Noordegraaf A, Long-Boyle J, Dash R, Yang PC, et al. Low-dose FK506 (Tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med 2015;192:254–257. 13. Sheikh AQ, Misra A, Rosas IO, Adams RH, Greif DM. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension. Sci Transl Med 2015;7:308ra159. 14. He M, Zheng B, Zhang Y, Zhang XH, Wang C, Yang Z, Sun Y, Wu XL, Wen JK. KLF4 mediates the link between TGF-b1-induced gene transcription and H3 acetylation in vascular smooth muscle cells. FASEB J 2015;29:4059–4070. 15. Chen PY, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, Tellides G, Schwartz MA, Simons M. Endothelial-to-mesenchymal transition drives atherosclerosis progression. J Clin Invest 2015;125:4514–4528.
16. Cooley BC, Nevado J, Mellad J, Yang D, St Hilaire C, Negro A, Fang F, Chen G, San H, Walts AD, et al. TGF-b signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med 2014;6:227ra34. 17. Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Pechoux ´ C, Bogaard HJ, Dorfmuller ¨ P, Remy S, Lecerf F, Plante´ S, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 2015;131:1006–1018. 18. Carrancio S, Markovics J, Wong P, Leisten J, Castiglioni P, Groza MC, Raymon HK, Heise C, Daniel T, Chopra R, et al. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. Br J Haematol 2014;165: 870–882. 19. Fajardo RJ, Manoharan RK, Pearsall RS, Davies MV, Marvell T, Monnell TE, Ucran JA, Pearsall AE, Khanzode D, Kumar R, et al. Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis). Bone 2010;46: 64–71. 20. Mitchell D, Pobre EG, Mulivor AW, Grinberg AV, Castonguay R, Monnell TE, Solban N, Ucran JA, Pearsall RS, Underwood KW, et al. ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth. Mol Cancer Ther 2010;9:379–388. 21. Makker V, Filiaci VL, Chen LM, Darus CJ, Kendrick JE, Sutton G, Moxley K, Aghajanian C. Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor fusion protein, for the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study 0229N. Gynecol Oncol 2015; 138:24–29.
Copyright © 2016 by the American Thoracic Society
Contact Investigation: A Priority for Tuberculosis Control Programs Tuberculosis (TB) is one of the greatest threats to global health, productivity, and socioeconomic development (1). In 2014, TB killed 1.5 million people, 0.4 million of whom were HIV infected, and it now ranks as the leading cause of death from infectious disease worldwide (2). To address the persistent human suffering associated with TB, the World Health Organization has proposed a highly ambitious, multisectoral strategy to end the TB epidemic by 2035 (3). The enormity of this task is highlighted by the fact that at least one-third of all people suffering from TB are never diagnosed and treated, leading to persistent TB transmission by infectious cases within households and communities (4). Furthermore, an estimated 2 billion people have latent TB infection and therefore serve as a reservoir from which new cases of TB arise, propagating the global epidemic (5). Contact investigation is defined as the systematic evaluation for TB disease and/or latent TB infection in people who have close contact with TB “index” cases and is recommended by the World Health Organization (6). Such “contacts” have a high risk of concurrently having or subsequently developing TB disease
Supported by Wellcome Trust awards 105788/Z/14/Z and 201251/Z/16/Z, Joint Global Health Trials consortium award MR/K007467/1, Innovation for Health and Development, and Bill and Melinda Gates Foundation award OPP1118545.
