Comment
colleagues’ report3 show that allergic rhinoconjunctivitis is not associated with open fires. These wheezy children exposed to open fires are being labelled as having asthma, but the underlying pathology is likely to be different to that seen in most children with the same diagnostic label living in higher-income countries. By comparison with non-affluent countries, affluent countries are faced with what might seem a more trivial problem. As more energy-efficient homes have been built, concern has shifted to the health effects of exposure to highly reactive particles and nitrogen dioxide emitted by unflued gas appliances (especially gas cookers but also some gas fires). Indoor peak and background levels of these pollutants can reach levels in excess of those seen in outdoor air, and the indoor environment can be a major source of an individual’s total personal exposure. ISAAC showed no evidence that children in homes with gas (liquid petroleum gas in some countries, natural gas in others) have more symptoms than those in homes in which electricity is the main cooking or heating fuel. This provides some reassurance, although those who actually use the cooking appliance—eg, mothers preparing meals for families—are likely to have greater exposure. The ISAAC authors could have strengthened their argument further by comparing associations in children with and without allergic rhinoconjunctivitis and by presenting estimates at the centre level (or at least country level) for these risks, including a measure for heterogeneity in the associations. Wong and colleagues’ study adds to the evidence on the potential harmful effects of the indoor environment on respiratory health in non-affluent nations. Public
health interventions to improve maternal health, improve nutrition in mothers and children, reduce household crowding, and treat respiratory infections could improve resilience to the respiratory effects of acute and chronic indoor exposures, but there is some urgency to identify measures to limit populations’ exposure to open fires, and to show the respiratory health benefits of such measures in well designed clinical trials. Debbie Jarvis National Heart and Lung Institute and MRC-HPA Centre for Environment and Health, Imperial College, London, SW3 6LR, UK [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
6
7
8
9
Lim S, Vos T, Flaxman A, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60. Po J, Fitzgerald JM, Carlsten C. Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis. Thorax 2011; 66: 232–39. Wong GWK, Brunekreef B, Ellwood P, et al. Cooking fuels and prevelance of asthma: a global analysis of phase three of the International Study of Asthma and Allergies in Childhood (ISAAC). Lancet Respir Med 2013; published online May 31. http://dx.doi.org/10.1016/S22132600(13)70073-0. Brunekreef B, Von Mutius E, Wong G, et al. Early life exposure to farm animals and symptoms of asthma, rhinoconjunctivitis and eczema: an ISAAC Phase Three Study. Int J Epidemiol 2012; 41: 753–61. Dionisio KL, Howie SRC, Dominici F, et al. Household concentrations and exposure of children to particulate matter from biomass fuels in The Gambia. Environ Sci Technol 2012; 46: 3519–27. Pope DP, Mishra V, Thompson L, et al. Risk of low birth weight and stillbirth associated with indoor air pollution from solid fuel use in developing countries. Epidemiol Rev 2010; 32: 70–81. Smith K, McCracken J, Weber M, et al. Effect of reduction in household air pollution on childhood pneumonia in Guatemala (RESPIRE): a randomised controlled trial. Lancet 2011; 378: 1717–26. Roy A, Chapman R, Hu W, Wei F, Liu X, Zhang J. Indoor air pollution and lung function growth among children in four Chinese cities. Indoor Air 2012; 22: 3–11. Weinmayr G, Weiland S, Bjorksten B, et al. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med 2007; 176: 565–74.