Editorials
themselves and therefore represent an accessible population from which new cases may be promptly diagnosed and treated, and to which TB preventive therapy may be targeted (7). Despite these potential opportunities, contact investigation has generally been neglected as an intervention in low- and middle-income countries because of inadequate human and material resources, insufficient programmatic emphasis, ineffective tools for predicting which contacts are at highest risk of developing TB disease, and a shortage of evidence with which to optimize guidelines (7). In this issue of the Journal, the study by Martinez and colleagues (pp. 1152–1163) contributes important evidence to this field (8). In their large study of household contacts of TB index cases in a high TB- and HIV-burden setting, the authors aimed to characterize the relationship between index case HIV status and the rate of latent TB infection (defined through tuberculin skin testing) among contacts in order to make inferences about infectiousness. In this study, contacts of an HIV-infected index case were less likely to have latent TB infection, regardless of the threshold used for a positive tuberculin skin test or the age of the contact. In addition, the contacts of HIV-infected index cases with sputum smear–positive or apparent cavitary TB disease were as likely to have latent TB infection as the contacts of non–HIVinfected index cases. These findings highlight the interaction between contagion and the presentation of TB disease in 1049
EDITORIALS HIV-infected persons, who are less likely to have a prolonged illness, lung cavities, or be smear positive and therefore are considered to be less infectious (9). Of note, all index cases recruited to the study were culture positive, partially explaining the unusually high smear-positivity rates and classic radiological findings observed within the cohort, which are uncommon in HIV/TB coinfection (10). Although limited by their inability to confirm transmission directly between index cases and contacts, the current findings suggest that the subgroup of HIV-infected index cases with sputum smear–negative or noncavitary disease may be less infectious than are non–HIV-infected index cases with the same disease characteristics (8). While a smear-negative culture-positive status indicates paucibacillary TB disease, HIV-infected index cases may have had more pronounced immunosuppression, thus were more unwell and had less frequent or weaker cough to produce infectious aerosols (11). Indeed, a limitation of the current study is the absence of data on severity of immunosuppression, antiretroviral use, and indication of general health status or frailty of the index case, including duration of hospitalization. Furthermore, the study baseline characteristics imply that households with HIV-infected index cases had a different demographic and socioeconomic structure. The authors’ findings may have been strengthened by more detailed characterization of the household environment, which plays an important role in the dynamics of TB transmission (12). Another possibility is that the host–pathogen interaction in immune-competent individuals may change the Mycobacterium to a more infectious phenotype (13), a phenomenon that may not occur in immunosuppressed individuals. So what do these findings really mean for TB control programs in high TB- and HIV-burden settings where contacts are typically defined by sharing a household with the index case? Overall, the rates of latent TB infection and TB disease in this cohort were high, with approximately 70% latently infected and 6% having or subsequently developing disease over 2 years. Even among contacts of the less infectious HIV-infected index cases, more than half had latent TB infection and, importantly, the rates of coprevalent and incident TB disease did not differ by index case HIV status. These findings emphasize the limited value of tuberculin skin testing for predicting which individuals actually become ill with TB disease (14). It is well established that latent TB infection and subsequent development of TB disease in contacts is the result of a complex interplay between index case, environmental, and contact characteristics, which are frequently clustered within households (12). In high-burden settings, this complexity is exacerbated by the fact that community transmission accounts for a higher proportion of contact TB cases than does household