Autopsy in ARDS: insights into natural history Published Online May 15, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70093-6 See Articles page 395
352
The acute respiratory distress syndrome (ARDS) is a common clinical syndrome whose clinical features are well described.1 However, comprehensive histopathological characterisation of the natural history of the ARDS in human beings has been challenging. Lung biopsy samples are not obtained in most patients with ARDS and few autopsy studies have been published. In this issue of The Lancet Respiratory Medicine, Arnaud Thille and colleagues2 present an analysis of autopsy results in 159 patients who met both the Berlin definition of ARDS3
and had histological evidence of diffuse alveolar damage. The patients were drawn from a series of 712 autopsies in critically ill patients at one hospital and represent those who had both clinical and histological evidence of ARDS. Of note, those presented in the study2 represent only a small subset of the entire autopsy cohort. A report from the same group4 stresses the fact that many in the series of 712 autopsies met either clinical criteria for ARDS or histological criteria for diffuse alveolar damage, but not both. Thus, despite recent modifications,3 the www.thelancet.com/respiratory Vol 1 July 2013
clinical definitions of ARDS continue to lack sensitivity and specificity when pathological evidence of diffuse alveolar damage is used as the gold standard. The primary findings of this study confirm classic studies5–7 that identified three histological stages in ARDS: an early exudative phase, characterised by intra-alveolar oedema and capillary congestion; a proliferative phase characterised by alveolar epithelial type 2 cell proliferation, fibroblast proliferation, and organising interstitial fibrosis; and a late fibrotic phase characterised by collagen deposition and microcystic honeycombing. In the present study,2 most patients died early in their course (52% within a week of onset) and the predominant histology was exudative. However, proliferative and exudative findings coexisted in many patients, emphasising that exudative and proliferative responses to injury may occur simultaneously in the same patient and cannot readily be distinguished on the basis of duration of ARDS. Overall, only 30 (19%) of 159 patients exhibited fibrotic changes suggesting that fibrosis is not a prominent feature in most patients with ARDS. In longterm survivors of ARDS, radiographical or physiological evidence of significant pulmonary fibrosis is also rare.8 By comparison, in a prospective study of open lung biopsy in patients with ARDS of 5 or more days duration, Papazian and colleagues9 reported a 53% incidence of fibrotic changes, but these data might overestimate the overall incidence of fibrosis since all patients had nonresolving ARDS. High resolution CT studies in patients with ARDS have also been used to assess the degree of fibrotic changes. Ichikado and colleagues detected traction bronchiectasis or traction bronchiolitis, or both (the radiographical correlates of fibroproliferative changes in ARDS)10,11 in 40 (47%) of 85 patients who underwent CT scanning on the first day of ARDS12 and in 28 (64%) of 44 patients who underwent CT scanning within 5 days of ARDS onset.13 However, these studies were done early in the course; they were not able to differentiate radiographically between proliferative and fibrotic changes; and honeycombing, the radiographical correlate of significant fibrosis, was rarely noted. A novel aspect of the study by Thille and colleagues2 is that it includes autopsies from 1991 to 2010, spanning both the eras of higher tidal volume and lower tidal volume ventilation. With the improved survival that accompanies reductions in ventilator-associated lung injury, one might expect that fibrotic changes would be www.thelancet.com/respiratory Vol 1 July 2013
Photostock-Israel/Science Photo Library
Comment
less common in the low tidal volume era. Surprisingly, fibrosis was more common in patients undergoing autopsy in 2000–10 than in the previous decade (32% [21 of 64] vs 9% [9 of 95], p=0·0003). There are several possible explanations for this finding. First, the overall number of patients with fibrotic changes was small and the study is probably underpowered to examine this question. Second, in the low tidal volume era, better supportive care might have prolonged survival of some patients with more severe lung injury, allowing more time for fibrotic changes to develop and be detected at autopsy. Finally, since the only ventilator parameters available in the study were from the time of death, there is no way to know to what degree a protective ventilator strategy was actually in use. In a similar autopsy series reported by the same authors,4 histological evidence of diffuse alveolar damage was less common during the low tidal volume era in all patients with clinical ARDS, suggesting that reduction in tidal volume has had some effect on histopathological findings in ARDS. In summary, the new findings by Thille and colleagues2 provide information about the natural history of histopathological lesions in non-survivors who meet current clinical definitions of ARDS and suggest that the overall incidence of fibrotic changes is low. However, we are still left with unanswered questions regarding the effect of current therapies on injury and repair in the lung. To better answer these questions, human lung tissue should be collected where possible as an adjunct to observational and interventional clinical trials. 353
Comment
Lorraine B Ware
7
T1218 MCN, 1161 21st Avenue S, Nashville, TN 37232-2650, USA [email protected]
8
I declare that I have no conflicts of interest. 1 2
3 4
5
6
Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122: 2731–40. Thille AW, Esteban A, Fernández-Segoviano P, et al. Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies. Lancet Respir Med 2013; published online May 15. http://dx.doi. org/10.1016/S2213-2600(13)70053-5. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526–33. Thille AW, Esteban A, Fernandez-Segoviano P, et al. Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med 2013; 187: 761–67. Bachofen M, Weibel ER. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis 1977; 116: 589–615. Pratt PC, Vollmer RT, Shelburne JD, Crapo JD. Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. Am J Pathol 1979; 95: 191–214.
9
10
11
12
13
Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage—the role of oxygen, shock, and related factors. A review. Am J Pathol 1976; 85: 209–28. Wilcox ME, Patsios D, Murphy G, et al. Radiologic outcomes at 5 years after severe acute respiratory distress syndrome (ARDS). Chest 2012; published online Oct 1. DOI:10.1378/chest.12-0685. Papazian L, Doddoli C, Chetaille B, et al. A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients. Crit Care Med 2007; 35: 755–62. Ichikado K, Johkoh T, Ikezoe J, et al. Acute interstitial pneumonia: high-resolution CT findings correlated with pathology. AJR Am J Roentgenol 1997; 168: 333–38. Ichikado K, Suga M, Gushima Y, et al. Hyperoxia-induced diffuse alveolar damage in pigs: correlation between thin-section CT and histopathologic findings. Radiology 2000; 216: 531–38. Ichikado K, Muranaka H, Gushima Y, et al. Fibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study. BMJ Open 2012; 2: e000545. Ichikado K, Suga M, Muranaka H, al. Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases. Radiology 2006; 238: 321–29.
Use of bronchoalveolar lavage to assess the respiratory microbiome: signal in the noise
BSIP, Vero/Carlo/Science Photo Library
In 2007, the US National Institutes of Health added the Human Microbiome Project to the National Institutes of Health Roadmap for Medical Research. The lung— traditionally thought to be a sterile site—was not part of the original programme. However, reports appeared describing a diverse population of non-cultivatable bacteria from other body sites, discovered using 16S rRNA sequencing, challenging notion that the lower respiratory tract was sterile. As a result, in 2009, the Lung HIV Microbiome Project was launched by the National Heart, Lung and Blood Institute to investigate the lung microbiome. Microbiome analysis using PCR-amplified 16S rRNA sequencing is highly sensitive1 and thus subject to contamination from the environment and neighbouring microbial communities. Prevention of contamination is especially problematic for the lower respiratory tract, which is directly connected to the densely colonised oral cavity.2 Analysis of the lung microbiome has largely relied on sputum and bronchoscopic samples, which can be contaminated by microorganisms in the upper respiratory tract. In one of the first studies3 to describe the lung microbiome—which used sequential bronchoscopes to take samples along the length of the respiratory tract from the oropharynx to the alveolar compartment—investigators reported that the bacterial 354
composition of the oral cavity and bronchoalveolar lavage were indistinguishable. The researchers concluded that “bacterial populations in the healthy lower respiratory tract largely reflect upper respiratory tract organisms, likely resulting from transient entry rather than independent communities with indistinguishable structure”.3 Unfortunately, many investigators accepted this work as evidence that a lower respiratory tract microbiome does not exist in healthy people. This assumption ignores the fact that if a lung microbiome is present, it is likely to be similar to that of the upper respiratory tract because of chronic asymptomatic aspiration.4 Furthermore, no physiological reason exists to assume that the lung, which is constantly exposed to the air we breathe, is not colonised like any other body cavity that is exposed to the environment. Finally, the lung filters the entire blood supply, and any episodes of bacteraemia could lead to colonisation of the lung. We believe that new data add to these theoretical considerations, providing evidence for a resident lung microbiome. The first argument for a lung microbiome comes from the discovery of a high incidence of Tropheryma whipplei in bronchoalveolar lavage samples from asymptomatic HIV-infected individuals compared with uninfected people.5 The organism was not detected in paired www.thelancet.com/respiratory Vol 1 July 2013