transmission, meaning that it is frequently difficult to identify who the index case actually is (15). These observations beg the question: in high-burden settings, why use index case characteristics to prioritize contact investigation at all? Once a household, through the diagnosis of one household member, has revealed itself to a TB control program as a TB hotspot, contact investigation to identify coprevalent cases should be prioritized immediately and contacts should be evaluated systematically for their risk of developing TB disease in order to provide TB preventive therapy to those who are at highest risk. This process may include HIV testing and could incorporate locally 1050
developed risk factor assessments, enabling TB control programs to move away from the current “one size fits all” approach that is often dependent on unreliable and impractical tuberculin skin testing (16). If the highly ambitious targets set out in the End TB Strategy are to be made a reality, the missing third of people suffering from TB are to be diagnosed and treated, and TB is to be prevented in vulnerable people, then contact investigation should rapidly become a priority for TB control programs. This should be accompanied by further research better characterizing the intricate relationship between index case, environmental, and contact characteristics with TB infection and disease. n Author disclosures are available with the text of this article at www.atsjournals.org. Matthew J. Saunders, M.B. Ch.B. Sumona Datta, M.B. Ch.B., D.T.M.H. Innovacion ´ Por la Salud y Desarrollo Asociacion ´ Benefica ´ PRISMA Lima, Peru´ Laboratory of Research and Development Universidad Peruana Cayetano Heredia Lima, Peru´ Section of Infectious Diseases and Immunity Imperial College London London, United Kingdom and Wellcome Trust Imperial College Centre for Global Health Research London, United Kingdom
References 1. Lonnroth ¨ K, Castro KG, Chakaya JM, Chauhan LS, Floyd K, Glaziou P, Raviglione MC. Tuberculosis control and elimination 2010-50: cure, care, and social development. Lancet 2010;375:1814–1829. 2. World Health Organization. Global tuberculosis report (WHO/HTM/TB/2015.22). Geneva, Switzerland: World Health Organization; 2015. 3. Uplekar M, Weil D, Lonnroth K, Jaramillo E, Lienhardt C, Dias HM, Falzon D, Floyd K, Gargioni G, Getahun H, et al.; WHO’s Global TB Programme. WHO’s new End TB Strategy. Lancet 2015;385: 1799–1801. 4. Yuen CM, Amanullah F, Dharmadhikari A, Nardell EA, Seddon JA, Vasilyeva I, Zhao Y, Keshavjee S, Becerra MC. Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment. Lancet 2015;386:2334–2343. 5. Rangaka MX, Cavalcante SC, Marais BJ, Thim S, Martinson NA, Swaminathan S, Chaisson RE. Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection. Lancet 2015;386:2344–2353. 6. World Health Organization. Recommendations for investigating contacts of persons with infectious tuberculosis in low- and middle-income countries (WHO/HTM/TB/2012.9). Geneva, Switzerland: World Health Organization; 2012. 7. Fox GJ, Barry SE, Britton WJ, Marks GB. Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur Respir J 2013;41:140–156. 8. Martinez L, Sekandi JN, Castellanos ME, Zalwango S, Whalen CC. Infectiousness of HIV-seropositive patients with tuberculosis in a high-burden African setting. Am J Respir Crit Care Med 2016;194; 1152–1163. 9. Huang C-C, Tchetgen ET, Becerra MC, Cohen T, Hughes KC, Zhang Z, Calderon R, Yataco R, Contreras C, Galea J, et al. The effect of HIV-related immunosuppression on the risk of tuberculosis transmission to household contacts. Clin Infect Dis 2014;58:765–774.
American Journal of Respiratory and Critical Care Medicine Volume 194 Number 9 | November 1 2016
EDITORIALS 10. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163: 1009–1021. 11. Fennelly KP, Jones-Lopez ´ EC, Ayakaka I, Kim S, Menyha H, Kirenga B, Muchwa C, Joloba M, Dryden-Peterson S, Reilly N, et al. Variability of infectious aerosols produced during coughing by patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2012;186: 450–457. 12. Yates TA, Khan PY, Knight GM, Taylor JG, McHugh TD, Lipman M, White RG, Cohen T, Cobelens FG, Wood R, et al. The transmission of Mycobacterium tuberculosis in high burden settings. Lancet Infect Dis 2016;16:227–238. 13. Datta S, Sherman JM, Valencia T, Tovar M, Ramos ES, Gilman RH, Evans CA. The role of sputum quantitative viability microscopy to predict patient infectiousness. Int J Tuberc Lung Dis 2015;190: S110.
14. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, Fielding K, Wilkinson RJ, Pai M. Predictive value of interferon-g release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:45–55. 15. Brooks-Pollock E, Becerra MC, Goldstein E, Cohen T, Murray MB. Epidemiologic inference from the distribution of tuberculosis cases in households in Lima, Peru. J Infect Dis 2011;203:1582–1589. 16. Saunders MJ, Tovar M, Zevallos K, Wingfield T, Datta S, Montoya R, Valencia T, Santillan C, Necochea A, Baldwin M, et al. Tuberculosis: who is at highest risk? Derivation and validation of a risk score for predicting tuberculosis disease in adult household contacts. Presented at the Joint 20th Conference of The Union North America Region and the National TB Controllers Association. February 24–27, 2016, Denver, CO.
Copyright © 2016 by the American Thoracic Society
FIFTY YEARS OF RESEARCH IN ARDS
Why Is Acute Respiratory Distress Syndrome So Important for Critical Care? The incidence of acute respiratory distress syndrome (ARDS) varies from 1.5 to 3.5 cases per 100,000 population (1) to nearly 79 cases per 100,000 (2). Its overall prevalence in the intensive care unit (ICU) was recently reported to be 10.4% (3). When strict definition criteria are applied, as those used in all ARDS clinical trials on the prone position performed in Europe, the enrollment rate does not exceed 0.4 patients per unit per month. Howsoever looked at, ARDS is not frequent in the ICU, despite its being the common final path of several diseases. If this is so, why is such a huge amount of literature and so much time at critical care congresses dedicated to this syndrome? We believe that there are at least five key reasons involved. The first reason is largely emotional and is typical for “first”generation intensivists. In fact, ARDS was undoubtedly the trademark of intensive care, which, at its beginning, was respiratory intensive care. The orotracheal tube and the first pneumatic mechanical ventilators (then called mechanical students) allowed the upcoming intensivists to observe and try to correct pathologies, primarily ARDS, which did not exist previously because the patients had died before onset due to the lack of mechanical respiratory support. “Buy time” was the first imperative. We would like to stress that mechanical ventilation was the first therapy to be applied to a patient as such and not directed at his disease. This was the revolution produced by intensive care, where, in contrast to classic internal medicine, the intensivist first “cured” the patient’s physiology, to keep him alive, regardless of the causative disease. ARDS perfectly fit this new approach to medicine: first, keep the patient alive, and second, cure the disease. This new way of thinking and acting explains why physiology, much more than pathology, was interwoven with intensive care. This is why in our generation of intensivists the word ARDS immediately triggers memories, emotions, and passions, as our way of thinking and acting in intensive care advanced together with our understanding of anatomy, physiology, and treatment of ARDS. Editorials
The second reason is that ARDS is a textbook of intensive care medicine. If we take a table of contents of any classic intensive care manual, it is easy to recognize that each chapter easily fits in the ARDS picture. Infectious, chemical, or toxic insults acting directly on the lung are key factors in ARDS, as are extrapulmonary infectious, chemical, or toxic insults, such as in secondary ARDS in abdominal disease. Sepsis, the other “queen” of the intensive care kingdom, is strictly interwoven with ARDS, which we consider per se an “organ-specific sepsis” due, in some cases, to the loss of compartmentalization (4). The hemodynamic effects and respiratory impairment of the septic state finally converge in the severe disturbances of the acid–base and electrolyte equilibrium. To this complex picture, we intensivists add further complications, either with mechanical ventilation or fluid and drug