colleagues’ report3 show that allergic rhinoconjunctivitis is not associated with open fires. These wheezy children exposed to open fires are being labelled as having asthma, but the underlying pathology is likely to be different to that seen in most children with the same diagnostic label living in higher-income countries. By comparison with non-affluent countries, affluent countries are faced with what might seem a more trivial problem. As more energy-efficient homes have been built, concern has shifted to the health effects of exposure to highly reactive particles and nitrogen dioxide emitted by unflued gas appliances (especially gas cookers but also some gas fires). Indoor peak and background levels of these pollutants can reach levels in excess of those seen in outdoor air, and the indoor environment can be a major source of an individual’s total personal exposure. ISAAC showed no evidence that children in homes with gas (liquid petroleum gas in some countries, natural gas in others) have more symptoms than those in homes in which electricity is the main cooking or heating fuel. This provides some reassurance, although those who actually use the cooking appliance—eg, mothers preparing meals for families—are likely to have greater exposure. The ISAAC authors could have strengthened their argument further by comparing associations in children with and without allergic rhinoconjunctivitis and by presenting estimates at the centre level (or at least country level) for these risks, including a measure for heterogeneity in the associations. Wong and colleagues’ study adds to the evidence on the potential harmful effects of the indoor environment on respiratory health in non-affluent nations. Public
health interventions to improve maternal health, improve nutrition in mothers and children, reduce household crowding, and treat respiratory infections could improve resilience to the respiratory effects of acute and chronic indoor exposures, but there is some urgency to identify measures to limit populations’ exposure to open fires, and to show the respiratory health benefits of such measures in well designed clinical trials. Debbie Jarvis National Heart and Lung Institute and MRC-HPA Centre for Environment and Health, Imperial College, London, SW3 6LR, UK [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
6
7
8
9
Lim S, Vos T, Flaxman A, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60. Po J, Fitzgerald JM, Carlsten C. Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis. Thorax 2011; 66: 232–39. Wong GWK, Brunekreef B, Ellwood P, et al. Cooking fuels and prevelance of asthma: a global analysis of phase three of the International Study of Asthma and Allergies in Childhood (ISAAC). Lancet Respir Med 2013; published online May 31. http://dx.doi.org/10.1016/S22132600(13)70073-0. Brunekreef B, Von Mutius E, Wong G, et al. Early life exposure to farm animals and symptoms of asthma, rhinoconjunctivitis and eczema: an ISAAC Phase Three Study. Int J Epidemiol 2012; 41: 753–61. Dionisio KL, Howie SRC, Dominici F, et al. Household concentrations and exposure of children to particulate matter from biomass fuels in The Gambia. Environ Sci Technol 2012; 46: 3519–27. Pope DP, Mishra V, Thompson L, et al. Risk of low birth weight and stillbirth associated with indoor air pollution from solid fuel use in developing countries. Epidemiol Rev 2010; 32: 70–81. Smith K, McCracken J, Weber M, et al. Effect of reduction in household air pollution on childhood pneumonia in Guatemala (RESPIRE): a randomised controlled trial. Lancet 2011; 378: 1717–26. Roy A, Chapman R, Hu W, Wei F, Liu X, Zhang J. Indoor air pollution and lung function growth among children in four Chinese cities. Indoor Air 2012; 22: 3–11. Weinmayr G, Weiland S, Bjorksten B, et al. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med 2007; 176: 565–74.
Autopsy in ARDS: insights into natural history Published Online May 15, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70093-6 See Articles page 395
352
The acute respiratory distress syndrome (ARDS) is a common clinical syndrome whose clinical features are well described.1 However, comprehensive histopathological characterisation of the natural history of the ARDS in human beings has been challenging. Lung biopsy samples are not obtained in most patients with ARDS and few autopsy studies have been published. In this issue of The Lancet Respiratory Medicine, Arnaud Thille and colleagues2 present an analysis of autopsy results in 159 patients who met both the Berlin definition of ARDS3
and had histological evidence of diffuse alveolar damage. The patients were drawn from a series of 712 autopsies in critically ill patients at one hospital and represent those who had both clinical and histological evidence of ARDS. Of note, those presented in the study2 represent only a small subset of the entire autopsy cohort. A report from the same group4 stresses the fact that many in the series of 712 autopsies met either clinical criteria for ARDS or histological criteria for diffuse alveolar damage, but not both. Thus, despite recent modifications,3 the www.thelancet.com/respiratory Vol 1 July 2013
clinical definitions of ARDS continue to lack sensitivity and specificity when pathological evidence of diffuse alveolar damage is used as the gold standard. The primary findings of this study confirm classic studies5–7 that identified three histological stages in ARDS: an early exudative phase, characterised by intra-alveolar oedema and capillary congestion; a proliferative phase characterised by alveolar epithelial type 2 cell proliferation, fibroblast proliferation, and organising interstitial fibrosis; and a late fibrotic phase characterised by collagen deposition and microcystic honeycombing. In the present study,2 most patients died early in their course (52% within a week of onset) and the predominant histology was exudative. However, proliferative and exudative findings coexisted in many patients, emphasising that exudative and proliferative responses to injury may occur simultaneously in the same patient and cannot readily be distinguished on the basis of duration of ARDS. Overall, only 30 (19%) of 159 patients exhibited fibrotic changes suggesting that fibrosis is not a prominent feature in most patients with ARDS. In longterm survivors of ARDS, radiographical or physiological evidence of significant pulmonary fibrosis is also rare.8 By comparison, in a prospective study of open lung biopsy in patients with ARDS of 5 or more days duration, Papazian and colleagues9 reported a 53% incidence of fibrotic changes, but these data might overestimate the overall incidence of fibrosis since all patients had nonresolving ARDS. High resolution CT studies in patients with ARDS have also been used to assess the degree of fibrotic changes. Ichikado and colleagues detected traction bronchiectasis or traction bronchiolitis, or both (the radiographical correlates of fibroproliferative changes in ARDS)10,11 in 40 (47%) of 85 patients who underwent CT scanning on the first day of ARDS12 and in 28 (64%) of 44 patients who underwent CT scanning within 5 days of ARDS onset.13 However, these studies were done early in the course; they were not able to differentiate radiographically between proliferative and fibrotic changes; and honeycombing, the radiographical correlate of significant fibrosis, was rarely noted. A novel aspect of the study by Thille and colleagues2 is that it includes autopsies from 1991 to 2010, spanning both the eras of higher tidal volume and lower tidal volume ventilation. With the improved survival that accompanies reductions in ventilator-associated lung injury, one might expect that fibrotic changes would be www.thelancet.com/respiratory Vol 1 July 2013
Photostock-Israel/Science Photo Library
Comment
less common in the low tidal volume era. Surprisingly, fibrosis was more common in patients undergoing autopsy in 2000–10 than in the previous decade (32% [21 of 64] vs 9% [9 of 95], p=0·0003). There are several possible explanations for this finding. First, the overall number of patients with fibrotic changes was small and the study is probably underpowered to examine this question. Second, in the low tidal volume era, better supportive care might have prolonged survival of some patients with more severe lung injury, allowing more time for fibrotic changes to develop and be detected at autopsy. Finally, since the only ventilator parameters available in the study were from the time of death, there is no way to know to what degree a protective ventilator strategy was actually in use. In a similar autopsy series reported by the same authors,4 histological evidence of diffuse alveolar damage was less common during the low tidal volume era in all patients with clinical ARDS, suggesting that reduction in tidal volume has had some effect on histopathological findings in ARDS. In summary, the new findings by Thille and colleagues2 provide information about the natural history of histopathological lesions in non-survivors who meet current clinical definitions of ARDS and suggest that the overall incidence of fibrotic changes is low. However, we are still left with unanswered questions regarding the effect of current therapies on injury and repair in the lung. To better answer these questions, human lung tissue should be collected where possible as an adjunct to observational and interventional clinical trials. 353
Comment
Lorraine B Ware
7
T1218 MCN, 1161 21st Avenue S, Nashville, TN 37232-2650, USA [email protected]
8
I declare that I have no conflicts of interest. 1 2
3 4
5
6
Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122: 2731–40. Thille AW, Esteban A, Fernández-Segoviano P, et al. Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies. Lancet Respir Med 2013; published online May 15. http://dx.doi. org/10.1016/S2213-2600(13)70053-5. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526–33. Thille AW, Esteban A, Fernandez-Segoviano P, et al. Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med 2013; 187: 761–67. Bachofen M, Weibel ER. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis 1977; 116: 589–615. Pratt PC, Vollmer RT, Shelburne JD, Crapo JD. Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. Am J Pathol 1979; 95: 191–214.