therapy. ARDS is therefore the sum of most of the problems encountered in intensive care. The third reason for the importance of ARDS is that it represents the arena in which the intensivist was likely to have made the most relevant mistakes. Qualitatively, we have been right all along: nobody can deny that patients with ARDS need mechanical ventilation, that they might need antiinflammatory drugs for a possible excessive inflammatory response, that they may require antibiotics to cure the underlying disease, nutrition to keep them alive, and fluids for stable hemodynamics and adequate hydration. Qualitatively, not much has changed from the early days, but quantitatively . . . The early reasoning was simple: if normal tidal volumes do not normalize PaCO2, larger tidal volumes (12–15 ml/kg) must be better (5); if calories are necessary, hypercaloric diets up to 5,000 kcal must be even better (6); if 100 mg of hydrocortisone per day can attenuate the inflammatory response, 2,000 mg should eliminate it completely (7); and so on. On the contrary, patients with ARDS taught us over the years that treating the lungs gently and providing them with some rest is a better way to buy time for healing (8, 9); that giving fewer 1051
16. Cooley BC, Nevado J, Mellad J, Yang D, St Hilaire C, Negro A, Fang F, Chen G, San H, Walts AD, et al. TGF-b signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med 2014;6:227ra34. 17. Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Pechoux ´ C, Bogaard HJ, Dorfmuller ¨ P, Remy S, Lecerf F, Plante´ S, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 2015;131:1006–1018. 18. Carrancio S, Markovics J, Wong P, Leisten J, Castiglioni P, Groza MC, Raymon HK, Heise C, Daniel T, Chopra R, et al. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. Br J Haematol 2014;165: 870–882. 19. Fajardo RJ, Manoharan RK, Pearsall RS, Davies MV, Marvell T, Monnell TE, Ucran JA, Pearsall AE, Khanzode D, Kumar R, et al. Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis). Bone 2010;46: 64–71. 20. Mitchell D, Pobre EG, Mulivor AW, Grinberg AV, Castonguay R, Monnell TE, Solban N, Ucran JA, Pearsall RS, Underwood KW, et al. ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth. Mol Cancer Ther 2010;9:379–388. 21. Makker V, Filiaci VL, Chen LM, Darus CJ, Kendrick JE, Sutton G, Moxley K, Aghajanian C. Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor fusion protein, for the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study 0229N. Gynecol Oncol 2015; 138:24–29.
Copyright © 2016 by the American Thoracic Society
Contact Investigation: A Priority for Tuberculosis Control Programs Tuberculosis (TB) is one of the greatest threats to global health, productivity, and socioeconomic development (1). In 2014, TB killed 1.5 million people, 0.4 million of whom were HIV infected, and it now ranks as the leading cause of death from infectious disease worldwide (2). To address the persistent human suffering associated with TB, the World Health Organization has proposed a highly ambitious, multisectoral strategy to end the TB epidemic by 2035 (3). The enormity of this task is highlighted by the fact that at least one-third of all people suffering from TB are never diagnosed and treated, leading to persistent TB transmission by infectious cases within households and communities (4). Furthermore, an estimated 2 billion people have latent TB infection and therefore serve as a reservoir from which new cases of TB arise, propagating the global epidemic (5). Contact investigation is defined as the systematic evaluation for TB disease and/or latent TB infection in people who have close contact with TB “index” cases and is recommended by the World Health Organization (6). Such “contacts” have a high risk of concurrently having or subsequently developing TB disease
Supported by Wellcome Trust awards 105788/Z/14/Z and 201251/Z/16/Z, Joint Global Health Trials consortium award MR/K007467/1, Innovation for Health and Development, and Bill and Melinda Gates Foundation award OPP1118545.
Editorials
themselves and therefore represent an accessible population from which new cases may be promptly diagnosed and treated, and to which TB preventive therapy may be targeted (7). Despite these potential opportunities, contact investigation has generally been neglected as an intervention in low- and middle-income countries because of inadequate human and material resources, insufficient programmatic emphasis, ineffective tools for predicting which contacts are at highest risk of developing TB disease, and a shortage of evidence with which to optimize guidelines (7). In this issue of the Journal, the study by Martinez and colleagues (pp. 1152–1163) contributes important evidence to this field (8). In their large study of household contacts of TB index cases in a high TB- and HIV-burden setting, the authors aimed to characterize the relationship between index case HIV status and the rate of latent TB infection (defined through tuberculin skin testing) among contacts in order to make inferences about infectiousness. In this study, contacts of an HIV-infected index case were less likely to have latent TB infection, regardless of the threshold used for a positive tuberculin skin test or the age of the contact. In addition, the contacts of HIV-infected index cases with sputum smear–positive or apparent cavitary TB disease were as likely to have latent TB infection as the contacts of non–HIVinfected index cases. These findings highlight the interaction between contagion and the presentation of TB disease in 1049
EDITORIALS HIV-infected persons, who are less likely to have a prolonged illness, lung cavities, or be smear positive and therefore are considered to be less infectious (9). Of note, all index cases recruited to the study were culture positive, partially explaining the unusually high smear-positivity rates and classic radiological findings observed within the cohort, which are uncommon in HIV/TB coinfection (10). Although limited by their inability to confirm transmission directly between index cases and contacts, the current findings suggest that the subgroup of HIV-infected index cases with sputum smear–negative or noncavitary disease may be less infectious than are non–HIV-infected index cases with the same disease characteristics (8). While a smear-negative culture-positive status indicates paucibacillary TB disease, HIV-infected index cases may have had more pronounced immunosuppression, thus were more unwell and had less frequent or weaker cough to produce infectious aerosols (11). Indeed, a limitation of the current study is the absence of data on severity of immunosuppression, antiretroviral use, and indication of general health status or frailty of the index case, including duration of hospitalization. Furthermore, the study baseline characteristics imply that households with HIV-infected index cases had a different demographic and socioeconomic structure. The authors’ findings may have been strengthened by more detailed characterization of the household environment, which plays an important role in the dynamics of TB transmission (12). Another possibility is that the host–pathogen interaction in immune-competent individuals may change the Mycobacterium to a more infectious phenotype (13), a phenomenon that may not occur in immunosuppressed individuals. So what do these findings really mean for TB control programs in high TB- and HIV-burden settings where contacts are typically defined by sharing a household with the index case? Overall, the rates of latent TB infection and TB disease in this cohort were high, with approximately 70% latently infected and 6% having or subsequently developing disease over 2 years. Even among contacts of the less infectious HIV-infected index cases, more than half had latent TB infection and, importantly, the rates of coprevalent and incident TB disease did not differ by index case HIV status. These findings emphasize the limited value of tuberculin skin testing for predicting which individuals actually become ill with TB disease (14). It is well established that latent TB infection and subsequent development of TB disease in contacts is the result of a complex interplay between index case, environmental, and contact characteristics, which are frequently clustered within households (12). In high-burden settings, this complexity is exacerbated by the fact that community transmission accounts for a higher proportion of contact TB cases than does household transmission, meaning that it is frequently difficult to identify who the index case actually is (15). These observations beg the question: in high-burden settings, why use index case characteristics to prioritize contact investigation at all? Once a household, through the diagnosis of one household member, has revealed itself to a TB control program as a TB hotspot, contact investigation to identify coprevalent cases should be prioritized immediately and contacts should be evaluated systematically for their risk of developing TB disease in order to provide TB preventive therapy to those who are at highest risk. This process may include HIV testing and could incorporate locally 1050