9
10
11
12
13
Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage—the role of oxygen, shock, and related factors. A review. Am J Pathol 1976; 85: 209–28. Wilcox ME, Patsios D, Murphy G, et al. Radiologic outcomes at 5 years after severe acute respiratory distress syndrome (ARDS). Chest 2012; published online Oct 1. DOI:10.1378/chest.12-0685. Papazian L, Doddoli C, Chetaille B, et al. A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients. Crit Care Med 2007; 35: 755–62. Ichikado K, Johkoh T, Ikezoe J, et al. Acute interstitial pneumonia: high-resolution CT findings correlated with pathology. AJR Am J Roentgenol 1997; 168: 333–38. Ichikado K, Suga M, Gushima Y, et al. Hyperoxia-induced diffuse alveolar damage in pigs: correlation between thin-section CT and histopathologic findings. Radiology 2000; 216: 531–38. Ichikado K, Muranaka H, Gushima Y, et al. Fibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study. BMJ Open 2012; 2: e000545. Ichikado K, Suga M, Muranaka H, al. Prediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases. Radiology 2006; 238: 321–29.
Use of bronchoalveolar lavage to assess the respiratory microbiome: signal in the noise
BSIP, Vero/Carlo/Science Photo Library
In 2007, the US National Institutes of Health added the Human Microbiome Project to the National Institutes of Health Roadmap for Medical Research. The lung— traditionally thought to be a sterile site—was not part of the original programme. However, reports appeared describing a diverse population of non-cultivatable bacteria from other body sites, discovered using 16S rRNA sequencing, challenging notion that the lower respiratory tract was sterile. As a result, in 2009, the Lung HIV Microbiome Project was launched by the National Heart, Lung and Blood Institute to investigate the lung microbiome. Microbiome analysis using PCR-amplified 16S rRNA sequencing is highly sensitive1 and thus subject to contamination from the environment and neighbouring microbial communities. Prevention of contamination is especially problematic for the lower respiratory tract, which is directly connected to the densely colonised oral cavity.2 Analysis of the lung microbiome has largely relied on sputum and bronchoscopic samples, which can be contaminated by microorganisms in the upper respiratory tract. In one of the first studies3 to describe the lung microbiome—which used sequential bronchoscopes to take samples along the length of the respiratory tract from the oropharynx to the alveolar compartment—investigators reported that the bacterial 354
composition of the oral cavity and bronchoalveolar lavage were indistinguishable. The researchers concluded that “bacterial populations in the healthy lower respiratory tract largely reflect upper respiratory tract organisms, likely resulting from transient entry rather than independent communities with indistinguishable structure”.3 Unfortunately, many investigators accepted this work as evidence that a lower respiratory tract microbiome does not exist in healthy people. This assumption ignores the fact that if a lung microbiome is present, it is likely to be similar to that of the upper respiratory tract because of chronic asymptomatic aspiration.4 Furthermore, no physiological reason exists to assume that the lung, which is constantly exposed to the air we breathe, is not colonised like any other body cavity that is exposed to the environment. Finally, the lung filters the entire blood supply, and any episodes of bacteraemia could lead to colonisation of the lung. We believe that new data add to these theoretical considerations, providing evidence for a resident lung microbiome. The first argument for a lung microbiome comes from the discovery of a high incidence of Tropheryma whipplei in bronchoalveolar lavage samples from asymptomatic HIV-infected individuals compared with uninfected people.5 The organism was not detected in paired www.thelancet.com/respiratory Vol 1 July 2013