developed risk factor assessments, enabling TB control programs to move away from the current “one size fits all” approach that is often dependent on unreliable and impractical tuberculin skin testing (16). If the highly ambitious targets set out in the End TB Strategy are to be made a reality, the missing third of people suffering from TB are to be diagnosed and treated, and TB is to be prevented in vulnerable people, then contact investigation should rapidly become a priority for TB control programs. This should be accompanied by further research better characterizing the intricate relationship between index case, environmental, and contact characteristics with TB infection and disease. n Author disclosures are available with the text of this article at www.atsjournals.org. Matthew J. Saunders, M.B. Ch.B. Sumona Datta, M.B. Ch.B., D.T.M.H. Innovacion ´ Por la Salud y Desarrollo Asociacion ´ Benefica ´ PRISMA Lima, Peru´ Laboratory of Research and Development Universidad Peruana Cayetano Heredia Lima, Peru´ Section of Infectious Diseases and Immunity Imperial College London London, United Kingdom and Wellcome Trust Imperial College Centre for Global Health Research London, United Kingdom
References 1. Lonnroth ¨ K, Castro KG, Chakaya JM, Chauhan LS, Floyd K, Glaziou P, Raviglione MC. Tuberculosis control and elimination 2010-50: cure, care, and social development. Lancet 2010;375:1814–1829. 2. World Health Organization. Global tuberculosis report (WHO/HTM/TB/2015.22). Geneva, Switzerland: World Health Organization; 2015. 3. Uplekar M, Weil D, Lonnroth K, Jaramillo E, Lienhardt C, Dias HM, Falzon D, Floyd K, Gargioni G, Getahun H, et al.; WHO’s Global TB Programme. WHO’s new End TB Strategy. Lancet 2015;385: 1799–1801. 4. Yuen CM, Amanullah F, Dharmadhikari A, Nardell EA, Seddon JA, Vasilyeva I, Zhao Y, Keshavjee S, Becerra MC. Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment. Lancet 2015;386:2334–2343. 5. Rangaka MX, Cavalcante SC, Marais BJ, Thim S, Martinson NA, Swaminathan S, Chaisson RE. Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection. Lancet 2015;386:2344–2353. 6. World Health Organization. Recommendations for investigating contacts of persons with infectious tuberculosis in low- and middle-income countries (WHO/HTM/TB/2012.9). Geneva, Switzerland: World Health Organization; 2012. 7. Fox GJ, Barry SE, Britton WJ, Marks GB. Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur Respir J 2013;41:140–156. 8. Martinez L, Sekandi JN, Castellanos ME, Zalwango S, Whalen CC. Infectiousness of HIV-seropositive patients with tuberculosis in a high-burden African setting. Am J Respir Crit Care Med 2016;194; 1152–1163. 9. Huang C-C, Tchetgen ET, Becerra MC, Cohen T, Hughes KC, Zhang Z, Calderon R, Yataco R, Contreras C, Galea J, et al. The effect of HIV-related immunosuppression on the risk of tuberculosis transmission to household contacts. Clin Infect Dis 2014;58:765–774.
American Journal of Respiratory and Critical Care Medicine Volume 194 Number 9 | November 1 2016
EDITORIALS 10. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163: 1009–1021. 11. Fennelly KP, Jones-Lopez ´ EC, Ayakaka I, Kim S, Menyha H, Kirenga B, Muchwa C, Joloba M, Dryden-Peterson S, Reilly N, et al. Variability of infectious aerosols produced during coughing by patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2012;186: 450–457. 12. Yates TA, Khan PY, Knight GM, Taylor JG, McHugh TD, Lipman M, White RG, Cohen T, Cobelens FG, Wood R, et al. The transmission of Mycobacterium tuberculosis in high burden settings. Lancet Infect Dis 2016;16:227–238. 13. Datta S, Sherman JM, Valencia T, Tovar M, Ramos ES, Gilman RH, Evans CA. The role of sputum quantitative viability microscopy to predict patient infectiousness. Int J Tuberc Lung Dis 2015;190: S110.
14. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J, Fielding K, Wilkinson RJ, Pai M. Predictive value of interferon-g release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:45–55. 15. Brooks-Pollock E, Becerra MC, Goldstein E, Cohen T, Murray MB. Epidemiologic inference from the distribution of tuberculosis cases in households in Lima, Peru. J Infect Dis 2011;203:1582–1589. 16. Saunders MJ, Tovar M, Zevallos K, Wingfield T, Datta S, Montoya R, Valencia T, Santillan C, Necochea A, Baldwin M, et al. Tuberculosis: who is at highest risk? Derivation and validation of a risk score for predicting tuberculosis disease in adult household contacts. Presented at the Joint 20th Conference of The Union North America Region and the National TB Controllers Association. February 24–27, 2016, Denver, CO.
Copyright © 2016 by the American Thoracic Society
FIFTY YEARS OF RESEARCH IN ARDS
Why Is Acute Respiratory Distress Syndrome So Important for Critical Care? The incidence of acute respiratory distress syndrome (ARDS) varies from 1.5 to 3.5 cases per 100,000 population (1) to nearly 79 cases per 100,000 (2). Its overall prevalence in the intensive care unit (ICU) was recently reported to be 10.4% (3). When strict definition criteria are applied, as those used in all ARDS clinical trials on the prone position performed in Europe, the enrollment rate does not exceed 0.4 patients per unit per month. Howsoever looked at, ARDS is not frequent in the ICU, despite its being the common final path of several diseases. If this is so, why is such a huge amount of literature and so much time at critical care congresses dedicated to this syndrome? We believe that there are at least five key reasons involved. The first reason is largely emotional and is typical for “first”generation intensivists. In fact, ARDS was undoubtedly the trademark of intensive care, which, at its beginning, was respiratory intensive care. The orotracheal tube and the first pneumatic mechanical ventilators (then called mechanical students) allowed the upcoming intensivists to observe and try to correct pathologies, primarily ARDS, which did not exist previously because the patients had died before onset due to the lack of mechanical respiratory support. “Buy time” was the first imperative. We would like to stress that mechanical ventilation was the first therapy to be applied to a patient as such and not directed at his disease. This was the revolution produced by intensive care, where, in contrast to classic internal medicine, the intensivist first “cured” the patient’s physiology, to keep him alive, regardless of the causative disease. ARDS perfectly fit this new approach to medicine: first, keep the patient alive, and second, cure the disease. This new way of thinking and acting explains why physiology, much more than pathology, was interwoven with intensive care. This is why in our generation of intensivists the word ARDS immediately triggers memories, emotions, and passions, as our way of thinking and acting in intensive care advanced together with our understanding of anatomy, physiology, and treatment of ARDS. Editorials
The second reason is that ARDS is a textbook of intensive care medicine. If we take a table of contents of any classic intensive care manual, it is easy to recognize that each chapter easily fits in the ARDS picture. Infectious, chemical, or toxic insults acting directly on the lung are key factors in ARDS, as are extrapulmonary infectious, chemical, or toxic insults, such as in secondary ARDS in abdominal disease. Sepsis, the other “queen” of the intensive care kingdom, is strictly interwoven with ARDS, which we consider per se an “organ-specific sepsis” due, in some cases, to the loss of compartmentalization (4). The hemodynamic effects and respiratory impairment of the septic state finally converge in the severe disturbances of the acid–base and electrolyte equilibrium. To this complex picture, we intensivists add further complications, either with mechanical ventilation or fluid and drug therapy. ARDS is therefore the sum of most of the problems encountered in intensive care. The third reason for the importance of ARDS is that it represents the arena in which the intensivist was likely to have made the most relevant mistakes. Qualitatively, we have been right all along: nobody can deny that patients with ARDS need mechanical ventilation, that they might need antiinflammatory drugs for a possible excessive inflammatory response, that they may require antibiotics to cure the underlying disease, nutrition to keep them alive, and fluids for stable hemodynamics and adequate hydration. Qualitatively, not much has changed from the early days, but quantitatively . . . The early reasoning was simple: if normal tidal volumes do not normalize PaCO2, larger tidal volumes (12–15 ml/kg) must be better (5); if calories are necessary, hypercaloric diets up to 5,000 kcal must be even better (6); if 100 mg of hydrocortisone per day can attenuate the inflammatory response, 2,000 mg should eliminate it completely (7); and so on. On the contrary, patients with ARDS taught us over the years that treating the lungs gently and providing them with some rest is a better way to buy time for healing (8, 9); that giving fewer 1051
